title: Commission Directive 2009/120/EC of 14 September 2009 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use as regards advanced therapy medicinal products (Text with EEA relevance)

text:
               15.9.2009

               EN

               Official Journal of the European Union

               L 242/3

      COMMISSION DIRECTIVE 2009/120/EC
   of 14 September 2009
   amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use as regards advanced therapy medicinal products
   (Text with EEA relevance)
   THE COMMISSION OF THE EUROPEAN COMMUNITIES,
   Having regard to the Treaty establishing the European Community,
   Having regard to Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (1), and in particular Article 120 thereof,
   Whereas:

               (1)

               Medicinal products for human use may only be placed on the market if a marketing authorisation has been delivered by a competent authority on the basis of an application dossier containing the results of tests and trials carried out on the products concerned.

               (2)

               Annex I to Directive 2001/83/EC lays down detailed scientific and technical requirements regarding the testing of medicinal products for human use against which the quality, safety and efficacy of the medicinal product should be assessed. Those detailed scientific and technical requirements should be regularly adapted to take account of scientific and technical progress.

               (3)

               Due to scientific and technical progress in the field of advanced therapies, as reflected in Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (2), it is appropriate to adapt Annex I. The definitions and detailed scientific and technical requirements for gene therapy medicinal products and somatic cell therapy medicinal products should be updated. Moreover, detailed scientific and technical requirements should be established for tissue engineered products, as well as for advanced therapy medicinal product containing devices and combined advanced therapy medicinal products.

               (4)

               The measures provided for in this Directive are in accordance with the opinion of the Standing Committee for Medicinal Products for Human Use,

         HAS ADOPTED THIS DIRECTIVE:
   Article 1
   Part IV of Annex I to Directive 2001/83/EC is replaced by the text set out in the Annex to this Directive.
   Article 2
   1.   Member States shall bring into force the laws, regulations and administrative provisions necessary to comply with this Directive by 5 April 2010 at the latest. They shall forthwith communicate to the Commission the text of those provisions and a correlation table between those provisions and this Directive.
   When Member States adopt those provisions, they shall contain a reference to this Directive or be accompanied by such a reference on the occasion of their official publication. Member States shall determine how such reference is to be made.
   2.   Member States shall communicate to the Commission the text of the main provisions of national law which they adopt in the field covered by this Directive.
   Article 3
   This Directive shall enter into force on the 20th day following its publication in the Official Journal of the European Union.
   Article 4
   This Directive is addressed to the Member States.

      Done at Brussels, 14 September 2009.

            For the Commission

         Günter VERHEUGEN

            Vice-President

      (1)  OJ L 311, 28.11.2001, p. 67.

      (2)  OJ L 324, 10.12.2007, p. 121.

      ANNEX

         ‘PART IV

            ADVANCED THERAPY MEDICINAL PRODUCTS

         1.   INTRODUCTION
         Marketing authorisation applications for advanced therapy medicinal products, as defined in point (a) of Article 2(1) of Regulation (EC) No 1394/2007, shall follow the format requirements (Modules 1, 2, 3, 4 and 5) described in Part I of this Annex.
         The technical requirements for Modules 3, 4 and 5 for biological medicinal products, as described in Part I of this Annex, shall apply. The specific requirements for advanced therapy medicinal products described in sections 3, 4 and 5 of this part explain how the requirements in Part I apply to advanced therapy medicinal products. In addition, where appropriate and taking into account the specificities of advanced therapy medicinal products, additional requirements have been set.
         Due to the specific nature of advanced therapy medicinal products, a risk-based approach may be applied to determine the extent of quality, non-clinical and clinical data to be included in the marketing authorisation application, in accordance with the scientific guidelines relating to the quality, safety and efficacy of medicinal products referred to in point 4 of the “Introduction and general principles”.
         The risk analysis may cover the entire development. Risk factors that may be considered include: the origin of the cells (autologous, allogeneic, xenogeneic), the ability to proliferate and/or differentiate and to initiate an immune response, the level of cell manipulation, the combination of cells with bioactive molecules or structural materials, the nature of the gene therapy medicinal products, the extent of replication competence of viruses or micro-organisms used in vivo, the level of integration of nucleic acids sequences or genes into the genome, the long time functionality, the risk of oncogenicity and the mode of administration or use.
         Relevant available non-clinical and clinical data or experience with other, related advanced therapy medicinal products may also be considered in the risk analysis.
         Any deviation from the requirements of this Annex shall be scientifically justified in Module 2 of the application dossier. The risk analysis described above, when applied, shall also be included and described in Module 2. In this case, the methodology followed, the nature of the identified risks and the implications of the risk based approach for the development and evaluation program shall be discussed and any deviations from the requirements of this Annex resulting from the risk analysis shall be described.
         2.   DEFINITIONS
         For the purposes of this Annex, in addition to the definitions laid down in Regulation (EC) No 1394/2007, the definitions set out in sections 2.1 and 2.2 shall apply.
         2.1.   Gene therapy medicinal product

         Gene therapy medicinal product means a biological medicinal product which has the following characteristics:

                     (a)

                     it contains an active substance which contains or consists of a recombinant nucleic acid used in or administered to human beings with a view to regulating, repairing, replacing, adding or deleting a genetic sequence;

                     (b)

                     its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence.

               Gene therapy medicinal products shall not include vaccines against infectious diseases.
         2.2.   Somatic cell therapy medicinal product

         Somatic cell therapy medicinal product means a biological medicinal product which has the following characteristics:

                     (a)

                     contains or consists of cells or tissues that have been subject to substantial manipulation so that biological characteristics, physiological functions or structural properties relevant for the intended clinical use have been altered, or of cells or tissues that are not intended to be used for the same essential function(s) in the recipient and the donor;

                     (b)

                     is presented as having properties for, or is used in or administered to human beings with a view to treating, preventing or diagnosing a disease through the pharmacological, immunological or metabolic action of its cells or tissues.

               For the purposes of point (a), the manipulations listed in Annex I to Regulation (EC) No 1394/2007, in particular, shall not be considered as substantial manipulations.
         3.   SPECIFIC REQUIREMENTS REGARDING MODULE 3
         3.1.   Specific requirements for all advanced therapy medicinal products

         A description of the traceability system that the marketing authorisation holder intends to establish and maintain to ensure that the individual product and its starting and raw materials, including all substances coming into contact with the cells or tissues it may contain, can be traced through the sourcing, manufacturing, packaging, storage, transport and delivery to the hospital, institution or private practice where the product is used, shall be provided.
         The traceability system shall be complementary to, and compatible with, the requirements established in Directive 2004/23/EC of the European Parliament and of the Council (1), as regards human cells and tissues other than blood cells, and Directive 2002/98/EC, as regards human blood cells.
         3.2.   Specific requirements for gene therapy medicinal products

         3.2.1.   Introduction: finished product, active substance and starting materials

         3.2.1.1.   Gene therapy medicinal product containing recombinant nucleic acid sequence(s) or genetically modified microorganism(s) or virus(es)
         The finished medicinal product shall consist of nucleic acid sequence(s) or genetically modified microorganism(s) or virus(es) formulated in their final immediate container for the intended medical use. The finished medicinal product may be combined with a medical device or active implantable medical device.
         The active substance shall consist of nucleic acid sequence(s) or genetically modified microorganism(s) or virus(es).
         3.2.1.2.   Gene therapy medicinal product containing genetically modified cells
         The finished medicinal product shall consist of genetically modified cells formulated in the final immediate container for the intended medical use. The finished medicinal product may be combined with a medical device or active implantable medical device.
         The active substance shall consist of cells genetically modified by one of the products described in section 3.2.1.1 above.
         3.2.1.3.   In the case of products consisting of viruses or viral vectors, the starting materials shall be the components from which the viral vector is obtained, i.e. the master virus vector seed or the plasmids used to transfect the packaging cells and the master cell bank of the packaging cell line.
         3.2.1.4.   In the case of products consisting of plasmids, non-viral vectors and genetically modified microorganism(s) other than viruses or viral vectors, the starting materials shall be the components used to generate the producing cell, i.e. the plasmid, the host bacteria and the master cell bank of recombinant microbial cells.
         3.2.1.5.   In the case of genetically modified cells, the starting materials shall be the components used to obtain the genetically modified cells, i.e. the starting materials to produce the vector, the vector and the human or animal cells. The principles of good manufacturing practice shall apply from the bank system used to produce the vector onwards.
         3.2.2.   Specific requirements

         In addition to the requirements set out in sections 3.2.1 and 3.2.2 of Part I of this Annex, the following requirements shall apply:

                     (a)

                     information shall be provided on all the starting materials used for the manufacture of the active substance, including the products necessary for the genetic modification of human or animal cells and, as applicable, subsequent culture and preservation of the genetically modified cells, taking into consideration the possible absence of purification steps;

                     (b)

                     for products containing a microorganism or a virus, data on the genetic modification, sequence analysis, attenuation of virulence, tropism for specific tissues and cell types, cell cycle dependence of the microorganism or virus, pathogenicity and characteristics of the parental strain shall be provided;

                     (c)

                     process-related impurities and product-related impurities shall be described in the relevant sections of the dossier, and in particular replication competent virus contaminants if the vector is designed to be replication incompetent;

                     (d)

                     for plasmids, quantification of the different plasmid forms shall be undertaken throughout the shelf life of the product;

                     (e)

                     for genetically modified cells, the characteristics of the cells before and after the genetic modification, as well as before and after any subsequent freezing/storage procedures, shall be tested.

               For genetically modified cells, in addition to the specific requirements for gene therapy medicinal products, the quality requirements for somatic cell therapy medicinal products and tissue engineered products (see section 3.3) shall apply.
         3.3.   Specific requirements for somatic cell therapy medicinal products and tissue engineered products

         3.3.1.   Introduction: finished product, active substance and starting materials

         The finished medicinal product shall consist of the active substance formulated in its immediate container for the intended medical use, and in its final combination for combined advanced therapy medicinal products.
         The active substance shall be composed of the engineered cells and/or tissues.
         Additional substances (e.g. scaffolds, matrices, devices, biomaterials, biomolecules and/or other components) which are combined with manipulated cells of which they form an integral part shall be considered as starting materials, even if not of biological origin.
         Materials used during the manufacture of the active substance (e.g. culture media, growth factors) and that are not intended to form part of the active substance shall be considered as raw materials.
         3.3.2.   Specific requirements

         In addition to the requirements set out in sections 3.2.1 and 3.2.2 of Part I of this Annex, the following requirements shall apply:
         3.3.2.1.   Starting materials

                     (a)

                     Summary information shall be provided on donation, procurement and testing of the human tissue and cells used as starting materials and made in accordance with Directive 2004/23/EC. If non-healthy cells or tissues (e.g. cancer tissue) are used as starting materials, their use shall be justified.

                     (b)

                     If allogeneic cell populations are being pooled, the pooling strategies and measures to ensure traceability shall be described.

                     (c)

                     The potential variability introduced through the human or animal tissues and cells shall be addressed as part of the validation of the manufacturing process, characterisation of the active substance and the finished product, development of assays, setting of specifications and stability.

                     (d)

                     For xenogeneic cell-based products, information on the source of animals (such as geographical origin, animal husbandry, age), specific acceptance criteria, measures to prevent and monitor infections in the source/donor animals, testing of the animals for infectious agents, including vertically transmitted micro-organisms and viruses, and evidence of the suitability of the animal facilities shall be provided.

                     (e)

                     For cell-based products derived from genetically modified animals, the specific characteristics of the cells related to the genetic modification shall be described. A detailed description of the method of creation and the characterisation of the transgenic animal shall be provided.

                     (f)

                     For the genetic modification of the cells, the technical requirements specified in section 3.2 shall apply.

                     (g)

                     The testing regimen of any additional substance (scaffolds, matrices, devices, biomaterials, biomolecules or other components), which are combined with engineered cells of which they form an integral part, shall be described and justified.

                     (h)

                     For scaffolds, matrices and devices that fall under the definition of a medical device or active implantable medical device, the information required under section 3.4 for the evaluation of the combined advanced therapy medicinal product shall be provided.

               3.3.2.2.   Manufacturing process

                     (a)

                     The manufacturing process shall be validated to ensure batch and process consistency, functional integrity of the cells throughout manufacturing and transport up to the moment of application or administration, and proper differentiation state.

                     (b)

                     If cells are grown directly inside or on a matrix, scaffold or device, information shall be provided on the validation of the cell culture process with respect to cell-growth, function and integrity of the combination.

               3.3.2.3.   Characterisation and control strategy

                     (a)

                     Relevant information shall be provided on the characterisation of the cell population or cell mixture in terms of identity, purity (e.g. adventitious microbial agents and cellular contaminants), viability, potency, karyology, tumourigenicity and suitability for the intended medicinal use. The genetic stability of the cells shall be demonstrated.

                     (b)

                     Qualitative and, where possible, quantitative information on product- and process-related impurities, as well as on any material capable of introducing degradation products during production, shall be provided. The extent of the determination of impurities shall be justified.

                     (c)

                     If certain release tests cannot be performed on the active substance or finished product, but only on key intermediates and/or as in-process testing, this shall be justified.

                     (d)

                     Where biologically active molecules (such as growth factors, cytokines) are present as components of the cell-based product, their impact and interaction with other components of the active substance shall be characterised.

                     (e)

                     Where a three-dimensional structure is part of the intended function, the differentiation state, structural and functional organisation of the cells and, where applicable, the extracellular matrix generated shall be part of the characterisation for these cell-based products. Where needed, non-clinical investigations shall complement the physicochemical characterisation.

               3.3.2.4.   Excipients
         For excipient(s) used in cell or tissue-based medicinal products (e.g. the components of the transport medium), the requirements for novel excipients, as laid down in Part I of this Annex, shall apply, unless data exists on the interactions between the cells or tissues and the excipients.
         3.3.2.5.   Developmental studies
         The description of the development program shall address the choice of materials and processes. In particular, the integrity of the cell population as in the final formulation shall be discussed.
         3.3.2.6.   Reference materials
         A reference standard, relevant and specific for the active substance and/or the finished product, shall be documented and characterised.
         3.4.   Specific requirements for advanced therapy medicinal products containing devices

         3.4.1.   Advanced therapy medicinal product containing devices as referred to in Article 7 of Regulation (EC) No 1394/2007

         A description of the physical characteristics and performance of the product and a description of the product design methods shall be provided.
         The interaction and compatibility between genes, cells and/or tissues and the structural components shall be described.
         3.4.2.   Combined advanced therapy medicinal products as defined in Article 2(1)(d) of Regulation (EC) No 1394/2007

         For the cellular or tissue part of the combined advanced therapy medicinal product, the specific requirements for somatic cell therapy medicinal products and tissue engineered products set out in section 3.3 shall apply and, in the case of genetically modified cells, the specific requirements for gene therapy medicinal products set out in section 3.2 shall apply.
         The medical device or the active implantable medical device may be an integral part of the active substance. Where the medical device or active implantable medical device is combined with the cells at the time of the manufacture or application or administration of the finished products, they shall be considered as an integral part of the finished product.
         Information related to the medical device or the active implantable medical device (which is an integral part of the active substance or of the finished product) which is relevant for the evaluation of the combined advanced therapy medicinal product shall be provided. This information shall include:

                     (a)

                     information on the choice and intended function of the medical device or implantable medical device and demonstration of compatibility of the device with other components of the product;

                     (b)

                     evidence of conformity of the medical device part with the essential requirements laid down in Annex I to Council Directive 93/42/EEC (2), or of conformity of the active implantable device part with the essential requirements laid down in Annex 1 to Council Directive 90/385/EEC (3);

                     (c)

                     where applicable, evidence of compliance of the medical device or implantable medical device with the BSE/TSE requirements laid down in Commission Directive 2003/32/EC (4);

                     (d)

                     where available, the results of any assessment of the medical device part or the active implantable medical device part by a notified body in accordance with Directive 93/42/EEC or Directive 90/385/EEC.

               The notified body which has carried out the assessment referred to in point (d) of this section shall make available on request of the competent authority assessing the application, any information related to the results of the assessment in accordance with Directive 93/42/EEC or Directive 90/385/EEC. This may include information and documents contained in the conformity assessment application concerned, where necessary for the evaluation of the combined advanced therapy medicinal product as a whole.
         4.   SPECIFIC REQUIREMENTS REGARDING MODULE 4
         4.1.   Specific requirements for all advanced therapy medicinal products

         The requirements of Part I, Module 4 of this Annex on the pharmacological and toxicological testing of medicinal products may not always be appropriate due to unique and diverse structural and biological properties of advanced therapy medicinal products. The technical requirements in sections 4.1, 4.2 and 4.3 below explain how the requirements in Part I of this Annex apply to advanced therapy medicinal products. Where appropriate and taking into account the specificities of advanced therapy medicinal products, additional requirements have been set.
         The rationale for the non-clinical development and the criteria used to choose the relevant species and models (in vitro and in vivo) shall be discussed and justified in the non-clinical overview. The chosen animal model(s) may include immuno-compromised, knockout, humanised or transgenic animals. The use of homologous models (e.g. mouse cells analysed in mice) or disease mimicking models shall be considered, especially for immunogenicity and immunotoxicity studies.
         In addition to the requirements of Part I, the safety, suitability and biocompatibility of all structural components (such as matrices, scaffolds and devices) and any additional substances (such as cellular products, biomolecules, biomaterials, and chemical substances), which are present in the finished product, shall be provided. Their physical, mechanical, chemical and biological properties shall be taken into account.
         4.2.   Specific requirements for gene therapy medicinal products

         In order to determine the extent and type of non-clinical studies necessary to determine the appropriate level of non-clinical safety data, the design and type of the gene therapy medicinal product shall be taken into account.
         4.2.1.   Pharmacology

                     (a)

                        In vitro and in vivo studies of actions relating to the proposed therapeutic use (i.e. pharmacodynamic “proof of concept” studies) shall be provided using models and relevant animal species designed to show that the nucleic acid sequence reaches its intended target (target organ or cells) and provides its intended function (level of expression and functional activity). The duration of the nucleic acid sequence function and the proposed dosing regimen in the clinical studies shall be provided.

                     (b)

                     Target selectivity: When the gene therapy medicinal product is intended to have a selective or target-restricted functionality, studies to confirm the specificity and duration of functionality and activity in target cells and tissues shall be provided.

               4.2.2.   Pharmacokinetics

                     (a)

                     Biodistribution studies shall include investigations on persistence, clearance and mobilisation. Biodistribution studies shall additionally address the risk of germline transmission.

                     (b)

                     Investigations of shedding and risk of transmission to third parties shall be provided with the environmental risk assessment, unless otherwise duly justified in the application on the basis of the type of product concerned.

               4.2.3.   Toxicology

                     (a)

                     Toxicity of the finished gene therapy medicinal product shall be assessed. In addition, depending on the type of product, individual testing of active substance and excipients shall be taken into consideration, the in vivo effect of expressed nucleic acid sequence-related products which are not intended for the physiological function shall be evaluated.

                     (b)

                     Single-dose toxicity studies may be combined with safety pharmacology and pharmacokinetic studies, e.g. to investigate persistence.

                     (c)

                     Repeated dose toxicity studies shall be provided when multiple dosing of human subjects is intended. The mode and scheme of administration shall closely reflect the planned clinical dosing. For those cases where single dosing may result in prolonged functionality of the nucleic acid sequence in humans, repeated toxicity studies shall be considered. The duration of the studies may be longer than in standard toxicity studies depending on the persistence of the gene therapy medicinal product and the anticipated potential risks. A justification for the duration shall be provided.

                     (d)

                     Genotoxicity shall be studied. However, standard genotoxicity studies shall only be conducted when they are necessary for testing a specific impurity or a component of the delivery system.

                     (e)

                     Carcinogenicity shall be studied. Standard lifetime rodent carcinogenicity studies shall not be required. However, depending on the type of product, the tumourigenic potential shall be evaluated in relevant in vivo/in vitro models.

                     (f)

                     Reproductive and developmental toxicity: Studies on the effects on fertility and general reproductive function shall be provided. Embryo-foetal and perinatal toxicity studies and germline transmission studies shall be provided, unless otherwise duly justified in the application on the basis of the type of product concerned.

                     (g)

                        Additional toxicity studies

                                 —

                                 Integration studies: integration studies shall be provided for any gene therapy medicinal product, unless the lack of these studies is scientifically justified, e.g. because nucleic acid sequences will not enter into the cell nucleus. For gene therapy medicinal products not expected to be capable of integration, integration studies shall be performed, if biodistribution data indicate a risk for germline transmission.

                                 —

                                 Immunogenicity and immunotoxicity: potential immunogenic and immunotoxic effects shall be studied.

               4.3.   Specific requirements for somatic cell therapy medicinal products and tissue engineered products

         4.3.1.   Pharmacology

                     (a)

                     The primary pharmacological studies shall be adequate to demonstrate the proof of concept. The interaction of the cell-based products with the surrounding tissue shall be studied.

                     (b)

                     The amount of product needed to achieve the desired effect/the effective dose, and, depending on the type of product, the frequency of dosing shall be determined.

                     (c)

                     Secondary pharmacological studies shall be taken into account to evaluate potential physiological effects that are not related to the desired therapeutic effect of the somatic cell therapy medicinal product, of the tissue engineered product or of additional substances, as biologically active molecules besides the protein(s) of interest might be secreted or the protein(s) of interest could have unwanted target sites.

               4.3.2.   Pharmacokinetics

                     (a)

                     Conventional pharmacokinetic studies to investigate absorption, distribution, metabolism and excretion shall not be required. However, parameters such as viability, longevity, distribution, growth, differentiation and migration shall be investigated, unless otherwise duly justified in the application on the basis of the type of product concerned.

                     (b)

                     For somatic cell therapy medicinal products and tissue engineered products, producing systemically active biomolecules, the distribution, duration and amount of expression of these molecules shall be studied.

               4.3.3.   Toxicology

                     (a)

                     The toxicity of the finished product shall be assessed. Individual testing of active substance(s), excipients, additional substances and any process-related impurities shall be taken into consideration.

                     (b)

                     The duration of observations may be longer than in standard toxicity studies and the anticipated lifespan of the medicinal product, together with its pharmacodynamic and pharmacokinetic profile, shall be taken into consideration. A justification of the duration shall be provided.

                     (c)

                     Conventional carcinogenicity and genotoxicity studies shall not be required, except with regard to the tumourigenic potential of the product.

                     (d)

                     Potential immunogenic and immunotoxic effects shall be studied.

                     (e)

                     In the case of cell-based products containing animal cells, the associated specific safety concerns such as transmission to humans of xenogeneic pathogens shall be addressed.

               5.   SPECIFIC REQUIREMENTS REGARDING MODULE 5
         5.1.   Specific requirements for all advanced therapy medicinal products

         5.1.1.   The specific requirements in this section of Part IV are additional requirements to those set in Module 5 in Part I of this Annex.
         5.1.2.   Where the clinical application of advanced therapy medicinal products requires specific concomitant therapy and involve surgical procedures, the therapeutic procedure as a whole shall be investigated and described. Information on the standardisation and optimisation of those procedures during clinical development shall be provided.
         Where medical devices used during the surgical procedures for application, implantation or administration of the advanced therapy medicinal product may have an impact on the efficacy or safety of the advanced therapy product, information on these devices shall be provided.
         Specific expertise required to carry out the application, implantation, administration or follow-up activities shall be defined. Where necessary, the training plan of health care professionals on the use, application, implantation or administration procedures of these products shall be provided.
         5.1.3.   Given that, due to the nature of advanced therapy medicinal products, their manufacturing process may change during clinical development, additional studies to demonstrate comparability may be required.
         5.1.4.   During clinical development, risks arising from potential infectious agents or the use of material derived from animal sources and measures taken to reduce such risk shall be addressed.
         5.1.5.   Dose selection and schedule of use shall be defined by dose-finding studies.
         5.1.6.   The efficacy of the proposed indications shall be supported by relevant results from clinical studies using clinically meaningful endpoints for the intended use. In certain clinical conditions, evidence of long-term efficacy may be required. The strategy to evaluate long-term efficacy shall be provided.
         5.1.7.   A strategy for the long-term follow-up of safety and efficacy shall be included in the risk management plan.
         5.1.8.   For combined advanced therapy medicinal products, the safety and efficacy studies shall be designed for and performed on the combined product as a whole.
         5.2.   Specific requirements for gene therapy medicinal products

         5.2.1.   Human pharmacokinetic studies

         Human pharmacokinetic studies shall include the following aspects:

                     (a)

                     shedding studies to address the excretion of the gene therapy medicinal products;

                     (b)

                     biodistribution studies;

                     (c)

                     pharmacokinetic studies of the medicinal product and the gene expression moieties (e.g. expressed proteins or genomic signatures).

               5.2.2.   Human pharmacodynamic studies

         Human pharmacodynamic studies shall address the expression and function of the nucleic acid sequence following administration of the gene therapy medicinal product.
         5.2.3.   Safety studies

         Safety studies shall address the following aspects:

                     (a)

                     emergence of replication competent vector;

                     (b)

                     emergence of new strains;

                     (c)

                     reassortment of existing genomic sequences;

                     (d)

                     neoplastic proliferation due to insertional mutagenicity.

               5.3.   Specific requirements for somatic cell therapy medicinal products

         5.3.1.   Somatic cell therapy medicinal products where the mode of action is based on the production of defined active biomolecule(s)

         For somatic cell therapy medicinal products where the mode of action is based on the production of defined active biomolecule(s), the pharmacokinetic profile (in particular distribution, duration and amount of expression) of those molecules shall be addressed, if feasible.
         5.3.2.   Biodistribution, persistence and long-term engraftment of the somatic cell therapy medicinal product components

         The biodistribution, persistence and long-term engraftment of the somatic cell therapy medicinal product components shall be addressed during the clinical development.
         5.3.3.   Safety studies

         Safety studies shall address the following aspects:

                     (a)

                     distribution and engrafting following administration;

                     (b)

                     ectopic engraftment;

                     (c)

                     oncogenic transformation and cell/tissue lineage fidelity.

               5.4.   Specific requirements for tissue engineered products

         5.4.1.   Pharmacokinetic studies

         Where conventional pharmacokinetic studies are not relevant for tissue engineered products, the biodistribution, persistence and degradation of the tissue engineered product components shall be addressed during the clinical development.
         5.4.2.   Pharmacodynamic studies

         Pharmacodynamic studies shall be designed and tailored to the specificities of tissue engineered products. The evidence for the “proof of concept” and the kinetics of the product to obtain the intended regeneration, repairing or replacement shall be provided. Suitable pharmacodynamic markers, related to the intended function(s) and structure shall be taken into account.
         5.4.3.   Safety studies

         Section 5.3.3 shall apply.

         (1)  OJ L 102, 7.4.2004, p. 48.

         (2)  OJ L 169, 12.7.1993, p. 1.

         (3)  OJ L 189, 20.7.1990, p. 17.

         (4)  OJ L 105, 26.4.2003, p. 18.’


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Council Directive 86/467/EEC of 14 July 1986 concerning the Community list of less-favoured farming areas within the meaning of Directive 75/268/EEC (Portugal)

Official Journal L 273 , 24/09/1986 P. 0173 - 0180

COUNCIL DIRECTIVE of 14 July 1986 concerning the Community list of less-favoured farming areas within the meaning of Directive 75/268/EEC (Portugal)THE COUNCIL OF THE EUROPEAN COMMUNITIES,  Having regard to the treaty establishing the European Economic Community,  Having regard to Council Directive 75/268/EEC of 28 April 1975 on mountain and hill farming and farming in certain less-favoured areas (1), as last amended by Regulation (EEC) No 797/85 (2), and in particular Article 2 (2) thereof,  Having regard to the proposal from the Commission,  Having regard to the opinion of the European Parliament (3),  Whereas the Government of the Republic of Portugal has communicated to the Commission, pursuant to Article 2 (1) of Directive 75/268/EEC, areas suitable for inclusion in the Community list of less-favoured farming areas as well as information relating  to the characteristics of these areas;  Whereas the following criteria were used to define mountain areas according to Article 3 (3) of Directive 75/268/EEC: in the area north of the Tagus a minimum altitude of 700 metres, in the area south of the Tagus a minimum altitude of 800 metres; or  where slope is concerned a slope of greater than 25 %; whereas where there is a combination of the factors altitude and slope, mountain areas within the meaning of Article 3 (3) of Directive 75/268/EEC may be defined by: between 400 and 700 metres  altitude and a slope of at least 20 % in the area north of the Tagus, and by between 600 and 800 metres of altitude with a slope of at least 15 % in the area south of the Tagus;  Whereas the presence of infertile land as referred to in Article 3 (4) (a) of Directive 75/268/EEC has been characterized by the existence of soil with accentuated limitations occupying at least 50 % of the utilized agricultural area of the Concelho;  Whereas the economic results of farming appreciably lower than the mean, as referred to in Article 3 (4) (b) of Directive 75/268/EEC are calculated using indices relating to a livestock density below 0,2 livestock unit per hectare forage area in the  Concelho or in the region;  Whereas the following indices have been utilized in respect of low or dwindling population as predominantly dependent on agricultural activity within the meaning of Article 3 (4) (c) of Directive 75/268/EEC: population density of less than 56 persons  per square kilometre (national average 111) or an annual regression in the population of more than 0,5 %, and at least 30 % of the working population engaged in agriculture;  Whereas, concerning the delimitation of areas affected by specific handicaps which can be considered as less-favoured areas within the meaning of Article 3 (5) of Directive 75/268/EEC, the following criteria have been used: isolation giving rise to  heavy transport costs both from the mainland and between individual islands and lack of unity in the small local markets; in the Azores more than 50 % of the islands above 300 metres, and fragmented relief, strong winds, high humidity but lack of water  retention; in Porto Santo, soil salinity, very low rainfall (less than 380 mm per year), lack of water reserves which together with the broken relief leads to soil erosion problems; on the mainland calcareous soils associated with very rocky outcrops;  whereas moreover their combined area does not exceed 4,0 % of the area of this Member State (3,91 %);  Whereas the nature and level of the abovementioned indices used by the Government of the Portuguese Republic to define the three types of areas communicated to the Commission correspond respectively to the characteristics of the mountain areas, the  less-favoured areas and the areas affected by specific handicaps referred to in Article 3 (3), (4) and (5) of Directive 75/268/EEC;  Whereas the Government of the Portuguese Republic has provided information on the public infrastructure available in these areas; whereas in general this infrastructure is deficient; whereas the Community is helping to tackle the priority problems under  Regulation (EEC) No 3828/85 of 20 December 1985 on a specific programme for the development of Portuguese agriculture (4) and it therefore seems expedient to include the areas in question in the Community list of less-favoured farming areas,  HAS ADOPTED THIS DIRECTIVE:   Article 1  The areas of Portugal listed in the Annex hereto shall be included in the Community list of less-favoured agricultural areas within the meaning of Article 3 (3), (4) and (5) of Directive 75/268/EEC.   Article 2  This Directive is addressed to the Portuguese Republic.  Done at Brussels, 14 July 1986.  For the Council The President M. JOPLING (1)OJ No L 128, 19.5.1975, p. 1.(2)OJ No L 93, 30.3.1985, p. 1.(3)OJ No C 176, 14.7.1986.(4)OJ No L 372, 31.12.1985, p. 5.  P ANEXO - BILAG - ANHANG - APAPTHMA - ANNEX - ANNEXE - ALLEGATO - BIJLAGE - ANEXO    I. ZONAS DESFAVORECIDAS, NA ACEPÇAO DO No3DO ARTIGO 3o DA DIRECTIVA 75/268/CEE  "" ASSV="10" ID="1">Viana do Castelo> ID="2">Melgaço> ID="3">-"> ID="2">Monçao> ID="3">-"> ID="2">Valença> ID="3">-"> ID="2">Vila Nova de Cerveira> ID="3">-">  ID="2">Paredes de Coura> ID="3">-"> ID="2">Ponte de Lima> ID="3">-"> ID="2">Ponte da Barca> ID="3">-"> ID="2">Arcos de Valdevez> ID="3">-"> ID="2">Caminha> ID="3">-"> ID="2">Viana do Castelo> ID="3">-"> ASSV="8" ID="1">Braga> ID="2">Amares>  ID="3">-"> ID="2">Cabeceiras de Basto> ID="3">-"> ID="2">Celorico de Basto> ID="3">-"> ID="2">Fafe> ID="3">-"> ID="2">Póvoa de Lanhoso> ID="3">-"> ID="2">Terras do Bouro> ID="3">-"> ID="2">Vieira do Minho> ID="3">-"> ID="2">Vila Verde>  ID="3">-"> ASSV="12" ID="1">Bragança> ID="2">Alfândega da Fé> ID="3">-"> ID="2">Bragança> ID="3">-"> ID="2">Carrazeda de Ansiaes> ID="3">-"> ID="2">Freixo de Espada à Cinta> ID="3">-"> ID="2">Macedo de Cavaleiros> ID="3">-"> ID="2">Miranda do  Douro> ID="3">-"> ID="2">Mirandela> ID="3">-"> ID="2">Mogadouro> ID="3">-"> ID="2">Torre de Moncorvo> ID="3">-"> ID="2">Vila Flor> ID="3">-"> ID="2">Vimioso> ID="3">-"> ID="2">Vinhais> ID="3">-"> ASSV="14" ID="1">Vila Real> ID="2">Alijó>  ID="3">-"> ID="2">Boticas> ID="3">-"> ID="2">Chaves> ID="3">-"> ID="2">Mesao Frio> ID="3">-"> ID="2">Mondim de Basto> ID="3">-"> ID="2">Montalegre> ID="3">-"> ID="2">Murça> ID="3">-"> ID="2">Peso da Régua> ID="3">-"> ID="2">Ribeira de Pena>  ID="3">-"> ID="2">Sabrosa> ID="3">-"> ID="2">Santa Marta de Penaguiao> ID="3">-"> ID="2">Valpaços> ID="3">-"> ID="2">Vila Pouca de Aguiar> ID="3">-"> ID="2">Vila Real> ID="3">-"> ASSV="8" ID="1">Porto> ID="2">Amarante> ID="3">-"> ID="2">Baiao>  ID="3">-"> ID="2">Paredes> ID="3">-"> ID="2">Marco de Canaveses> ID="3">-"> ID="2">Gondomar> ID="3">Covelo Foz do Sousa Medas Melres Lomba"> ID="2">Valongo> ID="3">-"> ID="2">Penafiel> ID="3">Canelas Capela Luzim Abragao Castelões Sao Mamede de Recezinhos Sao Martinho de Recezinhos Sebolido Vila Cova"> ID="2">Felgueiras> ID="3">Friande Jugueiros Pinheiro Santao Sendim Vila Verde"> ASSV="8" ID="1">Aveiro> ID="2">Arouca> ID="3">-"> ID="2">Castelo de Paiva> ID="3">-"> ID="2">Vale de Cambra> ID="3">-"> ID="2">Sever do Vouga> ID="3">-"> ID="2">Águeda> ID="3">Agadao Belazaima do Chao Castanheira do Vouga Macieira de Alcoba Macinhata do Vouga Préstimo"> ID="2">Albergaria-a-Velha> ID="3">Ribeira de Fráguas Valmaior"> ID="2">Feira> ID="3">Canedo Romariz Louredo Vale"> ID="2">Oliveira de Azeméis> ID="3">César Carregosa Fajões Macinhata de Seixa Nogueira do Cravo Ossela Palmaz Pindelo Travanca Vila Cha de S. Roque"> ASSV="8" ID="1">Coimbra> ID="2">Arganil> ID="3">-"> ID="2">Góis> ID="3">-"> ID="2">Lousa> ID="3">-"> ID="2">Miranda do Corvo> ID="3">-"> ID="2">Pampilhosa da Serra> ID="3">-"> ID="2">Penacova> ID="3">-"> ID="2">Penela>  ID="3">Cumeeira Espinhal Santa Eufémia"> ID="2">Vila Nova de Poiares> ID="3">-"> ASSV="14" ID="1">Guarda> ID="2">Aguiar da Beira> ID="3">-"> ID="2">Almeida> ID="3">-"> ID="2">Celorico da Beira> ID="3">-"> ID="2">Figueira de Castelo Rodrigo> ID="3">-"> ID="2">Fornos de  Algodres> ID="3">-"> ID="2">Gouveia> ID="3">-"> ID="2">Guarda> ID="3">-"> ID="2">Manteigas> ID="3">-"> ID="2">Meda> ID="3">-"> ID="2">Pinhel> ID="3">-"> ID="2">Sabugal> ID="3">-"> ID="2">Seia> ID="3">-"> ID="2">Trancoso> ID="3">-"> ID="2">Vila  Nova de Foz Côa> ID="3">-"> ASSV="20" ID="1">Viseu> ID="2">Armamar> ID="3">-"> ID="2">Castro Daire> ID="3">-"> ID="2">Cinfaes> ID="3">-"> ID="2">Lamego> ID="3">-"> ID="2">Mangualde> ID="3">-"> ID="2">Moimenta da Beira> ID="3">-"> ID="2">Mortágua>  ID="3">-"> ID="2">Oliveira de Frades> ID="3">-"> ID="2">Penalva do Castelo> ID="3">-"> ID="2">Penedono> ID="3">-"> ID="2">Resende> ID="3">-"> ID="2">Sao Joao da Pesqueira> ID="3">-"> ID="2">Sao Pedro do Sul> ID="3">-"> ID="2">Sátao> ID="3">-">  ID="2">Sernancelhe> ID="3">-"> ID="2">Tabuaço> ID="3">-"> ID="2">Tarouca> ID="3">-"> ID="2">Vila Nova de Paiva> ID="3">-"> ID="2">Viseu> ID="3">-"> ID="2">Vouzela> ID="3">-"> ASSV="7" ID="1">Castelo Branco> ID="2">Covilha> ID="3">-">  ID="2">Fundao> ID="3">-"> ID="2">Proença-a-Nova> ID="3">-"> ID="2">Oleiros> ID="3">-"> ID="2">Serta> ID="3">-"> ID="2">Vila do Rei> ID="3">-"> ID="2">Vila Velha de Ródao> ID="3">-"> ASSV="5" ID="1">Leiria> ID="2">Alvaiázere> ID="3">Almoster Maças de Caminho Maças de D. Maria Pussos Rego da Murta"> ID="2">Ansiao> ID="3">Avelar"> ID="2">Castanheira de Pêra> ID="3">-"> ID="2">Figueiró dos Vinhos> ID="3">-"> ID="2">Pedrógao Grande> ID="3">-"> ASSV="2" ID="1">Santarém> ID="2">Maçao> ID="3">-"> ID="2">Tomar> ID="3">Alviobeira Beselga Carregueiros Junceira Olalhas Serra"> ASSV="3" ID="1">Beja> ID="2">Almodôvar> ID="3">Santa Clara-a-Nova Sao Barnabé"> ID="2">Odemira> ID="3">Santa Maria Relíquias Sabóia Santa Clara-a-Velha Sao Martinho das Amoreiras"> ID="2">Ourique> ID="3">Santa Luzia Santana da Serra"> ASSV="12" ID="1">Faro> ID="2">Alcoutim> ID="3">-"> ID="2">Aljezur> ID="3">-"> ID="2">Castro Marim> ID="3">-"> ID="2">Monchique> ID="3">-"> ID="2">Alportel> ID="3">-"> ID="2">Faro> ID="3">Estói Santa Bárbara de Nexe"> ID="2">Lagos> ID="3">Bensafrim Barao de Sao Joao"> ID="2">Loulé> ID="3">Alte Ameixial Boliqueime Sao Sebastiao Sao Clemente Querença Salir"> ID="2">Portimao> ID="3">Mexilhoeira Grande"> ID="2">Silves> ID="3">Sao Bartolomeu de Messines Sao Marcos da Serra Silves"> ID="2">Tavira> ID="3">Cachopo Santa Catarina da Fonte do Bispo Santa Maria"> ID="2">Vila do Bispo> ID="3">Vila do Bispo">  REGIÕES AUTONOMAS Madeira - Ilha da Madeira    II. ZONAS DESFAVORECIDAS, NA ACEPÇAO DO No4DO ARTIGO 3oDA DIRECTIVA 75/268/CEE  "" ASSV="2" ID="1">Coimbra> ID="2">Oliveira do Hospital> ID="3">-"> ID="2">Tábua> ID="3">-"> ASSV="4" ID="1">Viseu> ID="2">Tondela> ID="3">-"> ID="2">Carregal do Sal>  ID="3">-"> ID="2">Santa Comba Dao> ID="3">-"> ID="2">Nelas> ID="3">-"> ASSV="4" ID="1">Castelo Branco> ID="2">Belmonte> ID="3">-"> ID="2">Castelo Branco> ID="3">-"> ID="2">Idanha-a-Nova> ID="3">-"> ID="2">Penamacor> ID="3">-"> ASSV="6"  ID="1">Santarém> ID="2">Abrantes> ID="3">-"> ID="2">Chamusca> ID="3">-"> ID="2">Constância> ID="3">-"> ID="2">Coruche> ID="3">Couço Sao José de Lamarosa"> ID="2">Sardoal> ID="3">-"> ID="2">Ferreira do Zêzere> ID="3">Águas Belas Beco Dormes Ferreira do Zêzere Igreja Nova do Sobral Pias Paio Mendes"> ASSV="15" ID="1">Portalegre> ID="2">Alter do Chao> ID="3">-"> ID="2">Arronches> ID="3">-"> ID="2">Avis> ID="3">-"> ID="2">Campo Maior> ID="3">-"> ID="2">Castelo de Vide> ID="3">-"> ID="2">Crato> ID="3">-"> ID="2">Elvas> ID="3">-">  ID="2">Fronteira> ID="3">-"> ID="2">Gaviao> ID="3">-"> ID="2">Marvao> ID="3">-"> ID="2">Monforte> ID="3">-"> ID="2">Nisa> ID="3">-"> ID="2">Ponte de Sor> ID="3">-"> ID="2">Portalegre> ID="3">-"> ID="2">Sousel> ID="3">-"> ASSV="14" ID="1">Évora>  ID="2">Alandroal> ID="3">-"> ID="2">Arraiolos> ID="3">-"> ID="2">Borba> ID="3">-"> ID="2">Estremoz> ID="3">-"> ID="2">Évora> ID="3">-"> ID="2">Montemor-o-Novo> ID="3">-"> ID="2">Mora> ID="3">-"> ID="2">Mourao> ID="3">-"> ID="2">Portel>  ID="3">-"> ID="2">Redondo> ID="3">-"> ID="2">Reguengos de Monsaraz> ID="3">-"> ID="2">Vendas Novas> ID="3">-"> ID="2">Viana do Alentejo> ID="3">-"> ID="2">Vila Viçosa> ID="3">-"> ASSV="6" ID="1">Setúbal> ID="2">Alcácer do Sal> ID="3">-">  ID="2">Grândola> ID="3">-"> ID="2">Montijo> ID="3">Canha Santo Isidro de Pegões"> ID="2">Palmela> ID="3">Marateca"> ID="2">Santiago de Cacém> ID="3">-"> ID="2">Sines> ID="3">-"> ASSV="14" ID="1">Beja> ID="2">Aljustrel> ID="3">-"> ID="2">Almodôvar> ID="3">Gomes Aires Almodôvar Rosário Santa Cruz Senhora da Graça de Padrões"> ID="2">Alvito> ID="3">-"> ID="2">Barrancos> ID="3">-"> ID="2">Beja> ID="3">-"> ID="2">Castro Verde> ID="3">-"> ID="2">Cuba> ID="3">-"> ID="2">Ferreira do Alentejo> ID="3">-"> ID="2">Mértola> ID="3">-"> ID="2">Moura>  ID="3">-"> ID="2">Odemira> ID="3">Colos Odemira Sao Salvador Sao Luís Sao Teotónio Vale de Santiago Vila Nova de Milfontes"> ID="2">Ourique> ID="3">Conceiçao Garvao Ourique Panóias"> ID="2">Serpa> ID="3">-"> ID="2">Vidigueira> ID="3">-"> ID="1">Faro> ID="2">Vila do Bispo> ID="3">Barao de Sao Miguel Budens Raposeira Sagres">   III. ZONAS DESFAVORECIDAS, NA ACEPÇAO DO No5DO ARTIGO 3°DA DIRECTIVA 75/268/CEE  "" ASSV="3" ID="1">Coimbra> ID="2">Condeixa-a-Nova> ID="3">Bem da Fé Condeixa-a-Velha Furadouro Vila Seca Zambujal"> ID="2">Penela> ID="3">Sao Miguel Podentes Rabaçal"> ID="2">Soure> ID="3">Degracias Pombalinho Tapéus"> ASSV="7" ID="1">Leiria> ID="2">Alcobaça> ID="3">Prazeres de Aljubarrota Sao Vicente de Aljubarrota"> ID="2">Alvaiázere> ID="3">Alvaiázere Pelma"> ID="2">Ansiao> ID="3">Alvorge Ansiao Chao de Couce Lagarteira Pousaflores Santiago da Guarda Torre de Vale de Todos"> ID="2">Batalha> ID="3">Reguengo do Fetal Sao Mamede"> ID="2">Leiria> ID="3">Arrabal Santa Catarina da Serra"> ID="2">Pombal> ID="3">Vila Cha Sao Simao de Litém Santiago de Litém Abiul Redinha"> ID="2">Porto de Mós> ID="3">-"> ASSV="6" ID="1">Santarém> ID="2">Alcanena> ID="3">Serra de Santo António"> ID="2">Ferreira do Zêzere> ID="3">Chaos Areias"> ID="2">Rio Maior> ID="3">Alcobertas"> ID="2">Tomar> ID="3">Casais Pedreira Sabacheira"> ID="2">Torres Novas> ID="3">Assentiz Chancelaria Pedrógao"> ID="2">Vila Nova de Ourém> ID="3">Atouguia Fátima Vila Nova de Ourém Alburitel Gondemaria">  REGIÕES AUTONOMAS AÇORES Madeira - Ilha de Porto Santo


title: Commission Directive 2009/90/EC of 31 July 2009 laying down, pursuant to Directive 2000/60/EC of the European Parliament and of the Council, technical specifications for chemical analysis and monitoring of water status (Text with EEA relevance)

text:
               1.8.2009

               EN

               Official Journal of the European Union

               L 201/36

      COMMISSION DIRECTIVE 2009/90/EC
   of 31 July 2009
   laying down, pursuant to Directive 2000/60/EC of the European Parliament and of the Council, technical specifications for chemical analysis and monitoring of water status
   (Text with EEA relevance)
   THE COMMISSION OF THE EUROPEAN COMMUNITIES,
   Having regard to the Treaty establishing the European Community,
   Having regard to Directive 2000/60/EC of the European Parliament and of the Council of 23 October 2000 establishing a framework for Community action in the field of water policy (1), and in particular Article 8(3) thereof,
   Whereas:

               (1)

               The quality and comparability of analytical results generated by laboratories appointed by competent authorities of the Member States to perform water chemical monitoring pursuant to Article 8 of Directive 2000/60/EC should be ensured. The EN ISO/IEC-17025 standard on general requirements for the competence of testing and calibration laboratories provides appropriate international standards for the validation of the methods of analysis used.

               (2)

               In order to fulfil validation requirements, all methods of analysis applied by Member States for the purposes of chemical monitoring programmes of water status should meet certain minimum performance criteria, including rules on the uncertainty of measurements and on the limit of quantification of the methods. To ensure comparability of chemical monitoring results, the limit of quantification should be determined in accordance with a commonly agreed definition.

               (3)

               Where there are no methods which comply with the minimum performance criteria, monitoring should be based on best available techniques not entailing excessive costs.

               (4)

               The calculation of mean values should take account of measurement results that are below the limit of quantification of methods of analysis. Rules to be used in this respect should be provided.

               (5)

               Technical operations to ensure the quality and comparability of analytical results should follow quality management system practices accepted at international level. For that purpose, the practices set out in EN ISO/IEC-17025 are appropriate. It is appropriate to ensure that laboratories performing chemical analysis demonstrate their competence through the participation in internationally or nationally recognised proficiency testing programmes and through the use of available reference materials. In view of harmonising practices at the Community level, the organisation of proficiency testing programmes should be based on relevant international standards. To that end, ISO/IEC guide 43-1 on proficiency testing by interlaboratory comparisons — Part 1: Development and operation of proficiency testing schemes provides an appropriate guide. The results of those programmes should be evaluated on the basis of the internationally recognised scoring systems. In this regard, ISO-13528 on statistical methods for use in proficiency testing by interlaboratory comparisons provides appropriate standards.

               (6)

               The Committee referred to in Article 21(1) of Directive 2000/60/EC was consulted on 15 May 2008 and delivered a positive opinion on the draft Commission Directive laying down, pursuant to Directive 2000/60/EC, technical specifications for chemical analysis and monitoring of water status. On 6 June 2008 the Commission submitted the said draft for scrutiny by the European Parliament and the Council. The European Parliament did not oppose the draft measures within the set deadline. The Council opposed the adoption by the Commission indicating that the proposed measures exceeded the implementing powers provided for in Directive 2000/60/EC. As a consequence, the Commission did not adopt the draft measures and submitted an amended draft of the concerned Directive to the Committee referred to in Article 21(1) of Directive 2000/60/EC. The Committee was consulted on the said draft by written procedure launched on 28 January 2009 and delivered a positive opinion.

               (7)

               The measures provided for in this Directive are in accordance with the opinion of the Committee referred to in Article 21(1) of Directive 2000/60/EC,

         HAS ADOPTED THIS DIRECTIVE:
   Article 1
   Subject matter
   This Directive lays down technical specifications for chemical analysis and monitoring of water status in accordance with Article 8(3) of Directive 2000/60/EC. It establishes minimum performance criteria for methods of analysis to be applied by Member States when monitoring water status, sediment and biota, as well as rules for demonstrating the quality of analytical results.
   Article 2
   Definitions
   For the purpose of this Directive, the following definitions shall apply:

               1.

               ‘limit of detection’ means the output signal or concentration value above which it can be affirmed, with a stated level of confidence that a sample is different from a blank sample containing no determinand of interest;

               2.

               ‘limit of quantification’ means a stated multiple of the limit of detection at a concentration of the determinand that can reasonably be determined with an acceptable level of accuracy and precision. The limit of quantification can be calculated using an appropriate standard or sample, and may be obtained from the lowest calibration point on the calibration curve, excluding the blank;

               3.

               ‘uncertainty of measurement’ means a non-negative parameter characterizing the dispersion of the quantity values being attributed to a measurand, based on the information used.

         Article 3
   Methods of analysis
   Member States shall ensure that all methods of analysis, including laboratory, field and on-line methods, used for the purposes of chemical monitoring programmes carried out under Directive 2000/60/EC are validated and documented in accordance with EN ISO/IEC-17025 standard or other equivalent standards accepted at international level.
   Article 4
   Minimum performance criteria for methods of analysis
   1.   Member States shall ensure that the minimum performance criteria for all methods of analysis applied are based on an uncertainty of measurement of 50 % or below (k = 2) estimated at the level of relevant environmental quality standards and a limit of quantification equal or below a value of 30 % of the relevant environmental quality standards.
   2.   In the absence of relevant environmental quality standard for a given parameter, or in the absence of method of analysis meeting the minimum performance criteria set out in paragraph 1, Member States shall ensure that monitoring is carried out using best available techniques not entailing excessive costs.
   Article 5
   Calculation of mean values
   1.   Where the amounts of physico-chemical or chemical measurands in a given sample are below the limit of quantification, the measurement results shall be set to half of the value of the limit of quantification concerned for the calculation of mean values.
   2.   Where a calculated mean value of the measurement results referred to paragraph 1 is below the limits of quantification, the value shall be referred to as ‘less than limit of quantification’.
   3.   Paragraph 1 shall not apply to measurands that are total sums of a given group of physico-chemical parameters or chemical measurands, including their relevant metabolites, degradation and reaction products. In those cases, results below the limit of quantification of the individual substances shall be set to zero.
   Article 6
   Quality assurance and control
   1.   Member States shall ensure that laboratories or parties contracted by laboratories apply quality management system practices in accordance with EN ISO/IEC-17025 or other equivalent standards accepted at international level.
   2.   Member States shall ensure that laboratories or parties contracted by laboratories demonstrate their competences in analysing relevant physico-chemical or chemical measurands by:

               (a)

               participation in proficiency testing programmes covering the methods of analysis referred to in Article 3 of this Directive of measurands at levels of concentrations that are representative of chemical monitoring programmes carried out under Directive 2000/60/EC, and

               (b)

               analysis of available reference materials that are representative of collected samples which contain appropriate levels of concentrations in relation to relevant environmental quality standards referred to in Article 4(1).

         3.   The proficiency testing programmes referred to in paragraph 2(a) shall be organised by accredited organisations or internationally or nationally recognised organisations which meet the requirements of ISO/IEC guide 43-1 or of other equivalent standards accepted at international level.
   The results of participation in those programmes shall be evaluated on the basis of the scoring systems set out in ISO/IEC guide 43-1 or in the ISO-13528 standard or in other equivalent standards accepted at international level.
   Article 7
   Transposition
   1.   Member States shall bring into force the laws, regulations and administrative provisions necessary to comply with this Directive at the latest two years after its entry into force. They shall forthwith communicate to the Commission the text of those provisions.
   When Member States adopt those provisions, they shall contain a reference to this Directive or be accompanied by such a reference on the occasion of their official publication. Member States shall determine how such reference is to be made.
   2.   Member States shall communicate to the Commission the text of the main provisions of national law which they adopt in the field covered by this Directive.
   Article 8
   Entry into force
   This Directive shall enter into force on the 20th day following its publication in the Official Journal of the European Union.
   Article 9
   Addressees
   This Directive is addressed to the Member States.

      Done at Brussels, 31 July 2009.

            For the Commission

         Stavros DIMAS

            Member of the Commission

      (1)  OJ L 327, 22.12.2000, p. 1.


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Council Directive 87/153/EEC of 16 February 1987 fixing guidelines for the assessment of additives in animal nutrition

Official Journal L 064 , 07/03/1987 P. 0019 - 0028 Finnish special edition: Chapter 3 Volume 22 P. 0226  Swedish special edition: Chapter 3 Volume 22 P. 0226

*****COUNCIL  DIRECTIVE  of 16 February 1987  fixing guidelines for the assessment of additives in animal nutrition  (87/153/EEC)  THE COUNCIL OF THE EUROPEAN COMMUNITIES,  Having regard to the Treaty establishing the European Economic Community,  Having regard to Council Directive 70/524/EEC of 23 November 1970 concerning additives in feedingstuffs (1), as last amended by Commission Directive 86/525/EEC (2), and in particular Article 9 thereof,  Having regard to the proposal from the Commission,  Whereas Directive 70/524/EEC provides that the examination of additives must be performed on the basis of a dossier forwarded officially to the Member States and to the Commission;  Whereas such dossiers must make it possible to verify that additives comply, in respect of their proposed use, with the general principles laid down in the Directive for their inclusion in the Annexes thereto;  Whereas it has been found necessary to provide for the dossiers to be compiled in accordance with common guidelines defining the scientific data which make it possible to identify and characterize the products concerned and the studies necessary in order to evaluate, in particular, their efficacy and their safety for man, animals and the environment;  Whereas the guidelines are intended primarily as a general guide; whereas, depending on the nature of the additive or its conditions of use, the extent of the studies necessary in order to evaluate its properties or its effects may vary;  Whereas it is indispensable to apply the principles of good laboratory practice when developing additives intended for use in feedingstuffs to ensure that the results of laboratory tests are not disputed; whereas recourse to procedures involving the use of laboratory animals for experimental or other scientific purposes should be kept to a minimum;  Whereas the guidelines have been drawn up on the basis of present scientific and technical knowledge and they may be adapted if necessary to any developments in this sphere,  HAS ADOPTED THIS DIRECTIVE:  Article 1  Member States shall prescribe that the dossiers which must accompany every request for the inclusion of an additive or a new use of an additive in the Annexes to Directive 70/524/EEC are to be compiled in accordance with the guidelines set out in the Annex to this Directive.  Article 2  This Directive shall apply without prejudice to provisions on:  (a) good laboratory practice for the purposes of mutual acceptance of data for the evaluation of chemical products; and  (b) the protection of animals used for experimental or other scientific purposes.  Article 3  Member States shall bring into force the laws, regulations or administrative provisions necessary in order to comply with this Directive by 31 December 1987 at the latest. They shall forthwith inform the Commission thereof.  Article 4  This Directive is addressed to the Member States.  Done at Brussels, 16 February 1987.  For the Council  The President  L. TINDEMANS  (1) OJ No L 270, 14. 12. 1970, p. 1.  (2) OJ No L 310, 5. 11. 1986, p. 19.  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 Council Directive 70/524/EEC of 23 November 1970 concerning additives in feedingstuffs (1).  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. 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 will not always be necessary to subject additives intended exclusively for pet food to as exhaustive a programme of chronic toxicity, mutagenicity and carcinogenicity testing as that required for additives intended for feeding to livestock from which are derived produce for human consumption. 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 food producing stock, of the residues and their bioavailability 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 do 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 and reference number 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. A statement from the person responsible for good laboratory practice regarding observance of such practice is to be attached to the reports.  The determination of physico-chemical, toxicological and ecotoxicological properties shall be performed in accordance with the methods established by Commission Directive 84/449/EEC of 25 April 1984 adapting to technical progress for the sixth time 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), 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 and growth promoters 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.  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 micro-organisms, the genetic characteristics of which have been modified or which arise as natural mutants.  (1) OJ No L 270, 14. 12. 1970, p. 1 and  OJ No L 319, 8. 12. 1984, p. 13.  (2) OJ No L 251, 19. 9. 1984, p. 1.  CONTENTS  1.2 // 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 effectiveness of the additive   //  // 1. Studies concerning improvements in the quality of feedingstuffs   //   // 2. Studies concerning the effects of additives on animal produce   //   // 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 of the active substance   //   // 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 THE USE OF THE ADDITIVE METHODS OF CONTROL  1. Identity of the additive  1.1. Proposed proprietary names.  1.2. Type of additive according to its main function (e.g. antibiotic, coccidiostat, histomonostat, preservative, etc.).  1.3. Physical state, particle size.  1.4. Qualitative and quantitative composition (active substance, other components, impurities).  1.5. Manufacturing process including any specific processing procedures.  2. Specifications concerning the active substance  2.1. Generic name, chemical name according to IUPAC nomenclature, other generic names and abbreviations. Chemical Abstracts Service Number (CAS).  2.2. Formula, empirical and structural, and molecular weight. If the active substance is a fermentation product, qualitative and quantitative composition of the main components.  2.3. Degree of purity. Qualitative and quantitative composition of the impurities.  2.4. Electrostatic properties, melting point, boiling point, decomposition temperature, density, vapour pressure, solubility in water and organic solvents, mass and absorption spectre and any other appropriate physical properties.  2.5. Manufacturing and purification processes. Variation in the composition of the batches in the course of production.  NB: If the active substance is a mixture of active components, each chemically definable, main component must be described separately and the proportions of the mixture given.  3. Physico-chemical and technological properties of the additive  3.1. Stability on exposure to atmospheric agents (light, temperature, moisture, oxygen, etc.).  3.2. Stability during the preparation of premixtures and feedingstuffs, in particular, stability to heat, pressure and moisture. Possible decomposition products.  3.3. Stability during the storage of premixtures and feedingstuffs (storage time).  3.4. Other appropriate physico-chemical and technological properties such as ability to obtain homogeneous mixtures in premixtures and feedingstuffs, dust-forming properties.  3.5. Physico-chemical interactions (incompatibility with feedingstuffs, other additives or with medicinal products, etc.).  4. Conditions of use of the additive  4.1. Proposed use in animal nutrition (species or category of animal, category of feedingstuff, period of administration, withdrawal period, etc.).  4.2. Contra-indications.  4.3. Proposed concentrations in premixtures and feedingstuffs (expressed as a percentage of the active substance by weight for premixtures; as mg/kg for feedingstuffs).  4.4. Other known uses of the active substance or the preparation (in foodstuffs, human or veterinary medicine, agriculture, etc.). 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 1.4, 2.3, 2.4, 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.  NB: The methods specified should be accompanied by information as to percentage recovery, specificity, sensitivity, possible interferences, limits of detection, reproducibility and to the sampling method used. Reference standards of the preparation and of the active substance must be available.  SECTION III  STUDIES CONCERNING THE EFFECTIVENESS OF THE ADDITIVE  1. Studies concerning improvements in the quality of feedingstuffs  These studies concern technological additives such antioxidants, preservatives, emulsifiers, gelling agents, etc., which are intended to improve the quality of premixtures and feedingstuffs or to prolong their preservation time.  Evidence of the effectiveness of the additive should be shown 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 substance in premixtures and feedingstuffs, the testing conditions (temperature, humidity etc.) and also the dates and duration of testing, the adverse effects and further negative effects which occurred during testing shall be specified for each experiment.  2. Studies concerning the effects of additives on animal produce  These studies concern zootechnical additives such as antibiotics, growth promoters, coccidiostats and other medicinal substances, etc. which have effects on animal produce. The following studies should be performed on each target species in comparison with negative control groups and, possibly, groups receiving feedingstuffs containing additives of known effectiveness.  2.1. For antibioitcs and growth promoters, study of the effects on nutritional efficiency, growth of the animal and yield of animal paroduce. Determination of the dose/response relationship.  2.2. For coccidiostats and other medicinal substances, importance should primarily be attached to evidence of specific effects and particularly to prophylactic properties (e.g. morbidity, oocyst counts, assessment of impairment etc.). Information on the effect on feed efficiency, animal growth and amount and marketable quality of the animal produce should be attached.  2.3. Experimental conditions:  The test performed must be described individually in detail. The test record should enable statistical analyses to be made. 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 test animals of both sexes selected must be sufficient for statistical purposes.  2.3.3. Concentration of the active substance in the feedingstuffs established by a control analysis. Reference number of the batches. Nutritional composition of the daily ration in terms of quality and quantity.  2.3.4. Location of each experiment, physiological and animal health conditions, feeding and rearing conditions in accordance with standard practice in the Community.  2.3.5. Date and exact duration of testing, date of examinations performed.  2.3.6. Adverse effects and further negative effects 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 edible produce of 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 risks to the consumer which could result from the consumption of food containing residues of the additive,  - the risks from inhalation or cutaneous contact for persons likely to handle the additive as such or as incorporated into premixtures or feedingstuffs,  - the risks of pollution of the environment from products derived from the additive and excreted by animals.  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. Knowledge of the metabolism of the active substance in the various target species and also of the composition and the bioavailability 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 of the environment.  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 factor (margin between the maximum proposed dose-level and the level resulting in adverse effects). It may be sufficient to indicate a minimum or approximate value for this factor if it can be shown that the level resulting in adverse effects greatly exceeds the maximum proposed dose-level.  1.2. Microbiological investigation of the additive  1.2.1. Investigation of the microbiological 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.  1.2.2. Investigation into the cross-resistance to therapeutic antibiotics by determination of the MIC in mutants produced in vitro which exhibit chromosomal resistance to the additive.  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 normal intestinal flora and on the colonization of the intestinal tract and the execretion of pathogenic micro-organisms.  1.2.5. Field studies to determine the percentage of bacteria resistant to the additive. These are to be carried out at major intervals before and during the use of the additive (monitoring).  1.3. Studies of the metabolism and residues of the active substance (1) (2)  1.3.1. Study of metabolic balance: rate and extent of elimination of the active substance in urine and faeces and, possibly, by expiration; residues in the target species.  1.3.2. Study of metabolism: absorption, distribution, biotransformation and elimination. If appropriate, estimation of the extent of excretion through bile, existence of an enterohepatic cycle, influence of caecotrophy.  1.3.3. Analytical studies of the residues: qualitative and quantitative composition of the residues (active substance, metabolites) in the various organs and tissues of the animal and in edible produce originating from the animal, when metabolic equilibrium is reached and under practical conditions of use of the additive.  1.3.4. Pharmacokinetic study of the residues (following repeated administration of the additive according to the proposed use): persistence of the active substance and the main metabolites in the various organs and tissues after withdrawal of the supplemented feedingstuff.  1.3.5. Study of the bioavailability of the residues in tissues and produce of target species (see 3.8).  1.3.6. Methods of monitoring: qualitative and quantitative methods of determination used in the studies mentioned under items 1.3.1. to 1.3.5. 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  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 (decomposition of plant and animal residues, N transformation, etc.).  2.6. Effects on terrestrial plants (seed germination, plant growth, plant up-take etc.) 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, 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 metabolize the additive in a similar way to man.  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  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.  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  In order to identify active substances or their metabolites 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 a 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 damage 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 for 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.  3.3. Metabolic and pharmacokinetic aspects  Balance studies and identification of metabolites must be performed using suitable labelled molecules 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 in 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 dogs or other non-rodents may be desirable to establish the variation in sensitivity of different animal species to the test substance.  3.5. Chronic toxicicity/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 adminsitered 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 two years in rats and 80 weeks 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.  3.6. Reproductive toxicity  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. Bioavailability  Investigation on the fate of residues of the labelled active substance in tissue and produce of target species will require bioavailability studies including at least a balance study of the residues when adminsitered to laboratory animals.  3.8. Toxicology of metabolites  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.  3.9. Other relevant studies  Any further study providing additional information useful for the assessment of test substance may be made available, e.g. studies on relay toxicity. SECTION V  FORM OF MONOGRAPH  1. Identity of the additive  1.1. Type of additive according to its main function (antibiotic, coccidiostat, histomonostat, growth promoter, etc.).  1.2. Physical state, particle size.  1.3. Qualitative and quantitative composition (active substance, other components, impurities).  1.4. Possible specific processing.  2. Specifications concerning the active substance  2.1. Generic name, chemical name according to IUPAC nomenclature, other generic names and abbreviations. Chemical Abstracts Service Number (CAS).  2.2. Formula, empirical and structural, and molecular weight. If the active substance is a fermentation product, qualitative and quantitative composition of the main components.  2.3. Degree of purity. Qualitative and quantitative composition of the impurities.  2.4. Appropriate physical properties such as electrostatic properties, melting point, boiling point, decomposition temperature, density, vapour pressure, solubility in water and organic solvents, absorption spectrum, etc.  NB: If the active substance is a mixture of active components, each chemically definable main component must be described separately and the proportions of the mixture be given.  3. Physico-chemical and technological properties of the additive  3.1. Stability on exposure to atmospheric agents (e.g. light, temperature, moisture, oxygen).  3.2. Stability during the preparation of premixtures and feedingstuffs, in particular, on exposure to heat, pressure and moisture. Possible decomposition products.  3.3. Stability during the storage of premixtures and feedingstuffs (storage time).  3.4. Other appropriate physico-chemical and technological properties such as ability to obtain homogeneous mixtures in premixtures and feedingstuffs, dust-forming properties.  3.5. Physico-chemical interactions (incompatibility with feedingstuffs, other additives or with medicinal products, etc).  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, literature references may suffice.  5. Biological properties of the additive  5.1. Particulars of the prophylactic effects for coccidiostats and other medicinal substances (morbidity, oocyst count, etc.).  5.2. Particulars of the effects on the feed efficiency, growth and quality of animal products for antibiotics and growth promoters.  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) The studies mentioned under 1.3.1., 1.3.2., 1.3.4. and 1.3.5. should be carried out preferably with labelled molecules. The labelling should be suitable for the purpose intended.  (2) If the active substance is a fermentation product, these studies should be extended to related substances derived from the production.


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31989L0359

Council Directive 89/359/EEC of 29 May 1989 amending Directive 77/93/EEC on protective measures against the introduction into the Member States of organisms harmful to plants or plant products

Official Journal L 153 , 06/06/1989 P. 0028 - 0028 Finnish special edition: Chapter 3 Volume 29 P. 0105  Swedish special edition: Chapter 3 Volume 29 P. 0105

*****COUNCIL  DIRECTIVE  of 29 May 1989  amending Directive 77/93/EEC on protective measures against the introduction into the Member States of organisms harmful to plants or plant products  (89/359/EEC)  THE COUNCIL OF THE EUROPEAN COMMUNITIES,  Having regard to the Treaty establishing the European Economic Community, and in particular Article 43 thereof,  Having regard to the proposal from the Commission (1),  Having regard to the opinion of the European Parliament (2),  Whereas by Directive 77/93/EEC (3), as last amended by Directive 88/572/EEC (4), the Council laid down protective measures against the introduction into the Member States of organisms harmful to plants or plant products; whereas the protection of plants against such organisms is absolutely necessary to increase agricultural productivity, which is one of the objectives of the common agricultural policy;  Whereas seeds are not included amongst the plants, plant products and other objects, listed in Annex V to Directive 77/93/EEC, which must be subjected to a plant health inspection in the country of origin or the consignor country before being permitted to enter any of the Member States;  Whereas, however, in the case of seeds, the measures to ensure compliance with the requirement that they be officially examined in order to make sure that they comply with the relevant special requirements listed in Annex IV, part A to the said Directive are to determined at Community level;  Whereas, since the adoption of Directive 77/93/EEC, special requirements relating to the importation of certain seeds into certain Member States have been included in the said Directive by amendment to Annex IV, Part B; whereas Member States are required by Article 6 (2) to lay down inspection measures in order to ensure compliance with the requirements set out in the Annexes to the said Directive; whereas the measures to ensure compliance with the requirements relating to the introduction of seeds into the Member States set out in Part B as well as those set out in Part A of Annex IV should be determined at Community level;  Whereas the period specified for the determination of the necessary measures at Community level has not been sufficient and should therefore be extended,  HAS ADOPTED THIS DIRECTIVE:  Article 1  In Article 7 (3) of Directive 77/93/EEC:  - 'Article 6 (3)' is replaced by 'Article 6 (2), in so far as seeds referred to in Annex IV, Part B are concerned and Article 6 (3)', and  - '31 December 1986' is replaced by '31 December 1991'.  Article 2  This Directive is addressed to the Member States.  Done at Brussels, 29 May 1989.  For the Council  The President  C. ROMERO HERRERA  (1) OJ No C 254, 30. 9. 1988, p. 4.  (2) OJ No C 326, 19. 12. 1988, p. 288.  (3) OJ No L 26, 31. 1. 1977, p. 20.  (4) OJ No L 313, 19. 11. 1988, p. 39.