the SAFETY assessment of nanomaterials

About this talk This talk will describe: The value of harmonised test guidelines for chemicals for use in hazard identification and risk assessment; The role of OECD’s test guidelines programme and the benefits for both governments and industry in using OECD test guidelines; It will cover the process by which many test guidelines were found to be suitable for nanomaterials; Not all test guidelines are suitable for nanomaterials and it should with the example of inhalation toxicity how new nano specifc approaches have been developed.

Mutual Acceptance of Data, Test Guidelines and Good Laboratory Practices

Mutual Acceptance of Data (MAD) Good Laboratory Practice Test Guidelines Recommendation on the Safety Testing and Assessment of MN A single quality standard should be applied for testing of all chemical substances A single quality standard for test facilities throughout OECD Mutual Acceptance of Data Legally binding on OECD Member countries and other MAD Adherents “data generated in the testing of chemicals in an OECD Member country in accordance with OECD Test Guidelines and OECD Principles of Good Laboratory Practice shall be accepted in other Member countries for purposes of assessment and other uses relating to the protection of man and the environment” DATA QUALITY ENSURED BY TG and GLP Test Guidelines: Approximately 150 Test Guidelines to determine the safety of chemicals and chemical preparations, including pesticides and industrial chemicals. Physical-chemical properties Human toxicity Ecotoxicity Bio-degradation and accumulation Pesticide residue testing Good Laboratory Practice: Testing facility’s organisation and personnel, quality assurance programme, physical plant, apparatus, materials and reagents. In order to govern principles, testing facilities should provide; conditions for establishing and maintaining test systems; standard operating procedures; performance of the study; reporting of results; storage, retention and retrieval of records and materials etc. Full Adherents to MAD South Africa (since 2003) Singapore (since 2010) India (since 2011) Brazil (since 2011) Argentina (since 2011) Malaysia Provisional Adherent : Thailand →Avoids duplication of testing: around Euros 150 million saved each year →Reduces use of animals →Reduces trade barriers

C(81)30 Council Decision on MAD Country A Lab Chronic Tox Test Results Country B regulator Country C regulator Country D regulator Country B Lab Aquatic Tox Test Results Country A regulator Note: key aspects are “no repeat testing” and interpretation of test results is government prerogative

BY AVOIDING DUPLICATIVE TESTING: SAVINGS FROM MAD BY AVOIDING DUPLICATIVE TESTING: At least € 150 Million / Year Reduction in animal testing More chemicals can be evaluated quicker 1998 study www.oecd.org/ehs/publications

Approximately 150 Test Guidelines: Section 1: Physical Chemical Properties Section 2: Effects on Biotic Systems  Section 3: Degradation and Accumulation Section 4: Health Effects  Section 5: Other Test Guidelines (i.e. Pesticides residues) Every year new and updated Test Guidelines are adopted to meet the regulatory needs in OECD member countries. Toxicological evaluation and the processes…

Difference between OECD Test Guidelines and Guidance Documents . Test Guideline Regulatory need explained by the SPSF* Covered by MAD Fixed test protocol with validity criteria Thorough experimental validation needed with fixed protocol Takes time and resources and more cumbersome to update Guidance Document Regulatory need Not covered by MAD Can be a test method, or it provides technical guidance for the use of test guidelines Scientific validation could be limited and based on published literature Faster to develop and revise

China Lead sponsor(s) Co-sponsor(s) Contributor Fullerenes(C60) Japan, US     China SWCNTs Germany, Canada, EC, France,  China MWCNTs Korea, BIAC Silver nanoparticles US, Korea Germany, Canada Australia, EC, France,  China Iron nanoparticles  China Canada, US Carbon black Germany, US Titanium dioxide Germany Canada, Spain, BIAC, Korea, US France,  China Aluminium oxide Cerium oxide UK/BIAC, US Netherlands, Australia, Germany, EC Zinc oxide UK/BIAC BIAC Australia, Canada, Silicon dioxide  BIAC, Korea EC, France Polystyrene  Korea Dendrimers Spain US Nanoclays Note: - Countries with * have stated a clear interest - Countries in (brackets) have stated a clear interest but have yet to confirm their exact role, i.e., whether they will be sponsors, co-sponsors or contributors - # TiO2 is Spain’s initial choice but they may consider proposals for selecting other metal containing nanomaterial

http://www.oecd.org/chemicalsafety/nanosafety/testing-programme-manufactured-nanomaterials.htm Testing Programme Overview Dossiers and Endpoints ‌ Learn more about the Programme. Overview Download Manufactured Nanomaterials Dossiers or search for Tested Endpoints. Downloads and searches   Sponsors More information Learn more about our sponsoring countries and institutions. Request additional information about the Programme. Contact SPSF = Description of the project including e.g. regulatory requirements, timelines, validation status and needs, resources involved in a project Essential Criteria to be met before considering a proposal: Regulatory need/Data requirement Contributes to the International Harmonisation of Hazard/ Risk Assessment Addresses a health or environmental concern Considerable support from Member countries Lead country/Stakeholder identified

Process for Project proposals (SPSF) for the Test Guidelines Programme New and updated Test Guidelines are developed to: Meet regulatory needs of member countries Reflect scientific progress Address animal welfare aspects Improve cost-effectiveness of test methods Standard Project Submission Form (SPSF) Submission: November for discussion at the following WNT Meeting SPSF = Description of the project including e.g. regulatory requirements, timelines, validation status and needs, resources involved in a project Essential Criteria to be met before considering a proposal: Regulatory need/Data requirement Contributes to the International Harmonisation of Hazard/ Risk Assessment Addresses a health or environmental concern Considerable support from Member countries Lead country/Stakeholder identified

NANOSAFETY

Test Guidelines/ Guidance Documents under preparation Amendments to the Inhalation TGs and GD to Accommodate NM GD on Aquatic (and Sediment) Toxicology Testing of NM GD for Dispersion and Dissolution of NM in Aquatic Media – Decision Tree GD on Assessing the Apparent Accumulation Potential of NM TG for Dispersibility and Dispersion Behaviour of NM in Aquatic Media (new) TG for NMs Removal from Wastewater GD on the Adaptation of In Vitro Mammalian Cell Based Genotoxicity TGs for Testing of MNs New SPSF under development - review TG 110 - Particle Size Distribution/Fibre Length and Diameter Distributions

An example: Relationship to the test guidelines on dispersion stability and dissolution rate of nanomaterials in aqueous media GD on dissolution rate and dispersion stability of nanomaterials for environmental risk assessment TG 318 on dispersion stability in simulated environmental media (published) TG on dissolution rate in aquatic media (1 draft April 2017) Explanations and recommendations for a (jointly) consideration of testing, interpreting and usage of data on both dissolution rate and dispersion stability of NMs ©IUTA

What is Needed Session 1: Physical Chemical Properties TG 105 - Water Solubility – Specific Modification Suggested TG 108 - Complex Formation Ability in Water (Polarographic Method) TG 109 - Density of Liquids and Solids TG 112 - Dissociation Constants in Water TG 115 - Surface Tension of Aqueous Solutions Session 4: Health Effects TG 428 Skin Absorption: In Vitro Method TG 431 In vitro skin corrosion: reconstructed human epidermis (RHE) test method TG 437 Bovine Corneal Opacity and Permeability Test Method for Identifying Ocular Corrosives and Severe Irritants

What is Needed Session 2: Effects On Biotic Systems TG 201 - Freshwater Alga and Cyanobacteria, Growth Inhibition Test TG 202 - Daphnia sp. Acute Immobilisation Test TG 210 - Fish, Early-life Stage Toxicity Test TG 216 - Soil Microorganisms: Nitrogen Transformation Test TG 217 - Soil Microorganisms: Carbon Transformation Test TG 220 - Enchytraeid Reproduction Test TG 222 - Earthworm Reproduction Test (Eisenia fetida/Eisenia andrei) TG 225 - Sediment-Water Lumbriculus Toxicity Test Using Spiked Sediment A. Kerstin Hund-Rinke, Anders Baun, Denisa Cupi, Teresa F. Fernandes, Richard Handy, John H. Kinross, José M. Navas, Willie Peijnenburg, Karsten Schlich, Benjamin J. Shaw & Janeck J. Scott-Fordsmand (2016): Regulatory ecotoxicity testing of nanomaterials – proposed modifications of OECD test guidelines based on laboratory experience with silver and titanium dioxide nanoparticles, Nanotoxicology, DOI: 10.1080/17435390.2016.1229517 http://www.tandfonline.com/doi/full/10.1080/17435390.2016.1229517

Status of Revisions on Inhalation The amended TGs 412 and 413 are finalised published at the end of October 2017 – First TGs amended for NM! The amendments concern: Bronchoalveolar lavage (BAL) measurements; Particle-Size Distribution For Test Atmospheres; Post-Administration Duration; and Lung Burden Measurements.

TG 318- Dispersion behaviour of NMs in different environmental media This new TG is finalised and published – First TGs for NM! This TG aims to determine the dispersion stability of NM in aqueous media in dependence of environmental conditions.

NEW PROPOSALS (Agreed, February 2018) Determination of solubility and dissolution rate of nanomaterials in water and relevant synthetic biologically mediums Identification and quantification of the surface chemistry and coatings on nano- and microscale materials Determination of the Dustiness of Manufactured Nanomaterials Applicability of the TG 442D in vitro skin sensitisation for nanomaterials Aquatic (Environmental) Transformation of Nanomaterials Development of new Test Guideline on Toxicokinetics or Amendments to OECD TG 417 to accommodate NM Assessment of the durability of nanomaterials and their surface ligands in environmental surroundings

Manufactured Nanomaterials Thank you! Safety of Manufactured Nanomaterials www.oecd.org/env/nanosafety