Experience in preparation of technical dossier

1. Experience in preparation of technical dossier Maristella Rubbiani Istituto Superiore di Sanità Roma Italy TAIEX Belgrade

2. Introduction • Some info related to application • Some info related to dossier • Some info related to what’s going on TAIEX Belgrade

3. Who can apply for authorisation? • Application for authorisation shall be made by, or on behalf of, the natural person or legal entity responsible for the first placing the product on the market. TAIEX Belgrade

4. Applicant • The applicant may be either native or foreign but shall have a permanent office within the European Union, Norway or Switzerland. • If the applicant is not the manufacturer of the product or its active substance, he has to present a letter of access providing him the right to represent his principal in matters concerning the product or the active substance. TAIEX Belgrade

5. Applicant may be The future authorisation holder or • a company or person who handles practical issues of the application on behalf of future authorisation holder(s). • Authorisation holder is person/entity to whom the decision on authorisation is issued to. • Responsibility for the placing on the product on the market, classification and labelling etc. always lies on the authorisation holder. • Please note that different MS may have different interpretations on the applicant, i.e. they may require that application shall always be made by the future authorisation holder. TAIEX Belgrade

6. When to apply for authorisation? • Products already on the market: The deadline for the submission of product application can be found in the different MSs CA publication implementing the inclusion directives of active substances. • Authorisationhas to be applied for by the date of Annex I inclusion of the active substance used in the product. • Consolidated list of approved active substances by product type can be found at: http://ec.europa.eu/environment/biocides/index.htm • The inclusion directives can be found at: http://ec.europa.eu/environment/biocides/annexi_and_ia.htm TAIEX Belgrade

7. Specific issues • If a product contains more than one active substance the deadline for the product application is the one set out in the latest of the inclusion directives relating to its active substances • If a product belongs to several product types, authorisation for each product type shall be applied for separately at the deadline determined by the inclusion of the active substance. TAIEX Belgrade

8. Important ! • If no application for the authorisation of a biocidal product is submitted by the given deadline the product shall be phased out of the market in 6 months from this deadline for the application. TAIEX Belgrade

9. Phasing out • The 6month deadline for the phasing out of products not supported refers to the first placing on the market. • For subsequent storage, marketing, use and disposal of existing stocks different periods of grace applies depending on MS TAIEX Belgrade

10. Specific cases • Products that are not on the market: If you intend to start to place on the market a new biocidal product with active substance(s) which is already included in Annex I for the relevant product type there are no binding deadlines for submitting the application for authorisation. Placing the product on the market is not allowed before authorisation. • Products containing new active substances: If you intend to start to place on the market a biocidal product with a new active substance which is not yet included in Annex I procedures are according to the Art 11 of the BPD. Only after Annex I inclusion the product can be authorised. Application may be submitted at any time. Placing the product on the market is not allowed before authorisation. • Uses of active substances in product types not notified : and therefore not included in the review programme of existing active substances are treated the same way as products containing new active substances. TAIEX Belgrade

11. Before preparing application • In addition to the status of the active substances in Annex I there are a few other things to consider before preparing an application for a biocidal product: • Make sure that you consider the right product type with respect to the use purpose and pattern of your biocidal product. • Further information about scope of the BPD is compiled by the European Commission in the Manual of Decisions (MoD), http://ec.europa.eu/environment/biocides/manual.htm TAIEX Belgrade

12. ?????????? • If you have any doubts as to whether your products or active substances are biocides or to which product type they belong to take contact to the CA. TAIEX Belgrade

13. Technical equivalence • Check that the active substance of your product is technically equivalent to the one covered by the Annex I inclusion directive. • This means that the active substance has to be so similar in purity, impurities and possible isomers that the active substance evaluation for the Annex I inclusion is still applicable. TAIEX Belgrade

14. Technical equivalence • In case of similarity, an access to the data package used for the inclusion of the active substance or equivalent data is needed. • If the active substance is not considered equivalent corresponding data on the active substance as submitted for the Annex I active substance is needed. • The CA makes the final decision on the equivalence based on the data submitted by the applicant. TAIEX Belgrade

15. Guidance on technical equivalence is available at: • http://ihcp.jrc.ec.europa.eu/our_activities/health-env/risk_assessment_of_Biocides/ TAIEX Belgrade

16. Evaluation • Consider carefully the use purpose and pattern of your product. • Does the risk and efficacy assessment conducted with the representative product in the active substance evaluation for the Annex I inclusion directive apply to the use of your product and there are no further elements to be taken into account in the product phase? TAIEX Belgrade

17. Evaluation of efficacy • Applicants should always consider if the efficacy data meet the requirements. • If not, further data and risk assessment are necessary. • The applicant is responsible for providing further data and the outstanding risk assessment for the product TAIEX Belgrade

18. General requirements for documentation • The application consists of application forms and the dossier. • The applicant is responsible for providing the required information and for including the study reports and other documents needed. • The evaluation of the data by the applicant will form the basis of the evaluation by the CA. TAIEX Belgrade

19. Format • The MS and the European Commission have agreed that the information included in dossiers on biocidal products should be submitted in a standard format . • The format is the same in whichever MS the dossier is submitted. • This will make it easier for the applicants to know exactly what must be done and what a dossier must contain. TAIEX Belgrade

20. Application forms • Application form consists of two parts. • The whole form isavailable at the European Register for Biocidal Products (R4BP). • The first part of the application form for authorisation of a biocidal product is made via the R4BP. • The register is maintained by the European Commission. • The application form is available in all of the EU official languages. TAIEX Belgrade

21. The R4BP • In the R4BP the applicant fills in the details on the applicant and the product. • The applicant has to indicate in which MS he applies for the first product authorisation and in which EU/EEA countries mutual recognition. • Furthermore, the applicant is requested to indicate in which MS the product is already on the market. R4BP: https://webgate.ec.europa.eu/env/r4bp/ TAIEX Belgrade

22. Timing • The product may only stay on the market of a particular MS without interruption if this MS is indicated in the application form generated via the register and submitted to all of these MS by the deadline of the application. • The second part of the application form is a word document which contains further details about the product and the type of application. TAIEX Belgrade

23. Dossier • Product dossier consists of data and documents • In addition, proposal for Safety Data Sheet (SDS) and proposal for labelling in the official languages shall be presented by the applicant TAIEX Belgrade

24. Complete Dossier CAs' Report Summary Dossier Doc. IOverall Summary and Assessment1) Doc. IEvaluation/ AssessmentReport1 Doc. II Risk Assessment Doc. II Risk Assessment Doc. II-C Risk Ass. Use of A.S. in B.P.(s) Doc. II-C Risk Ass.Use of a.s. in b.p.(s) Doc II-AEffects Assessmenta.s. Doc II-AEffects Assessment a.s. Document III-AStudy Summariesa.s.2) Doc III-AStudy Summariesa.s.2) 1) To include: I.1 Subject Matter I.2 Overall Summary and Conclusions I.3 Proposal for Decision Annex I Inclusion; List of end points; List of abbreviations 2) To append: Reference lists 1) To append: List of end points List of abbreviations Check for completeness 2) To append: Reference lists Initial check for completeness of dossiers Doc. IV-B: Test Reports b.p.(s) Doc. IV-A: Test Reports a.s. Doc II-BEffects and Exposure Ass. b.p.(s) Doc II-BEffects and Exposure Ass. b.p.(s) Document III-BStudy Summariesb.p.(s)2) Document III-BStudy Summariesb.p.(s) 2) TNsG on Preparation of Dossiers How is the Dossier structured? TAIEX Belgrade

25. Data requirements Data requirements for the biocidal active substances and products are listed in Annexes II-IV of the BPD TAIEX Belgrade

26. Submission of the application • Application should be sent to CA TAIEX Belgrade

27. The structure of the dossier documentation required for the application for authorisation of a biocidal product, provided that the active substance is listed in Annex I. Doc. IVA or LoA*: Test and Study Reports a.s.(s) • Doc. IVB or LoA*: Test and Study Reports b.p.** • Doc IIB or LoA* - Effects Assess.** • - Exposure Assess. • - Efficacy Assess. • for Biocidal Prod.2) • Doc II-A or LoA* Effects and exposure Ass. Active Subst.(s)2) • Doc. II-C Risk Characterisation for Biocidal Product • Doc. II Risk and Efficacy Assess. • Doc. I Overall Summary and Assessment1) • Document III-A or LoA* Study Summaries Active Substance(s)2) • Document III-B or LoA*: Study Summaries Biocidal Product2) • 1) To append: List of end points 2) To append: Reference lists • List of abbreviations • Check for completeness • Summary Dossier • Complete Dossier • * LoA = Letter of access • ** In the case of applications for registration of low-risk products, the effects assessment is confined to data on the active substance(s) only. In general, the data to be provided in Doc. IV-B and III-B are limited. TAIEX Belgrade

28. Technical requirements: • one paper copy of the whole application (application forms, Doc I – IV, Safety Data Sheet (SDS), draft labels, use instructions, Summary of Products Characteristics (SPC)). • Docs I-II must be MS Word-documents or MS Word-compatible. • Doc III i.e. study summaries must be either in IUCLID 5 or Word-documents • one electronic copy of the whole application on CD-rom TAIEX Belgrade

29. Language • SDS, draft label and use instructions must be available in national languages • SPC, in national languages • Other documents are accepted also in English. • If the application is for an authorisation, which is to be used later for the purpose of mutual recognition, it is recommended that the dossier is submitted in English. TAIEX Belgrade

30. General principles on the submission of experimental studies • The applicant shall submit to the CA all data on physicalchemical properties, toxicological, environmental fate and ecotoxicological effects, efficacy and other properties of the chemical that is necessary for the assessment of the conditions for authorisation. TAIEX Belgrade

31. TNsG • The Technical Notes for Guidance (TNsG) on Data Requirements describes the data needed which was originally set by Annexes II and III of the BPD. • MS specific data may be required in some cases (e.g. country specific exposure data, data related to specific resistance phenomena). TAIEX Belgrade

32. Reports • The original study reports shall be attached to the application. • However, the original study reports (Doc IV) and the study summaries (Doc III) are not required if the applicant has a written proof of his right to refer to them in his application (letter of access, LoA) and these documents have already been submitted either for the evaluation of the active substance for Annex I or in another application for product authorisation. TAIEX Belgrade

33. Appendices • The appendices of the application shall be numbered using the codes in the TNsG on Data Requirements 7. • If several studies are related to one item, they should be distinguished by lower case letters following the appendix number (e.g. 6.1.1a, 6.1.1b). TAIEX Belgrade

34. Methods • Studies must be conducted and reported either according to the methods mentioned in the Council Regulation 440/2008 on test methods or according to the OECD (Organisation for Economic Cooperation and Development) guidelines for testing of chemicals. • The main rule is that studies must also comply with the principles of Good Laboratory Practice (GLP) and the study report shall contain a certificate of this. • Further guidance on GLP is given in the TNsG on Data Requirements, Chapter 6 6. TAIEX Belgrade

35. Animal welfare • The processing of the application will continue after the supplementary data has been presented. • The BPD encourages limiting the duplication of testing on vertebrate animals, whenever possible. TAIEX Belgrade

36. Attention! • According to this principle, before starting a new test, literature searches should be conducted and the other owners of the required documentation should be consulted in order to find out, whether the available information is sufficient for the reliable evaluation of the possible hazards of the chemical TAIEX Belgrade

37. Sharing data • In order to receive the contact details of other data owners the applicants are invited to contact the CA. • If information is available, but it is inadequate, the scope of the additional studies required will be considered on a case-by-case basis. TAIEX Belgrade

38. Information and data requirements Core data and additional data • Core data • always required • read across feasible • BPD Annex IIA for active substance • BPD Annex IIB for biocidal product • BPD Annex IV A for fungi, micro-organisms and viruses • BPD Annex IV B for biocidal product with fungi, micro-organisms and viruses • Additional data • Required under certain circumstances: product type, exposure/intended uses, characteristics of substance/product • BPD Annex IIIA for active substance • BPD Annex IIIB for biocidal product TAIEX Belgrade

39. Information and data requirements Core data IIA and IIB • Applicant • Identity • Physical and chemical properties • Analytical methods for detection and identification • Effectiveness against target organisms and intended uses • Exposure (ESD + monitoring) • Toxicological and metabolic studies: acute, irritation, sensitisation, (sub)chronic, CMR • Ecotoxicolgical studies: fate and behaviour, acute toxicity fish/invertebrate/algae, inhibition of microbiological activity, bio-concentration TAIEX Belgrade

40. Information and data requirements Additional data IIIA and IIIB – example Additional data Annex IIIA for substance, IIIB for product, e.g. • if indications of neurotoxicty from other studies ⇒ neurotoxicity endpoints • if necessary ⇒ mechanistic studies (es: placental passage) • if available ⇒ medical data • private area and health area disinfectants ⇒ chronic aquatic toxicity • Veterinary hygiene products with possible release to manure storage facility ⇒ anaerobic biodegradation, acute toxicity to plants. TAIEX Belgrade

41. waiving • If it is not technically possible or scientifically justifiable to submit the required information or carry out the required studies, or if the studies are not conducted according to the guidelines referred above, then the reasoning must be given in the application. • If such justifications are not given, or if the application is otherwise insufficient, the CA will ask the applicant to submit the missing information and studies. TAIEX Belgrade

42. Information and data requirements Waiving • For each endpoint necessary according to BPD Annexes IIA/IIB/IIIA/IIIB at least one acceptable study or ajustification for non-submission of data (= waiving) has to be submitted • Waiving arguments • Technically not possible to perform (es: 2nd gen. anticoagulants) • Sufficiently valid other existing data available • Read across to another similar substance or product • Other scientifically acceptable method, calculation method, alternative study, literature study • Study scientifically not necessary, e.g.Biodegradability of inorganic chemicals, eye irritation for skin corrosive substance … TAIEX Belgrade

43. Information and data requirements Waiving • Study not necessary due to limited exposure and toxicity profile: • Level of exposure: MOE > 1000 to rep. dose studies that cannot be waived • Frequency of exposure: < 12 x per year • Duration of exposure: < 3 months per year • AND • Low toxicological concern, e.g. • if subchronic studies in rodents and non-rodents are without indication of substance-related effects at the limit dose level – waive chronic toxicity studies • if no developmental effects in first species and no developmental or reproductive effects in 2-generation study – no developmental study in second species • for further details see: TNsG on data requirements (chapter 1, 1.3.) • actual practice: increasing flexibility, largely depending on “expert judgment” TAIEX Belgrade

44. Which methods are available for toxicological hazard assessment and how much it costs ? € sub-acute oral (OECD 407) 40 500 sub-acute inhalative (OECD 412) 71 400 sub-chronic oral (OECD 408) 110 000 Sub-chronic inhalative (OECD 409) 132 000 Fertility 2 generation (OECD 416) 250 000 Teratogenicity (OECD 414) 68 000 Toxicokinetics (OECD 417) 75 600 Chronic toxicity (OECD 452) 395 000 Chronic toxicity/carcinogenicity (OECD 453) 767 000 Fish acute toxicity (OECD 203) 6 000 Fish early life stage (OECD 210) 39 000 More than 1 Million Euro are necessary for testing a single new biocidal substance. TAIEX Belgrade

45. Animal Welfare Considerations: More than 3000 Animals are necessary for the evaluation of one biocidal substance TAIEX Belgrade

46. Which studies are used for risk assessment? The key study concept For each endpoint necessary according to BPD Annexes IIA/IIB/IIIA/IIIB at least one acceptable study or a justification for non-submission of data has to be submitted • If more than one study is submitted for an endpoint one key study should be defined: study regarded as sufficient and adequate for risk assessment • Key studies should be • the study with the most sensitive species and endpoint = lowest NOAEL or EC • GLP and test guideline-conform • each study’s value to the risk assessment has to be judged individually • detailed study summaries have to be provided just for key studies TAIEX Belgrade

47. Which studies are used for risk assessment? The key study concept • Several studies can be considered as key studies for the same endpoint, e.g. when • data are available on several species or different routes of exposure or if different results are observed in valid tests • several studies compensate the deficiencies of each other? TAIEX Belgrade

48. Which studies are used for risk assessment? The key study concept • Flexibility is necessary • All data for key studies should be of an acceptable quality, but flexibility is necessary for studies with deficiencies, if they are crucial or support special risk assessment aspects; • this would apply to all carcinogenicity, mutagenicity and reproductive toxicity studies with “positive” results • this could apply to literature data, studies on mechanisms of action, other non-guideline or non-GLP studies • For further details to the key study concept see TNsG on Dossier Preparation and Study Evaluation, Part I: Chapter 4.2 TAIEX Belgrade

49. What defines the validity of data? Reliability TNsG risk assessment, part I, 3(2), p86 • exact description of the test substances, including the impurities • OECD or Annex V method or complete method description • in case not accepted OECD or Annex V method: • proper test set up: like control groups, exclusion of unspecific effects, concentration range, replicate number ... • eventually supported by other literature data, QSAR • if approximate value for the specific endpoint is sufficient for risk assessment • Good Laboratory Practice TAIEX Belgrade

50. What defines the validity of data? RelevanceTNsG risk assessment, part I, 3(2), p86 • proper species • knowledge of toxicokinetics and metabolism (does not exclude extrapolation to human) • route of exposure relevant for population and exposure scenario • substance tested = substance supplied • dose-response established (where possible) • for in vitro data, QSAR: could established correlation to in vivo endpoint TAIEX Belgrade