The European Agency for the Evaluation of Medicinal Products Veterinary Medicines Evaluation Unit EMEA/CVMP/055/96-FINAL COMMITTEE FOR VETERINARY MEDICINAL PRODUCTS NOTE FOR GUIDANCE: ENVIRONMENTAL RISK ASSESSMENT FOR VETERINARY MEDICINAL PRODUCTS OTHER THAN GMO-CONTAINING AND IMMUNOLOGICAL PRODUCTS FINAL APPROVAL BY THE CVMP 14-16 January 1997 DATE FOR COMING INTO OPERATION1 1 January 1998 SUPERSEDED 1 Applications for new active substances will have to comply with this Note for Guidance as from 01.01.98 onwards. However, companies are advised to take this Note for Guidance into consideration as of its date of approval when planning and preparing their Environmental Risk Assessment. 7 Westferry Circus, Canary Wharf, London E14 4HB, UK Switchboard: (+44-171) 418 8400 Fax: (+44-171) 418 8447 E_Mail: [email protected] http://www.eudra.org/w3/emea.html NOTE FOR GUIDANCE: ENVIRONMENTAL RISK ASSESSMENT FOR VETERINARY MEDICINAL PRODUCTS OTHER THAN GMO1- CONTAINING AND IMMUNOLOGICAL PRODUCTS 1. GENERAL CONSIDERATIONS 4 2. PHASE I 7 3. PHASE II 9 3.1 Tier A - explanatory notes 12 3.2. Tier B - explanatory notes 12 3.3. Tier B Fish medicines - explanatory notes 12 ANNEX I - GUIDELINES FOR TESTING OF CHEMICALS 13 ANNEX II - EXPOSURE SCENARIOS 15 1. ESTIMATION OF PEC IN SOIL FROM SPREADING DRUG RESIDUES IN SLURRY 15 1.1. Calculation of PEC in soil 15 1.2. Degradation of compound in manure during storage 15 2. ESTIMATION OF PEC IN SOIL: DISPOSAL OF DRUG RESIDUES IN DIRTY WATER 15 3. ESTIMATION OF PEC IN SOIL FROM DRUG RESIDUES EXCRETED OUTDOORS 16 4. ESTIMATION OF PEC IN WATER 17 4.1. Surface water 17 4.2. PEC in ground water 17 5. PRODUCTS WITH DIRECT ENTRY TO THE AQUATIC ENVIRONMENT 18 5.1. PEC estimate for fish medicines used in freshwater 18 5.2. PEC estimates for fish medicines used in marine situations 18 ANNEX III - PHASE II - TIER A AND TIER B 19 TIER A 19 1. TERRESTRIAL ENVIRONMENT 19 1.1. Degradation in soil (DT 50) 19 1.2. Toxicity tests 19 2. AQUATIC ENVIRONMENT 20 2.1. Estimation of PEC in surface water 20 2.2. Other exposure scenarios 20 2.3. Acute toxicity tests 20 2.4 PEC/PNEC ratio for surface water and ground water 21 3. AIR EXPOSURE 21 TIER B 22 1. SOIL FAUNA 22 1.1. Degradation in soil (DT50) and soil transformation pathway 22 1.2. Sublethal effects on earthworms 22 1.3 Field studies 23 2. SOIL MICROBIALSUPERSEDED FUNCTION 23 2.1. Degradation in soil (DT50) 23 2.2. Tests for effects on soil microflora 23 2.3. Natural fluctuations in soil microflora 24 3. PHYTOTOXICITY 24 3.1. Refinement of PEC 24 3.2. Phytotoxicity to terrestrial plants 24 3.3. Effects in the field 24 4. DUNG FAUNA 24 4.1. Estimation of PEC 25 4.2. Laboratory studies 25 4.3. Use of trigger values for field testing 26 4.4. Field studies 26 1 Genetically Modified Organisms Reference: EMEA/CVMP/055/96 17/01/97 Page 2 5. GRASSLAND INVERTEBRATES 26 5.1. Choice of test species 26 5.2. Laboratory toxicity test: susceptible stage 27 5.3. Dose-response laboratory tests using natural substrate 27 5.4. Field studies 28 6. TERRESTRIAL VERTEBRATE WILDLIFE 28 6.1. Use of available short-term toxicity data 28 6.2. Potential routes of exposure 29 6.3. Toxicity data on vertebrate wildlife 29 6.4. Additional studies to refine the assessment 30 7. AQUATIC ENVIRONMENT 30 7.1. Refinement of the PEC and identification of relevant routes of exposure 30 7.2. Assessment of relevant routes of exposure 31 7.3. Further data on toxicity to aquatic species 32 ANNEX IV - FISH MEDICINES 34 1. STUDIES TO DETERMINE PEC AND PNEC 34 1.1. Properties of the active ingredient(s) and relevant major metabolites 34 1.2. Predicted environmental concentration (PEC) 34 1.3. Acute toxicity test methods 34 1.4. Routes of environmental exposure 35 2. PEC/PNEC RATIOS 36 3. BEHAVIOUR OF SUBSTANCES IN NATURAL SEDIMENT AND WATER SYSTEMS 36 3.1 Additional toxicity studies 36 3.2 Fate in the natural environment 37 3.3 Biological effects 38 REFERENCES 39 SUPERSEDED Reference: EMEA/CVMP/055/96 17/01/97 Page 3 1. GENERAL CONSIDERATIONS Directive 81/852/EEC as amended by Directive 92/18/EEC states that the purpose of the study of environmental safety of a veterinary medicinal product is to assess the potential harmful effects which the use of the product may cause to the environment and to identify any precautionary measures which may be necessary to reduce such risks1. Such an assessment shall be included in applications for marketing authorization for veterinary medicinal products other than those submitted in accordance with Article 5, second paragraph point 10 of Directive 81/851/EEC concerning abridged applications. This assessment should normally be conducted in two phases. The first phase (Phase I) shall assess the potential of exposure of the environment to the product, its ingredients or relevant metabolites. This Note for Guidance presents, as a guide for the conduct of Phase I, a straightforward decision tree to identify products which can be exempted from further testing because they are unlikely to result in significant exposure of the environment and will consequently be of low environmental risk. In a second phase (Phase II), having regard to of the extent of exposure of the environment to the product, and the available information about the physical/chemical, pharmacological and/or toxicological properties of the product obtained during the conduct of the other tests required by Directive 81/852/EEC, the investigator shall then consider whether further specific investigation of the effects of the product on particular ecosystems is necessary. In this Note for Guidance, Phase II is divided in two parts, Tier A and Tier B. Tier A begins an evaluation of the possible fate and effects of the drug and/or its major metabolites which is more detailed than the evaluation performed in Phase I. There may further be a need for the determination of the degradation half-life of the active substance and/or the relevant metabolites in the environmental compartments of interest. If within Tier A, no hazard is detected or the risk management strategy proposed by the applicant is taking care of any potential hazard, thus avoiding harmful effects of the product on the environment, there would be no need to proceed to Tier B, which involves studies on the effects on fauna/flora within the environmental compartments that are likely to be affected. If the applicant is unable to demonstrate that exposure is minimised to a level of no concern to the environment, then the effects in the relevant compartments must be adequately investigated. However, the applicant is advised to contact the competent authorities prior to commencing any programme of testing at Tier B. Nevertheless, it is expected that for most veterinary medicinal products entering Phase II, the assessment will be completed at Tier A. For the purpose of assessing the environmental fate and effect of the product, test protocols from the following guidance documents may be used: Test protocolsSUPERSEDED listed in Annex II and III of this Note for Guidance; Test protocols listed in Annex V of Directive 67/548/EEC as amended on the approximation of the laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances; Tests protocols from OECD Guidelines on Testing of Chemicals; Testing methods and calculation models published in the Technical Guidance Documents in support of Directive 93/67/EEC on risk assessment for new notified 1 This Note only provides guidance on the assessment of potential harmful effects which the use of the product may cause to the environment. It does not impact on any precautionary measures that Competent Authorities may further require to be indicated in the SPC, the package insert and the labelling of any veterinary medicinal product to prevent exposure of the environment to unused product or waste materials, in order to comply with EU waste management legislation, including Council Directive 75/442/EEC on waste (25) and Council Directive 91/689/EEC on hazardous waste (28). Reference: EMEA/CVMP/055/96 17/01/97 Page 4 substances and Commission Regulation (EC) No 1488/94 on risk assessment for existing substances (36); The principles for evaluation of plant protection product as laid down in Annex VI to Directive 91/414/EEC concerning the placing of plant protection product on the market (29). Other tests protocols recommended by other Authorities such as the European Pharmacopeia, the US Food and Drug Administration (FDA) or the US Environment Protection Agency (EPA) may also be acceptable. The environmental risk assessment should take into consideration other possible use of the active substance contained in the product, in particular when the active substance is used as a pesticide or as an additive to animal feeding stuffs. In such cases, data available from previous evaluations may be cited in the application, including in particular the recommendations/conclusions from other relevant EU bodies (Scientific Committee for Animal Nutrition (SCAN), European Environmental Agency). Applicants are required to submit a complete report which would conclude with an environmental risk assessment (ERA) based on the characteristics of the product, its potential environmental exposure, environmental fate and effects, and risk management strategies as appropriate. The report should take into account the pattern of use and administration of the product, the excretion of active substance and major metabolites and the disposal of the product as set out in Directive 81/852/EEC. Finally, the environmental risk assessment made should be subject to an expert report.