The development of harmonised test methods that results in OECD Test Guidelines (TGs) is mainly driven by regulatory expert needs and, hence, more brought forward by governmental institutions. Whereas the development of standardised methods such as ISO and CEN is driven by market needs and strongly supported by industry. In addition, OECD TGs are downloadable free of cost, whereas ISO and CEN documents are available for a small fee. OECD TGs are covered under the
Mutual Acceptance of Data system, whereas ISO and other standards are not. ISO standards are internationally accepted standards and most of them are taken over by national standardisation bodies. CEN is the European Committee for standardisation that brings together European standardisation bodies.
Several different types of documents can be developed at OECD: OECD Test Guidelines (TGs) are technical guidelines that fall under the Mutual Acceptance of Data (MAD) system. Whereas OECD Guidance Documents (GDs) are providing more general guidance and do not fall under the MAD system. GDs can also be accompanying a TG. Scoping documents/Review reports provide the possibility to provide an overview of the current state of the art and knowledge in the field.
The Working Group of National Coordinators of the TGs programme (WNT) oversees the OECD Test Guidelines Programme and meets at least once a year (in April). They work towards the development of draft Test Guidelines (TGs) based on a consensus. The Working Party on Manufactured Nanomaterials (WPMN) brings together experts in the fields of nano and advanced materials from the different OECD Member countries. The WPMN meets at least once a year (in June) and it works towards the development of draft TGs suitable for nanomaterials and advanced materials. In the case of nanomaterials both the WNT and the heads of delegation of the WPMN are contacted to ensure a good coverage of the expertise in nanomaterial issues and TG development and form Joint WPMN/WNT expert groups.
The regulatory expert needs drive whether new Test Guidelines (TGs) are needed. Whether adaptations are needed to existing guidelines sometimes depends on how the science is progressing. New insights sometimes influence the need for new guidelines and adaptations. The initial need for test guidelines comes from national regulations and laws, not from the OECD. The OECD then assists and advises whether there is a common need and whether they will include this as part of the OECD process.
In general it is not the case that they are legally required unless OECD Test Guidelines (TGs) are specifically mentioned. Regulations will require specific endpoints which can be gathered via OECD TGs. The TG itself is usually aiming to identify hazards for specific chemicals and it is this information that legislation is usually asking for, rather than specifying the TG used.
Adherence to the OECD and Mutual Acceptance of Data (MAD) does not preclude the use or acceptance of test data obtained in accordance with other scientifically valid and specified test methods as developed for specific chemicals or product areas. In general and in almost all the cases, MAD adhering countries use OECD Test Guidelines conducted through the Good Laboratory Practice but there are some exceptions for example the pre-clinical safety evaluation that uses test methods produced by the International Council of Technical Requirements and GLP. So, yes, you can use other internationally valid methods as long as it's part of the legal requirements of the country where you want to submit your data.
What you really want to have with the validation is to have a trusted environment demonstrating reliability and relevance of the data . You have to make sure that the government or the regulatory experts can make a decision based on the information that you have. The purpose of the validation study is to learn about the applicability and the accuracy of a proposed experimental routine. You want to know whether the described procedures are interpreted and implemented correctly. You want to identify whether there are factors that can affect the result variability and perform the analysis of statistical variability. It is a document that will accompany the Test Guideline at the end and it will report how you designed your round-robin test. It will describe the procedures, for example which laboratories participated, what was the study design, the chemical tested, whether there was a validation of the results, what are the conclusions. One thing that is useful also to ensure the trust in this validation is that they are published as supporting materials at the same time as the test guidelines. To perform the validation, you do have to put in a lot of resources because you will need to have an inter-laboratory exercise. You will have to document all that in this validation study that is then published.
We have a procedure for non-OECD members to participate in our meetings so, for example, we have worked a lot with non-OECD countries that have adhered to Mutual Acceptance of Data (MAD), so for example Argentina, Brazil, Indonesia, India, Thailand and South Africa provide input. Also countries that do not adhere to MAD, so we have China, for example, participating in our meetings and providing input. In case of doubt, you can contact the OECD secretariat, who will be very pleased to help you and to assist you to participate or to help you to clarify what is the process to provide input. You can also go to the OECD website and look at draft Test Guidelines and draft Guidance Documents which are under the final review procedures so you can submit inputs through the forms that are available there.
Most of the Test Guidelines (TGs) are applicable for nanomaterials based on OECD review of the existing TGs when looking at what could be the most pressing needs for nanomaterials. Our approach to TGs at OECD is not to exclusively look at nanomaterials unless there is a specific need so TGs are for chemicals including nanomaterials. It is true that in some cases where nano is not applicable and in these cases we try to develop Guidance Documents (GDs), new TGs or update TGs. Not all the necessary tools for responding to regulatory needs are developed yet. Regulatory experts work with the OECD and they are part of the discussions so they are the best ones to advise when there is a specific doubt about the applicability of a TG and if there is a missing GD on how to adapt the test guidance so it generates the data required.
The OECD Test Guidelines (TGs) are not all yet available. That is why there are 18 projects underway within the OECD and we foresee that after that we will have some additional ones to come. As you know science is also advancing quite fast so TGs are updated on a regular basis as long as we have the scientific data that can assist us or can allow us to do those adaptations and that we can validate the test methods. There is a lot of work that needs to be done in advance for those TGs. It is not applicable to all but it's what we have right now to assist regulatory experts, to assist the industry to submit their commercial applications.
Firstly, how ECHA will respond is always a bit difficult to predict. What ECHA generally does is if OECD Test Guidelines are not available and something is really needed because REACH asks for it, they will come up with some guidance themselves. To what extent they can give that guidance clearly also depends on the scientific basis for any given guidance and if the scientific basis isn't there it is clearly difficult for them also to come up with guidance. Again, if you have doubts, just start a dialogue with the regulatory experts and see where you can go to provide data that will be acceptable for the regulatory experts and the requirements.
The latest list of OECD Test Guidelines is publicly available at the OECD website. That basically leads you to the OECD website where all information on testing of chemicals, both Test Guidelines (TGs) and Guidance Documents (GDs), can be found and also the other information on Mutual Acceptance of Data and all other information on this. The NANOMET webpage can also provide further NMs specific information.
We have to start with the principle, or at least this is the approach that we have at OECD, that most OECD TGs are applicable to nanomaterials (NMs). Then we did find out that in some cases, there was a need to adapt certain TG for nanomaterials and in some other cases to develop new TGs for NMs. Please note this distinction because, for example, with the TG on inhalation toxicity study has been shorten to 28 days and not 90 days studies, as originally done for general chemicals. We have also GDs that provide assistance on that, for example the one on aquatic and sediment ecotoxicity testing, (OECD GD 317), that gives guidance on how to apply a number of existing OECD TGs when testing NMs so there are no amendments needed on those TGs. You just need to make sure that you have this additional information at hand when you're going to test nanomaterials.
We collaborate with them on a daily basis. They are part of the work that we are doing on the NanoSafety and several experts from ISO TC229 are also experts in several of our expert groups assisting the development of the Test Guidelines and Guidance Documents. This is a collaboration that is long standing, I think for the last 12 years, so we will be happy to continue. You can always contact the OECD Test Guidelines Programme secretariat or the ISO committee chair to maintain this communication.
This refers to whether the information is repeatable. That is part of the validation process, whether you can repeat the test and have existing results across different laboratories following a specific test method. This definitely will affect whether your test methods can be accepted by a regulatory expert.
The test requirements depend on the legislation. On the environmental fate side, definitely dissolution is an important parameter as is dispersion. Things like bioaccumulation also fall under fate, at least in OECD and in many legislations that is a requirement for environmental fate. Developments are ongoing on there to, on the one hand, ensure that sufficient guidance is given to enable a fish test according to the TG 305 bioaccumulation test and, on the other hand, a new product has started to come up with alternatives for fish test may not always be needed. [see also Eric Bleeker’s presentation during the webinar The pathway to test guidelines; From science to standards for nanomaterials]
This will depend as you will need to have the science behind this and so it will depend how much testing you have been able to do i.e. how advanced a stage you are at. Once a Test Guideline is approved by the OECD, it is automatically part of the Mutual Acceptance of Data. This includes all the chemicals including nanomaterials. There is no waiting time between approval and the Mutual Acceptance of Data. It is worth noting here that we have been helped and collaborated with the large EU projects such as NanoHarmony & NANOMET, and that this international effort in assisting the OECD in producing the data and draft Test Guidelines that should help to reduce the time for approvals. OECD approval can be as fast as two years, but can also take up to six or more years, depending on how much data you have to start with.
Yes, we have the possibility within the NanoHarmony project to sponsor the work for aid Test Guidelines (TGs) and Guidance Document (GDs) developments directly. But it is not NanoHarmony who decides on TGs or GDs development and its funding. As a CSA action, this is not the only work package we have. We have two other work packages specifically dedicated to looking into the OECD and research process and regulatory processes: how to improve the flow of information; and secondly, one of our tasks is to help and facilitate the coordination of all the developments related to TGs and GDs to make them fit for use for nanomaterials. On the other hand, working on gap analysis, looking for which kind of endpoint is needed or where do we have really practical and usable and regulatory sensible tests, may lead to something. It may come up during workshops or specific sessions organised in the NanoHArmony context leading towards an activity that an OECD Member country takes over and says, yes, this is something which should be developed, which should be part of the OECD Test Guidelines Programme Work plan. We facilitate this by bringing together the international experts from the scientific sides and the experts coming from the OECD side but also the different Member countries and their regulatory representatives which help to see whether it's important to adapt or newly develop a TG for NMs and how we can get this going.The close cooperation between NANOMET and NanoHarmony can facilitate the exchanges between key stakeholders of the OECD Test Guidelines Programme and put that into perspective of all the other TGs which are developed. This is specifically of importance because if you have one endpoint and then other endpoints and they are somehow interlinked, it is important that there is an exchange and flow of information from one Test Guideline development to another. This is why we in NanoHarmony do not work closely only with EU based leaded TG or GD developments but happily include and try to facilitate the flow of information between all of them.
For the OECD Test Guideline (TG) on particle size distribution, I think it is quite advanced. We expect to have a draft TG that can be circulated for a final review at the end of the year. We hope that it can be approved in April 2020 by the Working Group of National Coordinators of the TGs programme (WNT) and then it goes through the usual OECD process for publication. We hope that the test guideline is publicly available in June. One thing perhaps that is of interest is that once we are in the final stages of the revision of a TG, the drafts are posted on the OECD public website and we welcome comments from anyone that is interested to provide inputs and to provide questions, that should be taken into account in the final revision of the document.
The implications of re-testing are both time consuming and cost effective and may lead to an unnecessary number of animals being tested. I think it's more general than dissolution alone. Similar questions could apply to other OECD Guidance Documents (GDs) and Test Guidelines (TGs) that are currently being worked on. It's basically asking, if we do a test now with nanomaterials with an OECD TG that may later on not be deemed not fully applicable or I'm testing nanomaterials where could I rely on ion toxicity and thus didn't need a test at all. Those are very valid questions. In those cases where you think you have these issues, a first step would be to discuss with the regulators who ask you for this data. If you come up with a plan such as “I think I can do it in this way”, have a discussion and see if the regulator can accept your plan ahead. More specifically for REACH there is the obligation that you keep your dossier up to date. You cannot completely prevent new tests from being needed in the future but clearly you hope to avoid needing new tests within the next couple of years.
As you have indicated, for dissolution and dissolution rate, the GD 318 is now available. However, there is still a lot of uncertainty around how to best optimise the experimental design for this test. Again, you rightly indicated this is a critical endpoint for REACH which can dictate e.g. the testing strategy for Ecotox. Whether long or short term should be executed or if the dissolution is fast enough to allow the registration to use the data based on the ion for metals for instance. There is now a Guidance Document (GD) on dissolution testing and dispersion stability of nanomaterials but not yet a Test Guideline as for dispersion stability so there is some uncertainty on what you have to do there. The GD is quite detailed about how such dissolution testing could be done but it's not as strict as what you would expect from a Test Guideline (TG). So indeed there is some uncertainty there. Nevertheless, there is some information that is useful for conducting such a test. If dissolution is fast enough to allow registration to use the data based on ions for metals that clearly depends on several things. The best way to convince a regulator if you want to use that data in a regulatory setting is probably to present both a dissolution test and a test on ions and so at least you have some comparison there. Still it will depend to some extent on your regulator and discussions with your regulator are generally good whatever the endpoint. The dissolution is a difficult one and a clearly critical parameter but, in general, if you have doubts whether a TG is fully applicable for your nanomaterials, discussions with the regulator who you want to accept the data is generally a good first step.
Dustiness is an important question, as an important test parameter, but it's also a not so easy endpoint because the Test Guideline (TG) and Guidance Documents (GDs) developments for dustiness are related to more than one area. We are looking into dustiness testing for spherical or neospherical or normal particles and we look into dustiness testing for fibres, which is one differentiation which is ongoing. Another one is the use of the data, whether the use of the data is for exposure assessment dustiness or whether it is used for ATEX for explosive materials and for explosive assessments. Hence there are a TG and 2 GDs being developed and therefore there is not only one answer possible for the current situation. The testing for the dustiness for particles is now starting with the round robin tests. The work for the GDs on the use for exposure assessment and in the use for ATEX for explosion assessments is ongoing. The dustiness testing for fibres is in the starting phase but we hope to start the round robin test within the next year. That is the current status.
For the current situation, you can get information, for example, during the NanoHarmony workshop on 3rd to 5th November 2021 and you can also get in contact with NanoHarmony or in contact with the current coordinator for the dustiness Test Guideline (TG) and Guidance Document (GD) developments. If you write to us at NanoHarmony, we will happily pass on your message so that you can have direct contact with those involved in the scientific developments for the OECD documents. For dustiness, the lead is with France, which is the Member country coordinating it in the OECD, and the research coordinated for dustiness is done by INERIS in France as a project leading institution.
Clarity on TG and when drafts may be available and possible final revisions would be helpful. A coordinated group including NanoHarmony, some EU projects and NANOMET are preparing a list which we will make available at the EU NanoSafety Cluster – The NanoSafety Community level and also to OECD and others, where we show which test guideline endpoints are ongoing, the brief status and also a list of possible further endpoints which may come up in the future. The report summarising the current status of projects to develop or adapt the OECD Test Guideline (TGs) and Guidance Documents (GDs) for nanomaterials is now available.
One obligation we have had from the beginning is that when we work on Test Guidelines (TGs) or Guidance Documents (GDs), we built our TGs and data on research which was done in previous projects, including European projects.There is great work done within the NanoSafety cluster where we already work together and we have an exchange and flow of information from NanoHarmony and TGs to the different ongoing EU projects and also to those which have recently finished. There has been a list compiled by Flemming Cassee, who is responsible for and working on this issue within the NanoSafety cluster for the European Commission. The latter clearly shows which endpoint is related to which project so that we can see where we can derive data from and use them for validation. We can build and use those round robin tests as a background or as additional validation data for the validation report for the OECD Test Guideline. Yes, it is possible. We are reaching out. We are the NanoSafety cluster. If you are from other EU projects or national projects and think you have important data you are very welcome to contact us and we will see how we can get them involved. Again by using workshops, expert participation, collaboration with other projects - that's how we try to get the flow of information and data included here without taking over the data but we certainly fulfil all requirements that the original data belongs to those people who have actually produced them.
This relates to workshops where they can say we have specific endpoints or SOPs or specific validation processes that we haven't exchanged upon yet. We see how they fit to the ongoing test guideline developments and also to those which are anticipated, for example NANORIGO is working on gap analysis so we will try to coordinate it. Again, as a CSA action and coordination support action for OECD Test Guideline developments, this is part of our task where we try to facilitate exchanges.
We moved a little bit towards asking for funding rather than giving a lot of funding so we are very happy to have funding from some national Member countries of the OECD as well as getting funding for two or three projects clearly related to the OECD test guideline developments. For the future, those of you from Europe know that Horizon 2020 has finished so it is not very clear at the moment where and how there will be funding available. We certainly are asking for it, notably through the NH White paper because there will be continuous effort, not only for Nano but also some for other materials coming up in the future, so to have that on a longer timeline than just having projects of three years is quite important from the NanoSafety cluster perspective.
European Committee for Standardization
CEN is an association that brings together the National Standardization Bodies of 34 European countries.
Integrated Approaches to Testing and Assessment
IATAs combine multiple sources of information to conclude on the toxicity of chemicals. IATAs may include existing information from the scientific literature or other resources, along with newly generated data resulting from new or traditional toxicity testing methods to fill data gaps. These approaches are developed to address a specific regulatory scenario or decision context.
Within an ILC two or more independent laboratories are performing and evaluating a test under controlled conditions in order to determine the variability of a new test method.
Mutual Acceptance of Data
The MAD system helps to avoid conflicting or duplicative national requirements, provides a common basis for cooperation among national authorities and avoids creating non-tariff barriers to trade. OECD countries and full adherents have agreed that a safety test carried out in accordance with the OECD Test Guidelines and Principles of Good Laboratory Practice in one OECD Member country must be accepted by other OECD countries for regulatory assessment purposes. This is the concept of “tested once, accepted for assessment everywhere”. Apart from saving large amounts of test animals, this saves the chemicals industry the expense of duplicate testing for products which are marketed in more than one country.
In the Malta Initiative, a voluntary network without an official mandate, representatives of European countries, several Directorates-General of the European Commission, the European Chemicals Agency (ECHA), authorities, research institutions, NGOs, universities and industry work together on a voluntary and self-organised basis. They work together to find possibilities for developing and amending the measurement and test methods required to enforce legislation (particularly in the field of chemicals). In order to make REACH enforceable for nanomaterials, in a first step the Malta Initiative is committed to facilitating projects in which OECD Test Guidelines (TGs) are amended or developed for nanoscale substances.
New Approach Methodologies
NAMs including in vitro (omics, cell-based, tissue-based, etc) assays, in silico models, and other computational approaches, are being developed to provide information on chemical hazards and risks for humans while limiting the use of animals.
The National Coordinators from the respective OECD Member countries, non-member economies adhering to the Mutual Acceptance of Data and the European Commission (EC) have a central position in the Test Guidelines Programme. They submit national proposals for new or revised Guidelines and provide comments agreed on at the national level on proposals circulated by the Secretariat. In order to be most efficient, NCs provide a national focal point to gather input from a network of experts and thus are required to be aware of developments related to test methods in their own country.
Organisation for Economic Co-operation and Development
The OECD is an international intergovernmental organisation that works towards shaping policies that foster prosperity, equality, opportunity and well-being for all.
Programme on Chemical Safety and Biosafety
In its programme on Chemical Safety and Biosafety, the OECD assists countries in developing and implementing policies and instruments that make their systems for managing chemicals as efficient and robust as possible, while protecting human health and the environment. The Chemical and Biotechnology Committee (CBC) oversees these activities.
OECD Guidance Document
Guidance Documents and Guidance Notes are developed either to supplement a Test Guideline or to provide assistance in the Test Guideline development. Like Detailed Review Paper (and other Test Guidelines related documents) they are advisory in nature. Consequently, the procedure for their adoption and further publication is different from that for Test Guidelines (OECD GD 1, as revised in 2009).
The Secretariat's main role is to provide structural and administrative support to the Test Guidelines Programme. It maintains and develops the three-year rolling work plan for the Programme (with annual updates), assists Member countries in the steps necessary for developing or revising Test Guidelines, including the organisation of workshops and meetings, and circulates the various Test Guideline-related documents. Where necessary, the Secretariat takes initiatives in the revision of existing Test Guidelines. It is responsible for periodically revising the compendium of Guidelines.
The OECD Series on Testing and Assessment includes publications related to testing and assessment of chemicals. Documents include but are not limited to Guidance Documents to (further) support the use of Test Guidelines, Case Study Reports on Integrated Approaches to Testing and Assessment (IATA), Validation Study Reports in support of newly developed Test Guidelines, but also other Study Reports or Dedicated Review Papers.
The purpose of the OECD Series on the Safety of Manufactured Nanomaterials is to provide up-to-date information on the OECD activities on manufactured nanomaterials that are related to human health and environmental safety. Documents include but are not limited to Guidance Documents to (further) support the assessment of nanomaterials, workshop reports on the applicability of Test Guidelines for nanomaterials, overviews of activities on nanomaterials in the different Member countries (so-called Tour de Table documents), or outputs from the OECD Testing Programme on nanomaterials.
OECD Test Guideline
The OECD Guidelines for the Testing of Chemicals are a unique tool for assessing the potential effects of chemicals on human health and the environment. They are split into five sections: Section 1: Physical-Chemical properties; Section 2: Effects on Biotic Systems; Section 3: Environmental fate and behaviour; Section 4: Health Effects and Section 5: Other Test Guidelines (with a focus on pesticides and their residues). Accepted internationally as standard methods for safety testing, the OECD Test Guidelines are used by professionals in industry, academia and governments involved in the testing and assessment of chemicals (industrial chemicals, pesticides, personal care products, etc.). As such they form a cornerstone under the OECD Mutual Acceptance of Data (MAD) system.
OECD Test Guidelines Programme
In the OECD Test Guidelines Programme, the Test Guidelines for the Mutual Acceptance of Data (MAD) system are continuously expanded and updated to ensure they reflect the state-of-the-art science and techniques to meet Member countries' regulatory needs. The Guidelines are elaborated with the assistance of experts from regulatory agencies, academia, industry, environmental and animal welfare organisations.
Working Group of National Coordinators of the Test Guidelines Programme
The WNT meets at least once a year. Collectively, the WNT oversees the Test Guidelines Programme and works towards the development of draft Test Guidelines based on a consensus.
Working Party on Manufactured Nanomaterials
The WPMN was launched in 2006 to ensure that the approaches for hazard, exposure and risk assessment for manufactured nanomaterials are of high quality, science-based and internationally harmonised.
Proposals for the development of new or updated Test Guidelines can be submitted in the form of a Standard Project Submission Form by the Member countries, the international scientific community, industry, and non-governmental organisations, all via a National Coordinator. They can also be submitted by the EC or the Secretariat. A proposal for a new
Test Guideline or the revision of an existing Test Guideline should undergo a critical appraisal concerning its scientific and regulatory justification (e.g. its existing or foreseen regulatory needs, validation status, relevance and reliability) prior to the addition of the project to the Programme’s work plan.
Standard Operating Procedure
A Standard Operating Procedure is a protocol or a step-by-step description to be followed when performing a specific test method. It helps to reduce miscommunication and to improve the reproducibility of the test methods (OECD GD 34, 2005).
Standard Project Submission Form
An SPSF is freely available online. The form specifies the information generally required to submit a proposal for new or updated Test Guidelines or related documents to the WNT, including the project description and the actions planned toward the development of the Test Guideline, the project milestones, and deliverables. Prior to formal submission, there is a possibility for lead countries to signal their intention by submitting a preliminary proposal to gain support and seek comments to refine the definitive proposal. The proposal included in an SPSF is reviewed by the WNT and a project is considered for inclusion in the work plan when the NCs agree that the proposal meets the information requirements described in the SPSF.
Stakeholders are persons or groups with a special interest or concern in a specific topic or action.
In the context of the overall OECD Test Guidelines Programme, a test method is an experimental system that can be used to obtain a range of information from chemical properties through the adverse effects of a substance. The term “test method” may be used interchangeably with “assay” for ecotoxicity as well as for human health studies (OECD GD 34, 2005).
Replacement, Reduction, Refinement
3Rs principle must be applied when possible in chemical safety and biosafety assessment, as it allows the reduction in animal numbers or suffering during testing.
A testing strategy provides a suggested approach for the evaluation of existing information and a sequential or tiered approach for the generation of additional information for hazard identification of a substance. The use of testing strategies is dependent on the regulatory needs of member countries (OECD GD 34, 2005).
Standing Expert Groups are formed by experts who focus on active areas of activities in the different Working Parties of the Chemicals and Biotechnology Committee.
Relevance describes the relationship between the test and the effect in the target species and whether the test method is meaningful and useful for a defined purpose, with the limitations identified (OECD GD 34, 2005).
Reliability is defined as the extent of reproducibility of results from a test within and among laboratories over time, when performed using the same harmonised protocol (OECD GD 34, 2005).
Standing Expert Groups of the Working Party of National Coordinators of the OECD Test Guidelines Programme (WNT) that includes experts consulted during activities of the Working Party of Manufactured Nanomaterials (WPMN).