Avis juridique important

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31994L0040

Commission Directive 94/40/EC of 22 July 1994 amending Council Directive 87/153/EEC fixing guidelines for the assessment of additives in animal nutrition

Official Journal L 208 , 11/08/1994 P. 0015 - 0026 Finnish special edition: Chapter 3 Volume 60 P. 0145  Swedish special edition: Chapter 3 Volume 60 P. 0145

COMMISSION DIRECTIVE 94/40/EC of 22 July 1994 amending Council Directive 87/153/EEC fixing guidelines for the assessment of additives in animal nutritionTHE COMMISSION OF THE EUROPEAN COMMUNITIES,  Having regard to the Treaty establishing the European Community,  Having regard to Council Directive 70/524/EEC of 23 November 1970 concerning additives in feedingstuffs (1), as last amended by Commission Directive 94/17/EC (2), and in particular Article 9 (2) thereof,  Whereas Council Directive 70/524/EEC provides for guidelines for the assessment of additives in animal nutrition subsequently adopted by Council Directive 87/153/EEC (3) and any amendment thereto in the light of advances in scientific and technical  knowledge;  Whereas those guidelines should be supplemented by the establishment of criteria for examining requests for the authorization of enzymes and microorganisms for use as feed additives;  Whereas pursuant to the provisions of Council Directive 93/114/EC (4) it is necessary to include in the Community procedure for the authorization of additives the requirements of Council Directive 90/220/EEC of 23 April 1990 on the deliberate release  into the environment of genetically modified organisms (5), as amended by Commission Directive 94/15/EC (6) for a specific environmental-risk evaluation, in order that they may be applicable to all additives containing or consisting of genetically  modified organisms; whereas as a consequence, it is appropriate to amend Directive 87/153/EEC in order to comply with the requirements of Directive 90/220/EEC;  Whereas, since numerous amendments have been made, it appears useful to provide a consolidation of the guidelines in the Annex to this Directive;  Whereas the measures provided for in this Directive are in accordance with the opinion of the Standing Committee on Feedingstuffs,  HAS ADOPTED THIS DIRECTIVE:   Article 1  The Annex to Directive 87/153/EEC is hereby replaced by the Annex to this Directive.   Article 2  Member States shall bring into force the laws, regulations or administrative provisions necessary to comply with this Directive by 1 October 1994 at the latest. They shall immediately inform the Commission thereof.  When Member States adopt these provisions, these shall contain a reference to this Directive or shall be accompanied by such reference at the time of their official publication. The procedure for such reference shall be adopted by Member States.   Article 3  This Directive shall enter into force on the twentieth day following that of its publication in the Official Journal of the European Communities.  Done at Brussels, 22 July 1994.  For the Commission René STEICHEN Member of the Commission  (1) OJ No L 270, 14. 12. 1970, p. 1.  (2) OJ No L 105, 26. 4. 1994, p. 19.  (3) OJ No L 64, 7. 3. 1987, p. 19.  (4) OJ No L 334, 31. 12. 1993, p. 24.  (5) OJ No L 117, 8. 5. 1990, p. 15.  (6) OJ No L 103, 22. 4. 1994, p. 20.      ANNEX   GUIDELINES FOR THE ASSESSMENT OF ADDITIVES IN FEEDINGSTUFFS   GENERAL ASPECTS  These guidelines are intended as a guide for establishing dossiers on substances and preparations being submitted for authorization as additives in feedingstuffs. These dossiers must enable an assessment to be made of the additives  based on the present state of knowledge and make it possible to ensure their compliance with the fundamental principles laid down for their admission, which are the subject of the provisions of Article 7 (2) of Directive 70/524/EEC.  All the studies outlined in these guidelines may be required and, if necessary, additional information will be requested. As a general rule, studies to establish the identity, conditions of use, physico-chemical properties, methods of determination and  efficacy of the additive, and also its metabolism, biological and toxicological effects on target species must be provided. When the additive is intended for a category of animals belonging to a defined species, these studies must be performed on this  target category. The studies necessary for the evaluation of risks to human health or the environment will depend essentially on the nature of the additive and the circumstances of its use. In this respect, no strict rule is applicable.  It may not always be necessary to subject additives intended exclusively for pet food to as exhaustive a program of chronic toxicity, mutagenicity and carcinogenicity testing as that required for additives intended for feeding to livestock from which  products for human consumption are derived. To determine chronic toxicity, studies on two target species or on one target species and rats for a period of one year will generally suffice. Mutagenesis and carcinogenesis studies can generally be dispensed  with if the chemical composition, practical experience, or other considerations do not indicate the likelihood of changes. It is possible to dispense with the analysis of residues in pet animals.  Knowledge of the metabolism of the additive in productive livestock and of the residues and their bio-availability is essential. In particular it must enable the extent of the toxicological studies to be performed on laboratory animals in order to  assess the risks, if any, to the consumer to be determined. This evaluation cannot be based solely on data confined to determining the direct effects of the additives on laboratory animals. The latter does not provide specific information on the actual  effects of residues resulting from the metabolism in the species for which the additive is intended.  Any application for authorization of an additive or a new usage for an additive shall be supported by a dossier which should include detailed reports presented in the order and with the numbering proposed in these guidelines. Reasons must be given for  the omission from the dossier of any data prescribed in these guidelines. Publications to which reference is made must be attached to it the reports of experiments must include the plan, the reference number, the date of the beginning and the end of the  experiment, detailed description of the tests, results and their analysis and also the name, address and signature of the person responsible for the study. Each batch of the feedingstuffs used in the experimental studies on animals must be analysed for  the concentration of the relevant active substances using an appropriate method and a report of the analytical results must be provided. The report must also mention the individual doses determined in each experimental study, the corresponding dates,  the name, address and signature of the person responsible for the controls. Furthermore, a certificate drawn up by the laboratory or laboratories where the experiments were conducted to the effect that the tests were carried out in accordance with the  principles of good laboratory practices pursuant to Council Directive 87/18/EEC, on the harmonization of laws, regulations and administrative provisions relating to the application of the principles of good laboratory practice and the verification of  their applications for tests on chemical substances (1), must be attached to the report.  The determination of physico-chemical, toxicological and ecotoxicological properties shall be performed in accordance with the methods established by Council Directive 67/548/EEC on the approximation of laws, regulations and administrative provisions  relating to the classification, packaging and labelling of dangerous substances (2), as last amended by Commission Directive 93/105/EC (3), or with methods internationally recognized by scientific bodies. The use of other methods should be justified.  Each dossier shall contain an adequate summary. The dossiers relating to antibiotics, coccidiostats and other medicinal substances, growth promoters, microorganisms and/or enzyme preparations, must be accompanied by a monograph, conforming with the  model provided in Section V, enabling the additive concerned to be identified and characterized in accordance with Article 8 (1) of Directive 70/524/EEC.  The term 'additive', as used in these guidelines, refers to the active substances or the preparations containing active substances in the state in which they will be incorporated in premixtures and feedingstuffs. An active substance may be a chemically  specified substance, a microorganism or an enzyme preparation.  In these guidelines the expression 'Chemically specified substances', means chemical substances for which a chemical name is agreed according to IUPAC nomenclature.  The Commission must be notified within a reasonable time by the Member State which forwarded the dossier to it of any modification to the manufacturing process or the composition of an additive, its field of application or its conditions of use. This  could necessitate the submission of documentation suitable for a new assessment. These requirements will be especially necessary for products derived from microorganisms, the genetic characteristics of which have been modified or which arise as natural  mutants.   CONTENTS SECTION I: Summary of the data in the dossier SECTION II: Identity, characterization and conditions of use of the additive Methods of control SECTION III: Studies concerning the efficacy of the additive 1. Studies concerning improvements in the  characteristics of feedingstuffs 2. Studies concerning the effects of additives on animal production 3. Studies concerning the quality of animal produce SECTION IV: Studies concerning the safety of use of the additive 1. Studies on target species 1.1.  Toxicological studies of the additive 1.2. Microbiological studies of the additive 1.3. Study of the metabolism and residues 2. Studies on excreted residues 3. Studies on laboratory animals SECTION V: Form of monograph   SECTION I   SUMMARY OF THE DATA IN THE DOSSIER   SECTION II   IDENTITY, CHARACTERIZATION AND CONDITIONS OF USE OF THE ADDITIVE METHODS OF CONTROL  1. Identity of the additive 1.1. Proposed proprietary name(s) 1.2. Type of additive according to its main function 1.3. Qualitative and quantitative composition (active substance, other components, impurities) 1.4. Physical state, particle size 1.5. Manufacturing process including any specific processing procedures N.B.: If the active substance is a mixture of active components, each of which is clearly definable, the main components must be described separately and the proportions in the mixture given.  2. Specifications concerning the active substance 2.1. For chemically specified substances: generic name, chemical name according to Iupac nomenclature, other generic international names and abbreviations. Chemical Abstracts Service Number (CAS).  For microorganisms: name and taxonomic description according to the internatinal Codes of Nomenclature. Other internationally recognized manuals of classification can also be used (4).  For enzyme preparations: name according to main enzymatic activities as described by IUB/Iupac. Einecs and CAS Number.  2.2. Formula, empirical and structural, and molecular weight. Qualitative and quantitative composition of the main components, if the active substance is a fermentation product.  For microorganisms: name and place of culture collection, if possible one in an EC collection, where the strain is deposited and depositing number, genetic modification and all relevant properties for its identification. In addition, origin, appropriate  morphological and physiological characteristics, developmental stages, relevant factors that may be involved in its biological activity (as an additive) and other genetic data for identification. Number of colony forming units (CFU) per gram.  For enzyme preparations: biological origin (in case of microbial origin: name and place of culture collection, if possible one in an EC collection, where the strain is deposited and depositing number, genetic modification and all relevant properties for  its identification including genetic data), the activities towards relevant chemically pure model substrates and other physico-chemical characteristics.  2.3. Degree of purity Qualitative and quantitative composition of the impurities.  For microorganisms: genetic stability and purity of strains cultivated.  For enzyme preparations:  - purity, by checking the level of contaminating microorganisms, heavy metals, absence of toxins derived from the source organism (e.g. mycotoxins), as shown by a suitable method;  - absence of antimicrobial activity at feed concentration level as determined by a suitable method;  - composition of the non-enzymatic components (particularly Total Organic Solids TOS (5)).  2.4. Relevant properties For chemically specified substances: Electrostatic properties, melting point, boiling point, decomposition temperature, density, vapour pressure, solubility in water and organic solvents, mass and absorption spectra and any other appropriate physical  properties.  For microorganisms: properties relevant to identification and proposed use (e.g. vegetative or sporulated form, CFU per g) For enzyme preparations: optimal PH (value(s), optimal temperature(s) and other appropriate properties).  2.5. Manufacturing, purification processes and media used Variation in the composition of the batches in the course of production.  3. Physico-chemical, technological and biological properties of the additive 3.1. Stability (for microorganisms: loss of biological activity, e.g. viability) on exposure to environmental conditions such as light, temperature, pH, moisture and oxygen. Shelf life.  3.2. Stability (for microorganisms: loss of biological activity, e.g. viability) during the preparation of premixtures and feedingstuffs, in particular stability to heat, pressure and moisture. Possible decomposition products.  3.3. Stability (for microorganisms: loss of biological activity, e.g. viability) during the storage of premixtures and feedingstuffs under defined conditions. Shelf life.  For enzyme preparations: Details of the presence of unexpected reaction products formed by either enzymatic or chemical reactions of the enzyme preparation with feed constituents or by degradation of the enzyme preparation during storage of the  feedingstuff.  3.4. Other appropriate physico-chemical, technological or biological properties such as ability to obtain homogeneous mixtures in premixtures and feedingstuffs, dust-forming properties, and for microorganisms and/or enzyme preparations, assessment of  resistance to degradation or loss of biological activity in the digestive tract or by systems of simulation in vitro.  3.5. Physico-chemical or biological incompatibilities or interactions (e.g. with feedingstuffs, other approved additives or with medicinal products).  4. Conditions of use of the additive 4.1. Proposed use in animal nutrition (e.g. species and category of animal, type of feedingstuff, period of administration and withdrawal period).  4.2. Contra-indications 4.3. Proposed dosing in premixtures and feedingstuffs expressed as:  - a percentage of the active substance by weight for premixtures and as mg/kg for feedingstuffs, in case of chemically specified substances,  - appropriate units of biological activity such as CFU per gram of product for microorganisms or relevant activity units for enzyme preparations.  4.4. Other known uses of the active substance or the preparation (e.g. in foodstuffs, human or veterinary medicine, agriculture and industry). For each use give the proprietary names, indications and contra-indications.  4.5. If necessary, measures for the prevention of risks and means of protection during manufacture and handling.  5. Control methods 5.1. Description of the methods used for the determination of the criteria listed under items 1.3., 2.3., 2.4., 2.5., 3.1., 3.2., 3.3., 3.4. and 4.3.  5.2. Description of the qualitative and quantitative analytical methods for routine control of the additive in premixtures and feedingstuffs.  5.3. Description of the qualitative and quantitative analytical methods for determining residues of additives in animal produce.  N.B. The methods specified and the results should be accompanied by information as to percentage recovery, specificity, sensitivity, limits of detection, possible interferences, reproducibility and to the sampling method used. Reference standards of the  preparation and of the active substance must be available.  In the case of microorganisms state methods of detection, enumeration, identification and relevant markets.   SECTION III   STUDIES CONCERNING THE EFFICACY OF THE ADDITIVE  1. Studies concerning improvements in the characteristics of feedingstuffs These studies concern technological additives such as antioxidants, preservatives, binders, emulsifiers, stabilizers, gelling agents etc., which are intended to improve or stabilize the characteristics of premixtures and feedingstuffs. Some  microorganisms and/or enzyme preparations could also be considered as technological additives, if they improve relevant feed characterictics.  Evidence of the efficacy of the additive should be provided by means of appropriate criteria under the intended conditions of use in comparison with negative control feedingstuffs and, possibly, feedingstuffs containing technological additives of known  effectiveness.  The precise nature of the active substances, preparations, premixes and feedingstuffs examined, the reference number of the batches, the concentration of the active substances in premixtures and feedingstuffs, the testing conditions (e.g. temperature  and humidity) and also the dates and duration of testing, the adverse and negative effects which occurred during testing shall be specified for each experiment 2. Studies concerning the effects of additives on animal production These studies concern zootechnical additives which have effects on animal production. The following studies, including dose/response relationship, should be performed on each target species in comparison with negative control groups and, possibly,  groups receiving feedingstuffs containing additives of known effectiveness.  If the active substance is a mixture of active components, the presence of each component must be justified.  2.1. For coccidiostats and other medicinal substances, importance should primarily be attached to evidence of the specific effects and particularly prophylactic properties (e.g. morbidity, oocyst count and lesion score). Information on the effect on  feed effciency, animal growth and marketable quantity and quality of the animal produce may be added.  2.2. For other zootechnical additives (including if appropriate microorgasnisms and/or enzyme preparations) information should be provided on the effects on: nutritional efficiency, animal growth, animal-product characteristics and yield, animal welfare  and other parameters having a positive influence on animal production.  2.3. Experimental conditions The test performed must be described and the results presented individually in detail. The statistical evaluation and the methods employed should be reported. The following data must be provided:  2.3.1. Species, breed, age and sex of the animals, identification procedure.  2.3.2. Number of test and control groups, number of animals in each group. The number of animals of both sexes must be sufficient for statistical purposes.  2.3.3. Concentration of the active substance (and, where it is the case, substances used for comparative purposes) in the feedingstuffs established by a control analysis, using the appropriate recognized method. Reference number of the batches.  Nutritional composition of the diet in terms of quality and quantity.  2.3.4. Location of each experiment. Animal health, physiological, feeding and rearing conditions as usually practised in the Community. Feed control and measures taken to avoid contamination of control groups during the experiment (particularly for  microorganisms through cross-contamination of feed by the microorganism).  2.3.5. Date and exact duration of testing. Date and nature of examinations performed.  2.3.6. Unfavourable effects and other incidents which occurred during the experiment and time of their appearance.  3. Studies concerning the quality of animal produce Studies on the organoleptic, nutritional, hygienic and technological qualities of produce from animals fed with feedingstuffs containing the additive.   SECTION IV   STUDIES CONCERNING THE SAFETY OF USE OF THE ADDITIVE  The studies outlined in this section are intended to permit assessment of:  - the safety of use of the additive in the target species,  - the from risks inhalation, other mucosal, eye or cutaneous contact for persons likely to handle the additive as such or as incorporated into premixtures or feedingstuffs,  - the risks to the consumer which could result from the consumption of food containing residues of the additive, or its metabolites,  - the risks of pollution or persistence in the enviroment from the additive itself or by products derived from the additive and excreted by animals,  - possible risks to non-target species.  These studies will be required in their entirety or in part depending on the nature of the additive and the conditions proposed for its use.  As a general principle microorganisms and/or enzyme preparations must be, or be derived from microorganisms that are non-pathogenic and non-toxicogenic for target species and humans under the expected conditons of use.  In the case of microorganisms and/or enzyme preparations appropriate safety tests must be performed, unless other satisfactory documentation for safety of use is provided. For microorganisms at least a tolerance test on target species must be performed.   In principle toxicological tests for enzymes derived from edible parts of animals or plants are not required; where such products are not generally considered a normal part of the diet used, some toxicological testing may be required.  If the active substance is chemically specified the knowledge of their metabolism in the various target species and also of the composition and the bio-availability of the tissue residues will be essential for determining the extent of studies on  laboratory animals to assess the risks for the consumer. Furthermore, knowledge of the composition and of the physico-chemical and biological properties of the excreted residues deriving from the additive will be indispensable to define the extent of  the studies necessary for assessment of the risk of pollution or persistence in the enviroment.  1. Studies on target species 1.1. Toxicological studies of the additive Tolerance tests Study of the biological, toxicological, macroscopic and histological effects. Determination of the safety margin between the maximum proposed dose-level and the level resulting in unfavourable effects. It may be sufficient to indicate a minimum or  approximate value for this margin if it can be shown that the level resulting in unfavourable effects greatly exceeds the maximum proposed dose-level.  1.2. Microbiological studies of the additive 1.2.1. If the active substance is chemically specified and possesses antimicrobial activity at feed concentration level, studies of the antibacterial spectrum of action of the additive by determination of the minimum inhibition concentration (MIC) in  various pathogenic and non-pathogenic Gram-negative and Gram-positive species of bacteria must be provided.  1.2.2. Studies on the cross-resistance to therapeutic antibiotics by determination of the MIL, in mutants produced in vitro which exhibit chromosomal resistance to the additive. In the case of microorganisms which are resistant to therapeutic  antibiotics, the genetic basis of this resistance should be shown.  1.2.3. Tests to find out whether the additive is capable of selecting resistance factors. These tests are to be performed under field conditions in the animal species for which the additive is primarily intended. Subsequently, it should be determined  whether R factors which may have been found carry multiple resistance and are transmissible.  1.2.4. Tests to determine the effect of the additive,  - on the microflora of the digestive tract,  - on the colonization of the digestive tract, if it is a microorganism or a mixture of several strains of microorganisms,  - on the shedding or excretion of pathogenic microorganisms, if the active substance is chemically specified and has antimicrobial activity.  1.2.5. In cases where the active substance shows an antimicrobial action, field studies to monitor the percentage of bacteria resistant to the additive should be provided. These are to be carried out at major intervals before, during and after (one  month) the use of the additive.  1.2.6. If the active substance is a microorganism, it should be determined if it is resistant to antibiotics.  1.2.7. If the active substance (e.g. enzyme preparations) is produced by a microorganism the level of the respective viable organism should be determined.  1.2.8. If the additive contains or consists of a genetically modified organism within the meaning of Article 2 (1) and (2) of Council Directive 90/220/EEC the following information must be provided:  - A copy of any written consent or consents of the competent authorities to the deliberate release of the genetically modified organisms for research and development purposes pursuant to Article 6 (4) of Directive 90/220/EEC and the summary of the  notification as referred in Article 9 of Directive 90/220/EEC according to the model set up in Council Decision 91/596/EEC (6);  - the complete technical file with the information required in Annex II of Directive 90/220/EEC, extended as necessary to take into account the diversity of sites of use of the additive, including information on data and results obtained from research  and developmental releases concerning the ecosystems which could be affected by the use of the additive and an assessment of any risks for human health, animal health and the environment related to the GMO(s) contained in the product including  information obtained from the research and development stage on the impact of the release on human health and the environment;  - the conditions for the placing on the market of the additive, including specific conditions of use and handling and a proposal for labelling and packaging which should comprise at least the requirements laid down in Annex III of Directive 90/220/EEC.   If on the basis of any release notified under Part B of Directive 90/220/EEC, or on substantive, reasoned scientific grounds, the person responsible for the dossier considers that the placing on the market or the use of the additive does not pose a risk  to human health, animal health and the environment, he may propose not to comply with one or more of the requirements of Annex III B.  Information on data or results from releases of the same GMO or the same combination of GMOs previously or currently notified and/or carried out by the person responsible for the dossier either inside or outside of Community, shall be included.  Other data or results from notifications previously submitted by other persons may also be referred, provided that the latter have given their agreement in writing.  1.3. Studies of the metabolism and residues (7) (8) (If the active substance is chemically specified).  1.3.1. Study of metabolism,  - metabolic balance: rate and extent of absorption and elimination of the active substance,  - identification of the metabolic pathways and main metabolites,  - distribution and excretion (biliary, urinary, faecal) of the metabolites,  - if appropriate, influence of the intestinal or ruminal microflora, of enterohepatic cycle, of caecotrophy, on the metabolism.  1.3.2. Analytical studies of the residues: qualitative and quantitative composition of the residues (active substance, metabolites) in the various animal food products at metabolic equilibrium and under practical conditions of use of the additive.  1.3.3. Kinetic study of the residues (following repeated administration of the additive according to the purposal use): persistence of the active substance and the main metabolites in the various organs and tissues after withdrawal of the supplemented  feedingstuff.  1.3.4. Study of the bio-availability of the residues in animal food products. (see 3.7.).  1.3.5. Methods of monitoring: qualitative and quantitative method of determination used in the studies mentioned under items 1.3.1. to 1.3.4. with information as to percentage recovery, specificity and limits of detection. The methods of determination  of the residues must be sufficiently sensitive to permit detection of residues at levels which are toxicologically negligible.  2. Study on excreted residues (where the active substance is chemically specified) 2.1. Nature and concentration of the residues derived from the additive (active substance, metabolites) in the excreta.  2.2. Persistence (half-life value) and kinetics of elimination of these residues in slurries, farm yard manure and litter.  2.3. Effects on methanogenesis.  2.4. Degradation, persistence (half-life value) and kinetics of elimination in soils (contrasting soil types).  2.5. Effects on soil fauna and microbial processes of transformation (e.g. decomposition of plant and animal residues).  2.6. Effects on terrestrial plants (e.g. seed germination, plant growth and plant uptake). These studies should be carried out under controlled conditions and field conditions, using different plant species.  2.7. Solubility and stability in water of the products derived from the additive (active substance, metabolites).  2.8. Effects on aquatic life 2.8.1. Effects on flora (e.g. Chlorella).  2.8.2. Toxicity in non-vertebrates (e.g. Daphnia magna).  2.8.3. Toxicity in fish (at least two wild species found in the Community territory).  3. Studies on laboratory animals These studies must be carried out with the active substance and its major metabolites or products, if the latter are also present in edible animal produce and are bioavailable. As far as possible attempts should be made to select laboratory animals  which may be expected to digest and metabolize the additive in a similar way to man or the target species.  Full detailed descriptions must be provided of the tests performed. These should cover the animal species and strains employed, the size and number of test and control groups, the dose levels administered, the composition of the diet and the results of  feed analyses, the rearing conditions, the exact duration of the tests, the dates of the various examinations performed and mortality. Full details must be given of the macroscopic pathological and histopathological findings in all animals tested with  an indication of the time of appearance of all pathological lesions. All results, including statistical assessment, must be presented in detail.  3.1. Acute toxicity (not relevant for microorganisms) 3.1.1. Acute oral toxicity studies must be carried out on two animal species (preferably the rat should be one). The maximum dosage should not be higher than 2,000 mg/kg body weight. Detailed observations should be reported of the biological effects  observed during a period of at least two weeks after ingestion. These studies are not relevant for enzyme preparations.  3.1.2. Studies on acute inhalational toxicity, skin and, where necessary, mucous membranes irritancy and also allergenic potential must be performed by appropriate tests for the assessment of possible risks associated with the handling of the additive.   3.2. Mutagenicity 3.2.1. If the active substance is chemically specified In order to identify active substances or their metabolites or products that possess mutagenic properties a selected combination of mutagenicity tests, based on different genetic endpoints, must be carried out. Tests must be performed, in the presence  and absence of a microsomal mammalian preparation, for metabolic activation.  The following package of tests is recommended:  (a) a test for gene mutations in a prokaryotic system,  (b) a test for gene mutations in an in-vitro eukaryotic system or a sex-linked recessive lethal test in Drosophila melanogaster,  (c) a test for chromosomal aberrations in-vitro and in-vivo.  The battery of tests suggested above does not imply, however, that other tests are inappropriate or that other tests, in particular in-vivo tests, would not be acceptable as alternatives.  In all cases reasons fo the choice of tests should be given. Tests must be carried out according to established validated procedures. Depending on the outcome of the tests and taking into consideration the whole toxicity profile of the substance as well  as the intended use, additional investigations may be indicated.  3.2.2. In the case of enzyme preparations derived from microorganisms the following tests are normally required:  (a) a test for gene mutations in bacteria,  (b) a test for chromosomal aberrations (preferably in vitro).  The toxicological tests shall, where possible, be performed on a batch from the final purified fermentation product, before addition of carriers, diluents or other substances. They should, as a general rule, be performed in accordance with established  guidelines (9) from recognized international Institutions although, because of the effects exerted at the cellular level by the proteinaceous nature and/or enzymatic activities of certain enzyme preparations, some modifications of the standard test  protocols, particularly in the case of in vitro tests, may be necessary. Such deviations will be acceptable if accompanied by adequate supporting arguments.  The test system is designed to uncover unspecified toxic reactions and to reveal genotoxic effects. The combined information from the general specifications and this test battery make it possible to evaluate the product for the presence of both  specific, well known toxins and unknown toxic compounds.  The toxicological report shall contain satisfactory documentation that the tests have been performed on the material which forms the basis of the commercial product as described in the technological dossier.  3.3. Pharmacokinetics aspects If the active substance is chemically specified balance studies and identification of metabolites must be performed using suitable labelled molecules or other appropriate techniques and should cover both single and multiple dose administration of the  active substance over appropriate periods. Metabolism studies must also include investigation of the pharmacokinetics of the active substance and of the major metabolites. Consideration must be given to the differences in the way that various species  metabolize the active substance when selecting the most relevant species for subsequent toxicological investigations.  3.4. Subchronic toxicity These studies must be carried out in general on two animal species (preferably the rat should be one). The second species may in some instances be a target species. The test substance may be administered orally and a dose-response relationship must be  established. The duration in rodents must be at least 90 days.  In certain cases investigations extending over six months to two years in non-rodents may be desirable to establish the variation in sensitivity of different animal species to the test substance.  These studies are not relevant for microorganisms. In the case of enzyme preparations derived from microorganisms a 90-day oral toxicity test in a rodent species may be sufficient.  3.5. Chronic toxicity/carcinogenicity Chronic toxicity studies must be carried out on one species (preferably the rat), carcinogenicity studies preferably on two species of rodent. The substance must be administered orally at several dose levels. A combined chronic toxicity/carcinogenicity  study with in-utero exposure is also acceptable. Experiments must extend for a minimum of 24 months in rats and 18 months in mice. If continued beyond the minimum period, the test must be terminated when survival in any but the highest dose level groups  has fallen to 20 %.  Full clinical chemistry, haematological and urine examinations must be carried out at appropriate intervals throughout the experiment. Full macroscopic and histological examinations must be carried out on all animals dying during the test and on all  survivors at the termination of the study.  These studies are not relevant for microorganisms and enzyme preparations.  3.6. Reproductive toxicity (where the active substance is chemically specified) Studies on reproduction must be carried out preferably on the rat. They must extend over at least two filial generations and may be combined with embryotoxicity including teratogenic studies. All relevant fertility, gestation, parturition, peri- and  postnatal parameters must be carefully observed and reported. Specific teratogenic studies must be carried out in at least two suitable species.  3.7. Toxicology of metabolites (where the active substance is chemically specified) Information for the calculation of residue concentration is required as a basis for assessing the risk for man.  The basis for calculation of the proposed withdrawal period must be made available. The studies mentioned in 1.3.4. must be carried out on laboratory animals.  3.8. Other relevant studies Any further special study providing additional information useful for the assessment of test substance may be made available (e.g. bio-availability, neurotoxicity or immunotoxicity).   SECTION V   FORM OF MONOGRAPH  1. Identity of the additive 1.1. Proposed proprietary name(s) 1.2. Type of additive according to its main function 1.3. Qualitative and quantitative composition (active substance, other components, impurities) 1.4. Physical state, particle size 1.5. Possible specific processing N.B. If the active substance is a mixture of active components, each of which is to be clearly definable, the main components must be described separately and the proportions in the mixture given.  2. Specifications concerning the active substance 2.1. For chemically specified substances: generic name, chemical name according to IUPAC nomenclature, other generic international names and abbreviations. Chemical Abstracts Service Number (CAS).  For microorganisms: name and taxonomic description according to the international Codes of Nomenclature. Other internationally recognized manuals of classification can also be used (9).  For enzyme preparations: name according to main enzymatic activities as described by IUB/Iupac, Einecs and CAS Number.  2.2. Formula, empirical and structural, and molecular weight. Qualitative and quantitative composition of the main components, if the active substance is a fermentation product.  For microorganisms: name and place of culture collection, if possible one in an EC collection, where the strain is deposited and depositing number, genetic modification and all relevant properties for its identification.  For enzyme preparations: the biological origin (in case of microbial origin: name and place of culture collection, if possible one in an EC collection, where the strain is deposited and depositing number, genetic modification and all relevant properties  for its identification), the activities towards relevant chemically pure model substrates and other physico-chemical characteristics.  2.3. Degree of purity Qualitative and quantitative composition of the impurities For microorganisms: genetic stability and purity of strains cultivated.  For enzyme preparations:  - purity [by checking the level of contaminating microorganisms, heavy metals, absence of toxins (e.g. mycotoxins) derived from the source organism as shown by a suitable method];  - absence of antimicrobial activity at feed concentration level as determined by a suitable method;  - composition of the non-enzymatic components (particularly Total Organic Solids T.O.S.) 2.4. Relevant properties For chemically specified substances: Electrostatic properties, melting point, boiling point, decomposition temperature, density, vapour pressure, solubility in water and organic solvents, mass and absorption spectra and any other appropriate physical  properties.  For microorganisms: properties relevant to identification and proposed use (e.g. vegetative or sporulated form, CFU per g).  For enzyme preparations: optimal pH value(s), optimal temperature(s) and other appropriate properties.  3. Physico-chemical, technological and biological properties of the additive 3.1. Stability (for microorganisms: loss of biological activity, e.g. viability) on exposure to environmental conditions such as light, temperature, pH, moisture and oxygen. Shelf life.  3.2. Stability (for microorganisms: loss of biological activity, e.g. viability) during the preparation of premixtures and feedingstuffs, in parlticular stability to heat, pressure and moisture. Possible decomposition products.  3.3. Stability (for microorganisms: loss of biological activity, e.g. viability) during the storage of premixtures and feedingstuffs under defined conditions. Shelf life.  3.4. Other appropriate physico-chemical, technological or biological properties such as ability to obtain homogeneous mixtures in premixtures and feedingstuffs, dust-forming properties, and for microorganisms and/or enzyme preparations, assessment of  resistance to degradation or loss of biological activity in the digestive tract or by systems of simulation in vitro.  3.5. Physico-chemical or biological incompatibilities or interactions (e.g. with feedingstuffs, other approved additives or with medicinal products).  4. Control methods 4.1. Description of the methods used for the determination of the criteria listed under items 1.3., 2.3., 2.4., 3.1., 3.2., 3.3. and 3.4. of this Section.  4.2. Description of the qualitative and quantitative analytical methods for determining residues of additives in animal produce.  4.3. If the said methods have been published the literature references may suffice and the corresponding reprints should be given.  5. Biological properties of the additive 5.1. Particulars of the prophylactic effects for coccidiostats and other medicinal substances (e.g. morbidity, oocyst count and lesion score).  5.2. For zootechnical additives other than those listed in 5.1. including if appropriate microorganisms and/or enzyme preparations: particulars of the effects on nutritional efficiency, animal growth, animal product characteristics and yield, animal  welfare and other parameters having a positive influence on animal production.  5.3. Any contra-indications or warnings, including biological incompatibilities, with particulars of their justification.  6. Details of the quantitative and qualitative residues, if any, found in animal produce following envisaged use of the additive.  7. Other characteristics suitable for identification of the additive.   (1) OJ No L 15, 17. 1. 1987, p. 29.  (2) OJ No L 196, 16. 8. 1967, p. 1.  (3) OJ No L 294, 30. 11. 1993, p. 21.  (4) Such as Bergey's Manual of Systematic Bacteriology, The Yeasts, a taxonomic study by Lodder and Kreger van Rij, Ainsworth and Bisby's Dictionary of the Fungi by Hawksworth, Sutton and Ainsworth or The Genus Aspergillus by Raper and Fennell. (5) TOS (%) = 100   (% ash + water + % diluents and/or additives and ingredients).  (6) OJ No L 322, 23. 11. 1991, p. 1.  (7) The studies mentioned under 1.3.1., 1.3.3. and 1.3.4. should be carried out with labelled molecules or other appropriate methods, in each case the choice of the method utilized should be justified. The labelling should be suitable for the purpose  intended.  (8) If the active substance is produced by fermentation, these studies should be extended to related substances derived from the production process.  (9) Such as: - Presentation of an application for assessment of a food additive prior to its authorization. 1989. (ISBN 92-826-0135-B) - Report of the Scientific Committee for Food on guidelines for the safety assessment of food additives. 1980. 10th  report series, (EUR 6892).  (10) Such as Bergey's Manual of Systematic Bacteriology, The Yeasts, a taxonomic study by Lodder and Kreger van Rij, Ainsworth and Bisby's Dictionary of the Fungi by Hawksworth, Sutton and Ainsworth or The Genus Aspergillus by Raper and Fennell.


Avis juridique important

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31993L0067

Commission Directive 93/67/EEC of 20 July 1993 laying down the principles for assessment of risks to man and the environment of subtances notified in accordance with Council Directive 67/548/EEC

Official Journal L 227 , 08/09/1993 P. 0009 - 0018 Finnish special edition: Chapter 13 Volume 25 P. 0003  Swedish special edition: Chapter 13 Volume 25 P. 0003

COMMISSION DIRECTIVE 93/67/EEC of 20 July 1993 laying down the principles for assessment of risks to man and the environment of subtances notified in accordance with Council Directive 67/548/EECTHE COMMISSION OF THE EUROPEAN COMMUNITIES,   Having regard to the Treaty establishing the European Economic Community,  Having regard to Council Directive 67/548/EEC of 27 June 1967, on the approximation of the laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances (1), as amended by Directive  93/21/EEC (2) and, in particular, Article 3 thereof,  Whereas, in accordance with the provisions of Directive 67/548/EEC, any new substance placed on the market should be notified to the competent authorities to Member States by means of a notification containing certain information;  Whereas Article 16 of Directive 67/548/EEC requires the competent authorities receiving notification of a new substance to carry out an assessment of its risks to man and the environment in accordance with general principles;  Whereas, given that the responsibility for risk assessment lies with the Member States, it is, however, appropriate that general principles be adopted at Community level to avoid disparities between Member States which not only affect the functioning of  the internal market but also do not guarantee the same level of protection of man and the environment thorughout the Community and whereas, therefore, Article 3 of Council Directive 67/548/EEC provides that the Commission shall lay down the general  principles;  Whereas the assessment of risks should be based on a comparison of the potential adverse effects of a substance with the reasonably foreseeable exposure of man and the environment to that substance;  Whereas, having regard to its classification in accordance with Directive 67/548/EEC, the assessment of risks to man should take account of the physico-chemical and toxicological properties of a substance;  Whereas, having regard to its classification in accordance with Directive 67/548/EEC, the assessment of risks to the environment should take account of the environmental effects of a substance;  Whereas, where the assessment of risks indicates that a substance is of concern, the competent authority may acquire further information including the results of further tests to determine the substance's intrinsic hazardous properties in accordance  with Council Directive 67/548/EEC;  Whereas the results of a risk assessment should be the principal basis of decisions under appropriate legislation to reduce the risks arising from the placing of substances on the market;  Whereas it is appropriate that, having carried out an assessment of risks, the competent authority may inform the notifier of a dangerous substance of its conclusions and that, further, the competent authority should forward a written report thereon to  the Commission;  Whereas it is appropriate to reduce to a minimum the number of animals used for experimental purposes in accordance with Council Directive 86/609/EEC of 24 November 1986 on the approximation of the laws, regulations and administrative provisions of the  Member States regarding the protection of animals used for experimental and other scientific purposes (3);  Whereas the provisions of this Directive shall be without prejudice to specific Community legislation concerning the safety and protection of health of workers at work, in particular Council Directive 89/391/EEC of 12 June 1989 on the introduction of  measures to encourage improvements in the health and safety of workers at work (4), which places an obligation on employers to evaluate the risks to the health and safety of workers arising from the use of new and existing chemical substances and, as  necessary, to take measures to ensure an appropriate protection of workers;  Whereas the measures set out in this Directive are in accordance with the opinion of the committee set up pursuant to Article 29 of Directive 67/548/EEC,  HAS ADOPTED THIS DIRECTIVE:   Article 1   Objectives  This Directive lays down general principles for the assessment of the risks posed by substances to man and the environment as required by Article 3 of Directive 67/548/EEC.   Article 2   Definitions  1. The definitions contained in Article 2 of Directive 67/548/EEC are applicable to this Directive.  2. For the purposes of this Directive:  (a) 'hazard identification' is the identification of the adverse effects which a substance has an inherent capacity to cause;  (b) 'dose (concentration) - response (effect) assessment' is the estimation of the relationship between dose, or level of exposure to a substance, and the incidence and severity of an effect;  (c) 'exposure assessment' is the determination of the emissions, pathways and rates of movement of a substance and its transformation or degradation in order to estimate the concentrations/doses to which human populations or environmental compartments  are or may be exposed;  (d) 'risk characterization' is the estimation of the incidence and severity of the adverse effects likely to occur in a human population or environmental compartment due to actual or predicted exposure to a substance, and may include 'risk estimation',  i.e., the quantification of that likelihood;  (e) 'recommendations for risk reduction' is the recommendation of measures which would enable the risks for man and/or the environment in connection with the marketing of the substance to be lessened. They may include:  (i) modifications to the classification, packaging or labelling of the substance proposed by the notifier in the notification submitted in accordance with Article 7 (1), 8 (1) or 8 (2) of Directive 67/548/EEC;  (ii) modifications to the safety data sheet proposed by the notifier in the notification submitted in accordance with Article 7 (1), 8 (1) or 8 (2) of Directive 67/548/EEC;  (iii) modifications to the recommended methods and precautions or emergency measures, as set out in sections 2.3, 2.4 and 2.5 of Annex VIIA, VIIB or VIIC, proposed by the notifier in the technical dossier of the notification submitted in accordance with  Article 7 (1), 8 (1) or 8 (2) of Directive 67/548/EEC;  (iv) advice to the relevant control authorities that they should consider appropriate measures for the protection of man and/or the environment from the risks identified.   Article 3   Principles of risk assessment  1. The risk assessment shall entail hazard identification and, as appropriate, dose (concentration) - response (effect) assessment, exposure assessment and risk characterization. It shall normally be conducted in  accordance with the procedures set out in Articles 4 and 5.  2. Notwithstanding paragraph 1, in relation to particular effects, such as ozone depletion, for which the procedures set out in Articles 4 and 5 are impracticable, the risks associated with such effects shall be assessed on a case-by-case basis and the  competent authority shall include a full description and justification of such assessments in the written report submitted to the Commission in accordance with Article 7.  3. In conducting an exposure assessment, the competent authority shall take into account those human populations or environmental compartments for which exposure to the substance is reasonably foreseeable in the light of available information on the  substance, with particular regard to storage, formulation into a preparation or other processing, use and disposal or recovery.  4. The risk assessment shall indicate one or more of the following conclusions:  (i) The substance is of no immediate concern and need not be considered again until further information is made available in accordance with Article 7 (2), 8 (3), 8 (4) or 14 (1) of Directive 67/548/EEC.  (ii) The substance is of concern and the competent authority shall decide what further information is required for revision of the assessment but shall defer a request for that information until the quantity placed on the market reaches the next tonnage  threshold as indicated in Article 7 (2), 8 (3) or 8 (4) of Directive 67/548/EEC.  (iii) The substance is of concern and further information shall be requested immediately.  (iv) The substance is of concern and the competent authority shall immediately make recommendations for risk reduction.  5. When the risk assessment indicated that the conclusions at paragraph 4 (ii), (iii) or (iv) above apply, the notifier may be informed by the competent authority of its conclusions and be given the opportunity to comment on those conclusions and to  provide additional information. The competent authority shall use any relevant information to revise the risk assessment before sending it to the Commission in accordance with Article 17 of Directive 67/548/EEC.  6. In making recommendations for risk reduction in relation to a substance, the competent authority shall take account of the possibility that reducing the exposure of certain human populations or environmental compartments may increase the exposure of  other human populations or environmental compartments.   Article 4   Risk assessment: human health  1. For each substance notified in accordance with Article 7 (1), Article 8 (1) or Article 8 (2) of Directive 67/548/EEC, the competent authority shall carry out a risk assessment, the first stage of which shall be hazard  identification which shall address, as a minimum, the properties and potential adverse effects specified in Annexes IA and IIA. Having conducted the hazard identification, the competent authority shall proceed to the following sequence of actions which  shall be carried out in accordance with the guidelines set out in Annexes IB and IIB:  (a) (i) dose (concentration)-response (effect) assessment, where appropriate;  (ii) exposure assessment for whichever of the human populations (i.e., workers, consumers and man exposed indirectly via the environment) is likely to be exposed to the substance;  (b) risk characterization.  2. In derogations from paragraph 1:  (i) if the test appropriate to hazard identification in relation to a particular effect or property has been conducted and the results have not led classification of the substance in accordance with Directive 67/548/EEC, the risk assessment in relation  to that effect or property need not include the actions at paragraph 1 (a) and (b) and the conclusion at Article 3 (4) (i) shall apply, unless there are other reasonable grounds for concern; and (ii) if the test appropriate to hazard identification in relation to a particular effect or property has not yet been conducted, that effect or property shall not be considered in the risk assessment unless there are other reasonable grounds for  concern.   Article 5   Risk assessment: environment  1. For each substance notified in accordance with Article 7 (1), 8 (1) or 8 (2) of Directive 67/548/EEC, the competent authority shall carry out a risk assessment in relation to its environmental effects, the first stage of  which shall be hazard identification. Having conducted the hazard identification, the competent authority shall proceed to the following sequence of actions which shall be carried out in accordance with the guidelines set out in Annex III:  (a) (i) dose (concentration)-response (effect) assessment, where appropriate;  (ii) exposure assessment for the environmental compartments (i.e. aquatic environment, terrestrial environment and air) likely to be exposed to the substance;  (b) risk characterization.  2. In derogation from paragraph 1:  (i) for substances notified in accordance with Article 7 (1) of Directive 67/548/EEC but not classified dangerous for the environment, the risk assessment need not include the actions at paragraph 1 (a) and (b) and the conclusion at Article 3 (4) (i)  shall apply, unless there are other reasonable grounds for concern; and (ii) for substances notified in accordance with Article 8 (1) or 8 (2) of Directive 67/548/EEC, if there are insufficient data to determine whether classification as dangerous for the environment is appropriate, the hazard identification shall entail  consideration of whether there are any reasonable grounds for concern in relation to environmental effects on the basis of other data, e.g. data on physico-chemical and toxic properties. Unless there are such reasonable grounds, the risk assessment need  not include the actions at paragraph 1 (a) and (b) and the conclusion at Article 3 (4) (i) shall apply.   Article 6   Risk assessment: conclusions  1. Having carried out a risk assessment in accordance with Articles 4 and 5 and in conformity with Annexes I, II and III, the competent authority shall determine, in conformity with Annex IV, which of the four conclusions  of Article 3 (4) is/are applicable and take action as described in Article 3 (5) if appropriate.  2. Where additional information is received in accordance with Articles 7 (2), 8 (3), 8 (4), 14 (1) or 16 of Directive 67/548/EEC or otherwise, the risk assessment carried out in accordance with Articles 4 and 5 and in conformity with Annexes I, II and  III shall be reviewed and, if necessary, revised.   Article 7   Content of written report to the Commission  1. Having carried out the risk assessment in accordance with Articles 4 and 5 and made conclusions in accordance with Article 6, the competent authority shall prepare a written report containing at least the  information set out at Annex V. That report shall be sent to the Commission in accordance with Article 17 of Directive 67/548/EEC. It shall be updated following any revision of the assessment in the light of additional information and the updated report  shall be sent to the Commission.  2. When, in accordance with Article 18 of Directive 67/548/EEC, the competent authorities have reached agreement on the written report of the risk assessment or any revision thereof, a copy shall be made available to the notifier on request.   Article 8   Final provisions  1. Member States shall adopt and publish the provisions necessary to comply with this Directive by 31 October 1993 and shall forthwith inform the Commission.  2. When Member States adopt these provisions, these shall contain a reference to this Directive or shall be accompanied by such reference at the time of their official publication. The procedure for such reference shall be adopted by Member States.   Article 9  This Directive is addressed to the Member States.  Done at Brussels, 20 July 1993.  For the Commission Yannis PALEOKRASSAS Member of the Commission  (1) OJ No 196, 16. 8. 1967, p. 1.  (2) OJ No L 110, 4. 5. 1993, p. 20.  (3) OJ No L 358, 18. 12. 1986, p. 1.  (4) OJ No L 183, 29. 6. 1989, p. 1.      ANNEX I  RISK ASSESSMENT: HUMAN HEALTH (TOXICITY)   PART A  The risk assessment conducted in accordance with Article 4 shall take account of the following potential toxic effects and populations liable to exposure:  Effects 1. Acute toxicity 2. Irritation 3. Corrosivity 4. Sensitization 5. Repeated dose toxicity 6. Mutagenicity 7. Carcinogenicity 8. Toxicity for reproduction Human populations 1. Workers 2. Consumers 3. Man exposed indirectly via environment  PART B  1. Hazard identification 1.1. In those cases where the test appropriate to hazard identification in relation to a particular potential effect has been conducted but the results have not led to classification (Article 4 (2) (i)), risk characterization in relation to that effect  shall not be necessary unless there are other reasonable grounds for concern, e.g. positive in vitro test results for mutagenicity.  1.2. In those cases where the test appropriate to hazard identification in relation to a particular potential effect has not yet been conducted (Article 4 (2) (ii)), risk characterization in relation to that effect shall not be necessary unless there  are other reasonable grounds for concern, e.g. exposure considerations or indications of potential toxicity from structure activity relationships.  2. Dose (concentration)-response (effect) assessment 2.1. For repeated-dose toxicity and reproductive toxicity, the dose-response relationship shall be assessed and, where possible, the no-observed-adverse-effect level (NOAEL) identified. If it is not possible to identify a NOAEL, the lowest  dose/concentration associated with an adverse effect, i.e., the lowest-observed-adverse-effect level (LOAEL), shall be identified.  2.2. For acute toxicity, corrosivity and irritation, it is not usually possible to derive a NOAEL or LOAEL on the basis of the results of tests conducted in accordance with the requirements of Directive 67/548/EEC. For acute toxicity, the LD50 or LC50  value or, where the fixed dose procedure has been used, the discriminating dose shall be derived. For the other effects, it shall be sufficient to determine whether the substance has an inherent capacity to cause such effects.  2.3. For mutagenicity and carcinogenicity, it shall be sufficient to determine whether the substance has an inherent capacity to cause such effects. However, if it can be demonstrated that a substance identified as a carcinogen is non-genotoxic, it will  be appropriate to identify a NOAEL/LOAEL as described in paragraph 2.1.  2.4. With respect to skin sensitization and respiratory sensitization, in so far as there is no consensus on the possibility of identifying a dose/concentration below which adverse effects are unlikely to occur in a subject already sensitized to a given  substance, it shall be sufficient to evaluate whether the substance has an inherent capacity to cause such effects.  3. Exposure assessment 3.1. An exposure assessment shall be conducted for each of the human populations (workers, consumers and man liable to exposure indirectly via the environment) for which exposure to the substance can reasonably be foreseen. The objective of the  assessment shall be to make a quantitative or qualitative estimate of the dose/concentration of the substance to which a population is or may be exposed. Such estimation shall take account of spatial and temporal variations in the exposure pattern.  3.2. The exposure assessment shall be based on the information in the technical dossier provided in conformity with section 2 of Annex VII A, VII B or VII C of Directive 67/548/EEC and on any other available and relevant information. Particular account  shall be taken, as appropriate, of:  (i) adequately measured exposure data;  (ii) the quantity of the substance on the market;  (iii) the form in which the substance is marketed and/or used (e.g. substance itself or as competent of a preparation);  (iv) use categories and degree of containment;  (v) process data, where relevant;  (vi) physico-chemical properties of the substance including, where relevant, those conferred by the process (e.g. aerosol formation);  (vii) likely routed of exposure and potential for absorption;  (viii) frequency and duration of exposure;  (ix) type and size of specific exposed population(s) where such information is available.  3.3. Where predictive methods are used for estimation of exposure levels, preference shall be given to relevant monitoring data from substances with analogous use and exposure patterns.  3.4. If a substance is contained in a preparation, consideration of exposure to the substance in that preparation shall be necessary only if the latter is classified on the basis of the toxicological properties of the substance in accordance with  Council Directive 88/379/EEC (1), unless there are other reasonable grounds for concern.  4. Risk characterization 4.1. Where, for any of the effects set out in Annex IA, a NOAEL or LOAEL has been identified, the risk characterization in relation to each of those effects shall entail comparison of the NOAEL or LOAEL with the estimate of the dose-concentration to  which the population(s) will be exposed. If a quantitative estimate of exposure is available, an exposure level/N(L)OAEL ratio shall be derived. On the basis of the comparison between the quantitative or qualitative estimate of exposure and the  N(L)OAEL, the competent authority shall decide which of the four conclusions at Article 3 (4) if applicable.  4.2. Where, for any of the effects set out in Annex IA, a N(L)OAEL has not been determined, the risk characterization in relation to each of those effects shall entail an evaluation, on the basis of the quantitative and/or qualitative information on  exposure relevant to the human populations under consideration, of the likelihood that the effect will occur (2). Having made the evaluation, the competent authority shall decide which of the four conclusions at Article 3 (4) is applicable.  4.3. When deciding which of the four conclusions at Article 3 (4) is applicable, the competent authority shall take into account, inter alia:  (i) the uncertainty arising, among other factors, from the variability in the experimental data and intra- and interspecies variation;  (ii) the nature and severity of the effect;  (iii) the human population to which the quantitative and/or qualitative information on exposure applies.  5. Integration In accordance with the provisions of Article 4 (1), a risk characterization may be carried out in relation to more than one potential adverse effect or human population. In such cases, the competent authority shall judge which of the four conclusions at  Article 3 (4) is applicable to each effect. Having completed the various conclusions and produce integrated conclusions in relation to the overall toxicity of the substance.   (1) OJ No L 187, 16. 7. 1988, p. 14.  (2) Where, despite a N(L)OAEL not having been determined, the test results nevertheless demonstrate a relationship between dose/concentration and the severity of an adverse effect or where, in connection with a test method which entails the use of only  one dose or concentration, it is possible to evaluate the relative severity of the effect, such information shall also be taken into account in evaluating the likelihood of the effect occurring.      ANNEX II  RISK ASSESSMENT: HUMAN HEALTH (PHYSICO-CHEMICAL PROPERTIES)   PART A  Risk assessment in accordance with Article 4 shall take account of the potential adverse effects which may occur in the following human populations liable to exposure to substances with the following properties.  Properties 1. Explosivity 2. Flammability 3. Oxidizing potential Human populations 1. Workers 2. Consumers 3. Man exposed indirectly via the environment  PART B  1. Hazard identification 1.1. In those cases where the test appropriate to hazard identification in relation to a particular property has been conducted but the results have not led to classification (Article 4 (2) (i)), risk characterization in relation to that property shall  not be necessary unless there are other reasonable grounds for concern.  1.2. In those cases where the test appropriate to hazard identification in relation to a particular property has not yet been conducted (Article 4 (2) (ii)), risk characterization in relation to that property shall not be necessary unless there are  other reasonable grounds for concern.  2. Exposure assessment 2.1. If risk characterization has to be conducted in accordance with Article 4 (2), it shall be necessary only to determine the reasonably foreseeable conditions of use on the basis of the information on the substance included in the technical dossier  as set out in section 2 of Annex VII A, VII B or VII C to Directive 67/548/EEC.  3. Risk characterization 3.1. The risk characterization shall entail an evaluation of the likelihood that an adverse effect will be caused under the reasonably foreseeable conditions of use. If this evaluation indicates that an adverse effect will not be caused, the conclusion  at Article 3 (4) (i) shall usually apply. If this evaluation indicates that an adverse effect will be caused, the conclusion at Article 3 (4) (iv) shall usually apply.  4. Integration 4.1. Where different recommendations for risk reduction have been made in relation to different effects or human populations, they shall be reviewed when the risk assessment has been completed and the competent authority shall produce integrated  recommendations.     ANNEX III  RISK ASSESSMENT: ENVIRONMENT  1. Hazard identification 1.1. For substances not classified dangerous for the environment (Article 5 (2) (i)), the competent authority shall consider whether there are other reasonable grounds for conducting a risk characterization and take particular account of:  (i) indications of bioaccumulation potential;  (ii) the shape of the toxicity/time curve in ecotoxicity testing;  (iii) indications of other adverse effects on the basis of toxicity studies, e.g. classification as a mutagen, toxic or very toxic or has harmful with risk phrase R 40 ('Possible risk of irreversible effects') or R 48 ('Danger of serious damage to  health by prolonged exposure');  (iv) data on structurally analogous substances.  1.2. If the competent authority considers that there are reasonable grounds for conducting a risk characterization for a substance not classified dangerous for the environment and for which are insufficient data on effects on organisms (Article 5 (2)  (ii)), it shall, as necessary, take action in accordance with Article 3 (4) (ii) or (iii).  2. Dose (concentration) - response (effect) assessment 2.1. The objective shall be to predict the concentration of the substance below which adverse effects in the environmental compartment of concern are not expected to occur. This concentration is known as the predicted no-effect concentration (PNEC).  2.2. The PNEC shall be determined on the basis of the information in the notification dossier which relates to effects on organisms as set out in section 5 of Annex VII A or VII B to Directive 67/548/EEC and the ecotoxicity studies listed in Annex VIII  (Levels 1 and 2) to that Directive.  2.3. The PNEC shall be calculated by applying an assessment factor to the values resulting from tests on organisms, e.g. LD50 (median lethal dose), LC50 (median lethal concentration), EC50 (median effective concentration), IC50 (concentration causing 50  % inhibition of a given parameter, e.g. growth), NOEL(C) (no-observed-effect level(concentration)), or LOEL(C) (lowest-observed-effect level (concentration)).  2.4. An assessment factor is an expression of the degree of uncertainty in extrapolation from test data on a limited number of species to the real environment. Therefore, in general, the more extensive the data and the longer the duration of the tests,  the smaller is the degree of uncertainty and the size of the assessment factor (1).  3. Exposure assessment 3.1. The objective of the exposure assessment shall be to predict the concentration of the substance which will eventually be found in the environment. That concentration is known as the predicted environmental concentration (PEC). However, in some  cases, it may not be possible to establish a PEC and a qualitative estimation of exposure would have to be made.  3.2. A PEC or, where necessary, a qualitative estimation of exposure need only be determined for the environmental compartments to which emissions, discharges, disposal or distributions are reasonable foreseeable.  3.3. The PEC or qualitative estimation of exposure shall be estimated on the basis of information included in the technical dossier as set out in Annex VII A, VII B, VII C or Annex VIII to Directive 67/548/EEC, including, as appropriate:  (i) adequately measured exposure data;  (ii) the quantity of the substance on the market;  (iii) the form in which the substance is marketed and/or used (e.g. substance itself or as component of a preparation);  (iv) use categories and degree of containment;  (v) process data, where relevant;  (vi) physico-chemical properties of the substance, in particular melting point, boiling point, vapour pressure, surface tension, water solubility, partition coefficient n-octanol/water;  (vii) likely pathways to environmental compartments and potential for adsorption/desorption and degradation;  (viii) frequency and duration of exposure.  3.4. For substances placed on the market in quantities at or below 10 tonnes per annum (or 50 tonnes cumulative), the PEC or qualitative estimation of exposure shall usually be determined for the generic local environment in which release of the  substance may occur.  4. Risk characterization 4.1. For any given environmental compartment, the risk characterization shall, as far as possible, entail comparison of the PEC with the PNEC so that a PEC/PNEC ratio may be direved. If the PEC/PNEC ratio is equal to or less than one, the conclusion at  Article 3 (4) (i) shall apply. If the ratio is greater than one, the competent authority shall judge, on the bais of the size of that ratio and other relevant factors, such as those listed in paragraph 1.1 (i) to (iv), which of the conclusions at  Article 3 (4) (ii), (iii) or (iv) is appropriate.  4.2. If it has not been possible to derive a PEC/PNEC ratio, the risk characterization shall entail a qualitative evaluation of the likelihood that an effect will occur under the expected conditions of exposure. Having made such an evaluation and taking  into account relevant factors such as those listed in paragraph 1 (1), the competent authority shall decide which of the four conclusions at Article 3 (4) is appropriate.  5. Integration 5.1. In accordance with the provisions of Article 5 (1), a risk characterization may be carried out in relation to more than one environmental compartment. In such cases, the competent authority shall judge which of the four conclusions at Article 3 (4)  is applicable to each compartment. Having completed the risk assessment, the competent authority shall review the different conclusions and produce integrated conclusions in relation to the overall environmental effects of the substance.   (1) An assessment factor of the order of 1 000 is typically applied to an L(E)C50 value derived from the results of testing for acute toxicity but that factor may be reduced in the light of other relevant information. A lower assessment factor  is typically applied to an NOEC derived from the results of testing for chronic toxicity.      ANNEX I  RISK ASSESSMENT: HUMAN HEALTH (TOXICITY)   PART A  The risk assessment conducted in accordance with Article 4 shall take account of the following potential toxic effects and populations liable to exposure:  Effects 1. Acute toxicity 2. Irritation 3. Corrosivity 4. Sensitization 5. Repeated dose toxicity 6. Mutagenicity 7. Carcinogenicity 8. Toxicity for reproduction Human populations 1. Workers 2. Consumers 3. Man exposed indirectly via environment  PART B  1. Hazard identification 1.1. In those cases where the test appropriate to hazard identification in relation to a particular potential effect has been conducted but the results have not led to classification (Article 4 (2) (i)), risk characterization in relation to that effect  shall not be necessary unless there are other reasonable grounds for concern, e.g. positive in vitro test results for mutagenicity.  1.2. In those cases where the test appropriate to hazard identification in relation to a particular potential effect has not yet been conducted (Article 4 (2) (ii)), risk characterization in relation to that effect shall not be necessary unless there  are other reasonable grounds for concern, e.g. exposure considerations or indications of potential toxicity from structure activity relationships.  2. Dose (concentration)-response (effect) assessment 2.1. For repeated-dose toxicity and reproductive toxicity, the dose-response relationship shall be assessed and, where possible, the no-observed-adverse-effect level (NOAEL) identified. If it is not possible to identify a NOAEL, the lowest  dose/concentration associated with an adverse effect, i.e., the lowest-observed-adverse-effect level (LOAEL), shall be identified.  2.2. For acute toxicity, corrosivity and irritation, it is not usually possible to derive a NOAEL or LOAEL on the basis of the results of tests conducted in accordance with the requirements of Directive 67/548/EEC. For acute toxicity, the LD50 or LC50  value or, where the fixed dose procedure has been used, the discriminating dose shall be derived. For the other effects, it shall be sufficient to determine whether the substance has an inherent capacity to cause such effects.  2.3. For mutagenicity and carcinogenicity, it shall be sufficient to determine whether the substance has an inherent capacity to cause such effects. However, if it can be demonstrated that a substance identified as a carcinogen is non-genotoxic, it will  be appropriate to identify a NOAEL/LOAEL as described in paragraph 2.1.  2.4. With respect to skin sensitization and respiratory sensitization, in so far as there is no consensus on the possibility of identifying a dose/concentration below which adverse effects are unlikely to occur in a subject already sensitized to a given  substance, it shall be sufficient to evaluate whether the substance has an inherent capacity to cause such effects.  3. Exposure assessment 3.1. An exposure assessment shall be conducted for each of the human populations (workers, consumers and man liable to exposure indirectly via the environment) for which exposure to the substance can reasonably be foreseen. The objective of the  assessment shall be to make a quantitative or qualitative estimate of the dose/concentration of the substance to which a population is or may be exposed. Such estimation shall take account of spatial and temporal variations in the exposure pattern.  3.2. The exposure assessment shall be based on the information in the technical dossier provided in conformity with section 2 of Annex VII A, VII B or VII C of Directive 67/548/EEC and on any other available and relevant information. Particular account  shall be taken, as appropriate, of:  (i) adequately measured exposure data;  (ii) the quantity of the substance on the market;  (iii) the form in which the substance is marketed and/or used (e.g. substance itself or as competent of a preparation);  (iv) use categories and degree of containment;  (v) process data, where relevant;  (vi) physico-chemical properties of the substance including, where relevant, those conferred by the process (e.g. aerosol formation);  (vii) likely routed of exposure and potential for absorption;  (viii) frequency and duration of exposure;  (ix) type and size of specific exposed population(s) where such information is available.  3.3. Where predictive methods are used for estimation of exposure levels, preference shall be given to relevant monitoring data from substances with analogous use and exposure patterns.  3.4. If a substance is contained in a preparation, consideration of exposure to the substance in that preparation shall be necessary only if the latter is classified on the basis of the toxicological properties of the substance in accordance with  Council Directive 88/379/EEC (1), unless there are other reasonable grounds for concern.  4. Risk characterization 4.1. Where, for any of the effects set out in Annex IA, a NOAEL or LOAEL has been identified, the risk characterization in relation to each of those effects shall entail comparison of the NOAEL or LOAEL with the estimate of the dose-concentration to  which the population(s) will be exposed. If a quantitative estimate of exposure is available, an exposure level/N(L)OAEL ratio shall be derived. On the basis of the comparison between the quantitative or qualitative estimate of exposure and the  N(L)OAEL, the competent authority shall decide which of the four conclusions at Article 3 (4) if applicable.  4.2. Where, for any of the effects set out in Annex IA, a N(L)OAEL has not been determined, the risk characterization in relation to each of those effects shall entail an evaluation, on the basis of the quantitative and/or qualitative information on  exposure relevant to the human populations under consideration, of the likelihood that the effect will occur (2). Having made the evaluation, the competent authority shall decide which of the four conclusions at Article 3 (4) is applicable.  4.3. When deciding which of the four conclusions at Article 3 (4) is applicable, the competent authority shall take into account, inter alia:  (i) the uncertainty arising, among other factors, from the variability in the experimental data and intra- and interspecies variation;  (ii) the nature and severity of the effect;  (iii) the human population to which the quantitative and/or qualitative information on exposure applies.  5. Integration In accordance with the provisions of Article 4 (1), a risk characterization may be carried out in relation to more than one potential adverse effect or human population. In such cases, the competent authority shall judge which of the four conclusions at  Article 3 (4) is applicable to each effect. Having completed the various conclusions and produce integrated conclusions in relation to the overall toxicity of the substance.   (1) OJ No L 187, 16. 7. 1988, p. 14.  (2) Where, despite a N(L)OAEL not having been determined, the test results nevertheless demonstrate a relationship between dose/concentration and the severity of an adverse effect or where, in connection with a test method which entails the use of only  one dose or concentration, it is possible to evaluate the relative severity of the effect, such information shall also be taken into account in evaluating the likelihood of the effect occurring.      ANNEX II  RISK ASSESSMENT: HUMAN HEALTH (PHYSICO-CHEMICAL PROPERTIES)   PART A  Risk assessment in accordance with Article 4 shall take account of the potential adverse effects which may occur in the following human populations liable to exposure to substances with the following properties.  Properties 1. Explosivity 2. Flammability 3. Oxidizing potential Human populations 1. Workers 2. Consumers 3. Man exposed indirectly via the environment  PART B  1. Hazard identification 1.1. In those cases where the test appropriate to hazard identification in relation to a particular property has been conducted but the results have not led to classification (Article 4 (2) (i)), risk characterization in relation to that property shall  not be necessary unless there are other reasonable grounds for concern.  1.2. In those cases where the test appropriate to hazard identification in relation to a particular property has not yet been conducted (Article 4 (2) (ii)), risk characterization in relation to that property shall not be necessary unless there are  other reasonable grounds for concern.  2. Exposure assessment 2.1. If risk characterization has to be conducted in accordance with Article 4 (2), it shall be necessary only to determine the reasonably foreseeable conditions of use on the basis of the information on the substance included in the technical dossier  as set out in section 2 of Annex VII A, VII B or VII C to Directive 67/548/EEC.  3. Risk characterization 3.1. The risk characterization shall entail an evaluation of the likelihood that an adverse effect will be caused under the reasonably foreseeable conditions of use. If this evaluation indicates that an adverse effect will not be caused, the conclusion  at Article 3 (4) (i) shall usually apply. If this evaluation indicates that an adverse effect will be caused, the conclusion at Article 3 (4) (iv) shall usually apply.  4. Integration 4.1. Where different recommendations for risk reduction have been made in relation to different effects or human populations, they shall be reviewed when the risk assessment has been completed and the competent authority shall produce integrated  recommendations.     ANNEX III  RISK ASSESSMENT: ENVIRONMENT  1. Hazard identification 1.1. For substances not classified dangerous for the environment (Article 5 (2) (i)), the competent authority shall consider whether there are other reasonable grounds for conducting a risk characterization and take particular account of:  (i) indications of bioaccumulation potential;  (ii) the shape of the toxicity/time curve in ecotoxicity testing;  (iii) indications of other adverse effects on the basis of toxicity studies, e.g. classification as a mutagen, toxic or very toxic or has harmful with risk phrase R 40 ('Possible risk of irreversible effects') or R 48 ('Danger of serious damage to  health by prolonged exposure');  (iv) data on structurally analogous substances.  1.2. If the competent authority considers that there are reasonable grounds for conducting a risk characterization for a substance not classified dangerous for the environment and for which are insufficient data on effects on organisms (Article 5 (2)  (ii)), it shall, as necessary, take action in accordance with Article 3 (4) (ii) or (iii).  2. Dose (concentration) - response (effect) assessment 2.1. The objective shall be to predict the concentration of the substance below which adverse effects in the environmental compartment of concern are not expected to occur. This concentration is known as the predicted no-effect concentration (PNEC).  2.2. The PNEC shall be determined on the basis of the information in the notification dossier which relates to effects on organisms as set out in section 5 of Annex VII A or VII B to Directive 67/548/EEC and the ecotoxicity studies listed in Annex VIII  (Levels 1 and 2) to that Directive.  2.3. The PNEC shall be calculated by applying an assessment factor to the values resulting from tests on organisms, e.g. LD50 (median lethal dose), LC50 (median lethal concentration), EC50 (median effective concentration), IC50 (concentration causing 50  % inhibition of a given parameter, e.g. growth), NOEL(C) (no-observed-effect level(concentration)), or LOEL(C) (lowest-observed-effect level (concentration)).  2.4. An assessment factor is an expression of the degree of uncertainty in extrapolation from test data on a limited number of species to the real environment. Therefore, in general, the more extensive the data and the longer the duration of the tests,  the smaller is the degree of uncertainty and the size of the assessment factor (1).  3. Exposure assessment 3.1. The objective of the exposure assessment shall be to predict the concentration of the substance which will eventually be found in the environment. That concentration is known as the predicted environmental concentration (PEC). However, in some  cases, it may not be possible to establish a PEC and a qualitative estimation of exposure would have to be made.  3.2. A PEC or, where necessary, a qualitative estimation of exposure need only be determined for the environmental compartments to which emissions, discharges, disposal or distributions are reasonable foreseeable.  3.3. The PEC or qualitative estimation of exposure shall be estimated on the basis of information included in the technical dossier as set out in Annex VII A, VII B, VII C or Annex VIII to Directive 67/548/EEC, including, as appropriate:  (i) adequately measured exposure data;  (ii) the quantity of the substance on the market;  (iii) the form in which the substance is marketed and/or used (e.g. substance itself or as component of a preparation);  (iv) use categories and degree of containment;  (v) process data, where relevant;  (vi) physico-chemical properties of the substance, in particular melting point, boiling point, vapour pressure, surface tension, water solubility, partition coefficient n-octanol/water;  (vii) likely pathways to environmental compartments and potential for adsorption/desorption and degradation;  (viii) frequency and duration of exposure.  3.4. For substances placed on the market in quantities at or below 10 tonnes per annum (or 50 tonnes cumulative), the PEC or qualitative estimation of exposure shall usually be determined for the generic local environment in which release of the  substance may occur.  4. Risk characterization 4.1. For any given environmental compartment, the risk characterization shall, as far as possible, entail comparison of the PEC with the PNEC so that a PEC/PNEC ratio may be direved. If the PEC/PNEC ratio is equal to or less than one, the conclusion at  Article 3 (4) (i) shall apply. If the ratio is greater than one, the competent authority shall judge, on the bais of the size of that ratio and other relevant factors, such as those listed in paragraph 1.1 (i) to (iv), which of the conclusions at  Article 3 (4) (ii), (iii) or (iv) is appropriate.  4.2. If it has not been possible to derive a PEC/PNEC ratio, the risk characterization shall entail a qualitative evaluation of the likelihood that an effect will occur under the expected conditions of exposure. Having made such an evaluation and taking  into account relevant factors such as those listed in paragraph 1 (1), the competent authority shall decide which of the four conclusions at Article 3 (4) is appropriate.  5. Integration 5.1. In accordance with the provisions of Article 5 (1), a risk characterization may be carried out in relation to more than one environmental compartment. In such cases, the competent authority shall judge which of the four conclusions at Article 3 (4)  is applicable to each compartment. Having completed the risk assessment, the competent authority shall review the different conclusions and produce integrated conclusions in relation to the overall environmental effects of the substance.   (1) An assessment factor of the order of 1 000 is typically applied to an L(E)C50 value derived from the results of testing for acute toxicity but that factor may be reduced in the light of other relevant information. A lower assessment factor  is typically applied to an NOEC derived from the results of testing for chronic toxicity.      ANNEX IV  OVERALL INTEGRATION OF CONCLUSIONS  1. The conclusions produced in conformity with section 5.1 of Annex I, section 4.1 of Annex II and section 5.1 of Annex III shall be reviewed by the competent authority and integrated in relation to the totality of  risks identified in the risk assessment.  2. Further information requirements (Article 3 (4) (ii) and (iii)) or recommendations for risk reduction (Article 3 (4) (iv)) shall be justified. The latter shall take account of Article 3 (6).     ANNEX V  INFORMATION TO BE INCLUDED IN SUMMARY OF RISK ASSESSMENT  1. The written report submitted to the Commission in accordance with Article 7 shall include the following elements:  (i) a general summary of the conclusionhs produced in accordance with Article 6 and in conformity with Annex IV;  (ii) if the conclusion at Article 3 (4) (i) applies to the substance in relation to all potential adverse effects, human populations and environmental compartments, a statement that, on the basis of available information, the substance is of no  immediate concern and that further consideration is unnecessary until the notifier submits additional information in accordance with Article 7 (2), 8 (3) or 14 (1) of Directive 67/548/EEC;  (iii) if the conclusion at Article 3 (4) (ii) or (iii) applies in relation to one or more potential adverse effect(s), human population(s) or environmental compartment(s), a description and justification of the further information required;  (iv) if the conclusion at Article 3 (4) (iv) applies in relation to one or more potential adverse effect(s), human population(s) or environmental compartment(s), a description and justification of recommendations for risk reduction;  (v) if action has been taken as provided for in Article 3 (5), a summary of the notifier's comments on the competent authoritiy's proposals and of any relevant additional information made available.  2. Where risk characterization has entailed the use of exposure/effect ratios as described in section 4 of Annex IB and section 4 of Annex III or the use of assessment factors as described in section 2 of Annex III, those ratios or factors shall be  stated.