1. Test procedures under REACH and CLP Regulation, requirements for test laboratories, acceptance of the test results, Good Laboratory Practice (GLP) Mariusz Godala Bureau for Chemical Substances Poland Yerevan, 2-3 May 2011

2. REACH -General requirements for generation of information on intrinsic properties of substances Information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI (GENERAL RULES FOR ADAPTATION OF THE STANDARD TESTING REGIME SET OUT IN ANNEXES VII TO X) are met. In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, through the use of alternative methods, for example, in vitro methods or qualitative or quantitative structure-activity relationship models or from information from structurally related substances (grouping or read-across).

3. REACH -General requirements for generation of information on intrinsic properties of substances Where tests on substances are required to generate information on intrinsic properties of substances, they shall be conducted in accordance with the test methods laid down in a Commission Regulation or in accordance with other international test methods recognised by the Commission or the Agency as being appropriate.

4. Test methods Council Regulation (EC) No 440/2008 of 30 May 2008 laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation and Restriction of Chemicals (REACH)

5. Test methods COMMISSION REGULATION (EU) No 1152/2010 of 8 December 2010 amending, for the purpose of its adaptation to technical progress, Regulation (EC) No 440/2008 laying down test methods pursuant to Regulation (EC) No 1907/2006 (REACH)  B. 47. BOVINE CORNEAL OPACITY AND PERMEABILITY TEST METHOD FOR IDENTIFYING OCULAR CORROSIVES AND SEVERE IRRITANTS - The Bovine Corneal Opacity and Permeability (BCOP) test method is an in vitro test method that can be used, under certain circumstances and with specific limitations, to classify substances and mixtures as “ocular corrosives and severe irritants ”  B. 48. ISOLATED CHICKEN EYE TEST METHOD FOR IDENTIFYING OCULAR CORROSIVES AND SEVERE IRRITANTS -The Isolated Chicken Eye (ICE) test method is an in vitro test method that can be used, under certain circumstances and with specific limitations, to classify substances and mixtures as ocular corrosives and severe irritants.

6. Test methods These methods shall be regularly reviewed and improved with a view to reducing testing on vertebrate animals and the number of animals involved. The Commission, following consultation with relevant stakeholders, shall, as soon as possible, make a proposal, if appropriate, to amend the Commission Regulation

7. Test methods  Part a: methods for the determination of physico-chemical properties  Part b: methods for the determination of toxicity and other health effects  Part c: methods for the determination of ecotoxicity

8. Test methods - example A.1. MELTING/FREEZING TEMPERATURE A.2. BOILING TEMPERATURE A.3. RELATIVE DENSITY A.4. VAPOUR PRESSURE A.5. SURFACE TENSION A.6. WATER SOLUBILITY A.8. PARTITION COEFFICIENT A.9. FLASH-POINT

9. Test methods - example B.1 bis. Acute oral toxicity — Fixed dose procedure B.1 tris. Acute oral toxicity — Acute toxic class method B.2. Acute toxicity (Inhalation) B.3. Acute toxicity (Dermal) B.4. Acute toxicity: Dermal irritation/corrosion B.5. Acute toxicity: Eye irritation/corrosion B.6. Skin sensitisation B.7. REPEATED DOSE (28 Days) Toxicity (Oral) B.8. Repeated dose (28 Days) Toxicity (Inhalation)

10. Test methods - example C.1. Acute toxicity for fish C.2. Daphnia sp. Acute immobilisation test C.3. Algal inhibition test C.4. Determination of ‘ready’ biodegradability PART I. General considerations PART II. DOC DIE-AWAY TEST (Method C.4-A) PART III. Modified OECD screening Test (Method C.4-B) PART IV. CO 2 evolution test (Method C.4-C) PART V. Manometric respirometry test (Method C.4-D) PART VI. Closed bottle test (Method C.4-E) PART VII. M.I.T.I. TEST (Method C.4-F) C.5. Degradation — BIOCHEMICAL OXYGEN DEMAND

11. REACH - General requirements for generation of information on intrinsic properties of substances Ecotoxicological and toxicological tests and analyses shall be carried out in compliance with the principles of good laboratory practice provided for in Directive 2004/10/EC or other international standards recognised as being equivalent by the Commission or the Agency and with the provisions of Directive 86/609/EEC, if applicable.

12. CLP - General requirements for generation of information on intrinsic properties of substances For the purposes of determining whether a substance or a mixture entails a health or environmental hazard as set out in Annex I to this Regulation, the manufacturer, importer or downstream user may, provided that he has exhausted all other means of generating information including by applying the rules provided for in section 1 of Annex XI to Regulation (EC) No 1907/ 2006, perform new tests.

13. CLP - General requirements for generation of information on intrinsic properties of substances Method of generating information on substances:  data generated during test,  epidemiological data,  occupational data or data from accident databases,  any other information generated in accordance with section 1 of Annex XI to Regulation (EC) No 1907/2006 (Grouping of substances and read-across approach)  any other information generated under internationally recognised chemical programmes.

14. CLP - General requirements for generation of information on intrinsic properties of substances Where the manufacturer, importer or downstream user carries out new ecotoxicological or toxicological tests and analyses, these shall be carried out in compliance with Article13(4) of Regulation (EC) No 1907/2006 = Good Laboratory Practice

15. CLP - General requirements for generation of information on intrinsic properties of substances Where new tests for physical hazards are carried out for the purposes of this Regulation, they shall be carried out, at the latest from 1 January 2014, in compliance with a relevant recognised quality system or by laboratories complying with a relevant recognised standard.

16. Directive 2004/10/EC Directive 2004/10/EC of the European Parliament and of the Council of 11 February 2004 on the harmonisation of laws, regulations and administrative provisions relating to the application of the principles of Good Laboratory Practice and the verification of their applications for tests on chemical substances - requires Member States to take all measures necessary to ensure that laboratories carrying out safety studies on chemical products comply with the OECD (Organisation for Economic Cooperation and Development) Principles of Good Laboratory Practice.

17. GLP: OECD The OECD Principles of GLP set out managerial concepts covering the organisation of test facilities and the conditions under which pre-clinical safety studies are executed. Their purpose is to ensure the generation of high quality and reliable test data (in vitro and in vivo) related to the safety of chemicals and preparations in the framework of the Mutual Acceptance of Data (MAD).

18. GLP – MAD (Mutual Acceptance Data) The testing of chemicals is labour-intensive and expensive. Often the same chemical is being tested and assessed in several countries. Because of the need to relieve some of this burden, the OECD Council adopted a Decision in 1981 stating that data generated in a Member country in accordance with OECD Test Guidelines and Principles of Good Laboratory Practice (GLP) shall be accepted in other Member countries for assessment purposes and other uses relating to the protection of human health and the environment.

19. OECD guidelines & documents concerning GLP The OECD has produced a number of documents concerning GLP. The first and the BASIC document is the “OECD PRINCIPLES OF GOOD LABORATORY PRACTICE” This is the document which provides the “regulatory standard”. However, the GLP group, conscious of the fact that regulatory texts often require further explanation to render them pragmatic, has promoted the publication of a number of explanatory texts to assist in the implementation of GLP Principles. The following slides provides the names of the 15 OECD publications concerning GLP.

20. OECD guidelines & documents concerning GLP 1. Guidance Documents for Compliance Monitoring Authorities 2. Revised Guides for Compliance Monitoring Procedures for Good Laboratory Practice. 3. Revised Guidance for the Conduct of Laboratory Inspections and Study Audit. 9. Guidance for the Preparation of GLP Inspection Reports. 4. Quality Assurance and GLP. 5. Compliance of Laboratory Suppliers with GLP Principles. 6. The Application of the GLP Principles to Field Studies.

21. OECD guidelines & documents concerning GLP 7. The Application of the GLP Principles to Short&Term Studies. 8. The Role and Responsibilities of the Study Director in GLP Studies 10. The Application of the Principles of GLP to Computerised Systems 13. The Application of the OECD Principles of GLP to the Organisation and Management of Multi-Site Studies. 11. The Role and Responsibility of the Sponsor in the Application of the Principles of GLP. 12. Requesting and Carrying Out Inspections and Study Audits in Another Country. 14. The Application of the Principles of GLP to in vitro Studies. 15. Establishment and Control of Archives that Operate in Compliance with the Principles of GLP.

22. What is GLP? GLP (Good Laboratory Practice) is a quality system covering the organisational process and the conditions under which non-clinical safety and environmental studies are planned, performed, monitored, recorded, reported and archived. The purpose of GLP is: - To promote the development of quality test data - To foster mutual acceptance of test data - To avoid duplicative testing - To avoid the creation of technical trade barriers - To improve the protection of human health and environment.

23. What is GLP? GLP defines the conditions under which studies are – Planned – Performed – Recorded – Reported – Archived – Monitored

24. GLP - scope Non-clinical health and environmental safety studies covered by the Principles of Good Laboratory Practice include work conducted in the laboratory, in greenhouses, and in the field. Unless specifically exempted by national legislation, these Principles of GLP apply to all non-clinical health and environmental safety studies required by regulations for the purpose of registering or licensing pharmaceuticals, pesticides, food and feed additives, cosmetic products, veterinary drug products and similar products, and for the regulation of industrial chemicals.

25. GLP Principles  Resources: Personnel, Facilities & Equipment  Characterization: - Test Article - Identification, Quality …… - Test system - Identification, Health status…  Rules: Protocols / Study Plans, Procedures  Results: Raw data, Final Report, Archives  Quality Assurance: Audit/Inspection - Training - Advice

26. GLP Principles - example Personnel:  Study Director – single point of study control  Study personel – perform study according to instructions  Quality Assurance – ensure management of GLP compliance  Archivist – manages archives

27. GLP Principles - example Personnel:  curriculum vitae  training records  job description these three documents meet the GLP requirement that records are maintained to demonstrate that staff have the competence, education, experience and training necessary to perform their tasks

28. GLP Principles - example Study Director  The individual responsible for the overall conduct of the non- clinical study  The Study Director has responsibility both for the science and for the GLP aspects of the study  Selected by management  One study = One Study Director  One study = One Study Plan approved by Study Director  One Study = One Report written by Study Director  Qualifications of Study Director should be  documented

29. GLP Principles - example Archives  What you can find in archive:  Study plan  Raw data  Final report  Personnel records  Historical SOP files  Facilities/equipment qualification records  Etc.

30. GLP Principles - example Archives: Function/security  Long-term, secure storage and fast retrieval of data  Only authorized entry permitted  Examination in-situ of documents is preffered  Photocopies made in place, if possible  Protection against fire, flood and vandalism if possible

31. GLP Principles - example Raw data and data collection:  „WHAT”: Data shoul show: that the protocol was followed; the results of observations; that the process complied with SOP instructions  „HOW”: Data should show that methods were carried out as indicated in the protocol and SOP or that any deviations from protocol/SOPs were recorded  „WHO”:  Data should show: identity of operator;

32. GLP Principles - example Raw data and data collection: During the study: Data should be recorded:  Directly  Promptly  Accurately  Legibly Then:  Sign & date  Explain corrections

33. GLP Compliance Programme (National) GLP Compliance Programme: The particular scheme established by a Member country to monitor good laboratory practice compliance by test facilities within its territories, by means of inspections and study audits.

34. GLP Inspection A regular inspection has the following components:  Interviews with management and Quality Assurance personnel  Review of the documentation  Inspection of facilities, equipment, test systems, procedures, practices, archives etc.  Audit of a number of studies  Exit meeting, at which a List of Observations will be issued, if appropriate

35. GLP in Poland Art. 3 of Directive 2004/9/EC: Member States shall designate the authorities responsible for the inspection of laboratories within their territories and for the audit of studies carried out by laboratories to assess compliance with GLP.

36. GLP in Poland  The Ministry of Health is in charge to indicate Poland's GLP Monitoring Authority.  The Bureau for Chemical Substances and Preparations is Poland's GLP Monitoring authority.  With regard to GLP, the Bureau inspects laboratories which carry out tests of a wide range of chemical products.  The GLP monitoring programme was started in 2002.  15 Test facilities with the certificate of compliance with the principles of Good Laboratory Practice, granted by the Bureau for Chemical Substances and Preparations.

37. GLP in Poland Field of compliance with GLP in test facility in Poland with the GLP cerificate: ecotoxicological studies of industrial chemicals, pesticides, veterinary medical products, feed additives, municipal and industrial sewage, a residue studies of pesticides, physicochemical studies; residue studies; pharmacokinetic studies analytical phase of pharmacokinetic studies including bioavailability and bioequivalence studies Histopathology testing in the area of toxic and cancerogenic activity in assessment of chemical substances an preparations

38. Good Laboratory Pratice

40. Thank you for your attention!