ECETOC task force ensures society benefits from safe nanomaterials via efficient safety assessments that require minimal animal testing

As more and more nanotechnology-enabled products enter the market, the importance of adequately assessing nanomaterial release, exposure, biokinetics, hazard and risk is now widely recognised. However, given the large number of these products today, carrying out hazard and risk assessment of every variant of nanomaterial is impracticable and undesirable for both economic reasons, as well as the legal requirement to reduce animal testing.

Read across is the most efficient way of reducing animal testing, while still providing information that fulfils regulatory requirements. For classical chemicals, industry has been developing expertise and gaining experience in how this can best be handled over a number of years. The European Chemical Agency (ECHA) has also provided guidance on how to use read across in a regulatory context (RAAF 2017). But for nanomaterials, or nanoforms, there is very little comparable experience available.

To address this gap, the Centre for chemical safety assessment (ECETOC) established a Task Force on Nanomaterials. Its goal is to ensure that society can benefit from safe nanotechnology-enabled products by providing efficient safety assessments, while requiring the least possible number of animal experiments.

The Task Force has adopted a two-pronged approach: it has developed a web-based tool to help companies register nanoforms under REACH; and, more recently, it has launched an Expert Group (EG) to develop ‘Strategies to overcome challenges in aquatic testing of particulate material’.

Several frameworks for grouping of nanoforms have already been developed. Some are conceptual (Oomen et al. 2015) or use statistics (Drew et al. 2017); others created specific grouping rules, as in DF4nano (Arts et al.2015), or Nanogravur (Hund-Rinke et al. 2018; Wohlleben et al. 2019). These decision rules are based on fixed boundaries and pre-defined categories that group broad ranges of nanomaterial, rather than nanoforms of the same substance.


Two parallel microscope images

Figure 1: Two industrial nanoforms of CeO2: should they be registered as a set? (Schaefer et al. (2012) ACS Nano 6:4603)

Registration of nanomaterials under REACH offers to define ‘sets of similar nanoforms’ of the same substance for a joined human health and environmental hazard, exposure and risk assessment. ECHA has issued guidance on the registration of nanoforms and defining sets of similar nanoforms (ECHA. 2019a and b).


Web-based NanoApp

The ECETOC Task Force has developed a tool based on the best available science and which adheres to the requirements specified by ECHA (EUoN. 2020). Its work was published in an ECETOC report (Janer, Landsiedel, Wohlleben, 2020), which then formed the basis for the development of a web-based tool (NanoApp) to help make decisions on the extent of similarity of nanoforms.

The  NanoApp performs pairwise similarity checks and so is not limited to pre-defined categories. The rules applied by the app consider evidence on the impact of intrinsic and extrinsic properties on the exposure, toxicokinetics, fate, and (eco)toxicity, and eventual risks to the environment and to humans. The NanoApp helps to create and justify sets of similar nanoforms and ensures that each of the nanoforms is sufficiently similar to all other nanoforms in the set.

The decision logic follows the ECHA guidance in a transparent and evidence-based manner. For each two nanoforms, the properties under consideration are compared and corresponding thresholds for maximal differences are proposed. In tier1, similarity is assessed based on intrinsic properties that mostly correspond to those required for nanoform identification under REACH: composition, impurities/additives, size, crystallinity, shape and surface treatment. Moreover, potential differences in the agglomeration/aggregation state resulting from different production processes are considered. If nanoforms are not sufficiently similar based on tier1 criteria, additional data from functional assays are required in tier2. The decision rules implemented in the NanoApp help REACH registrants and dossier evaluators to register sets of similar nanoforms.

Screenshot from an it-application
Figure 2: Interactive assessment during a case study: by clicking on the “yellow thumb”, the NanoApp explains why registration of the two NFs as one set is not yet supported, and guides the user to tier 2 data that is needed to justify the registration.

The application of the NanoApp in real case studies, including nanoforms of different sizes, or from different production processes, will be described in a follow-up manuscript. Applying the app to real-life nanoforms requires specific data of the individual nanoforms under scrutiny. Often, current datasets need to be amended because (i) nanoforms have rarely been characterized with all the descriptors required by the NanoApp, (ii) a low number of (comparable) in vivo studies for human health endpoints exist for nanoforms of the same substance, (iii) ongoing discussions on the adequacy of standard ecotoxicological tests (designed to test soluble substances) for nanoforms. The legal requirement to register nanoforms and the quest to define and justify sets of similar nanoforms will considerably increase these datasets.

The NanoApp was formally launched on 30 November 2020 and can now be accessed at A user account can be requested free of charge. Training is offered and recommended; the first online training sessions have already taken place and further training sessions might be scheduled in future.

ECETOC is currently gathering feedback from users and stakeholders – both registrants and authorities. This feedback, as well as future scientific insights and regulatory guidance, will be used to further improve and update the NanoApp. Among others, the following list of elements will be included in the next version: (i) the extension of the current report to include a data matrix on the functional assays used in the justification; (ii) a function to export the generated report for its direct use in IUCLID; (iii) the possibility of ‘freezing’ available cases and (iv) a function to assign a name to the generated sets of similar nanoforms. The next version of the NanoApp will also be amended to facilitate handling multicomponent and UVCB substances.


Nanomaterials in aquatic systems

Beyond the correct determination of similarity for read across between nanoforms, one of the major challenges ahead is the development of relevant data for nanomaterials in aquatic systems. ECHA developed appendices to the guidance documents on data requirements under REACH specific to nanomaterials, including for guidance R7b (endpoint specific guidance covering ecotoxicity and fate testing). The advice provided in these appendices is focused on specific recommendations for nanomaterials, although parts of the advice may also apply to other particulate materials (PMs).  Two recent OECD guidances, GD317 and GD318 excellently structure the challenges in obtaining a valid assessment of ecotoxicity, but cannot provide universal solutions.

With respect to the REACH guidance for nanomaterials, the aquatic testing of PMs has revealed inherent challenges aggravating the application of the respective guidance documents. For example, the preparation of stable PM dispersions is often not possible for standard test media (Fig. 3). To overcome this issue, the addition of humic substances, changes in pH and other modifications resulting in an adjustment of the test media composition, are possibilities to improve dispersion stability. However, these modifications do not always result in enhanced PM dispersion stability. In fact, those kinds of modifications frequently alter the behaviour and fate of PM, and consequently their ecotoxicological potential (e.g. reactivity, bioavailability, size distribution, etc.), which may cause acceptance issues with authorities.

Two parallel images of a laboratory bottle
Figure 3: Dispersion of a nanomaterial in a standardized test media, following preparation (left), and after approx. 24 h (right).

What is needed is a testing strategy which defines the best way forward for aquatic testing of PMs. Therefore, the EG that was launched by ECETOC in Q4 2020 aims to develop a white paper that addresses the following:

  1. Describing the current status of particulate material testing approaches;
  2. Identifying challenges in following these approaches; and 
  3. Developing a testing strategy to overcome these challenges. 

Furthermore, broader communication is anticipated, for example via a workshop which could potentially be organised at a SETAC annual meeting. ECETOC offers an excellent platform for dialogue and information exchange between regulatory bodies (e.g. ECHA), academia, and industry and it welcomes broader stakeholder participation in order to develop sustainable solutions for the challenges described above.

This broad discussion will be essential to agree jointly on the need for potential adaptions in aquatic PM testing, as well as to ensure regulatory acceptance of proposed strategies.

For more information on how to join the conversation, or how to get involved in this initiative, please contact Olivier de Matos, Secretary General of ECETOC (Olivier.dematos (at)

Bennard van Ravenzwaay

Bennard van Ravenzwaay

I am Senior Vice President for experimental toxicology and ecology at BASF and a professor for toxicology, working with new approach methods, at Wageningen University and Research. I am also the chairperson of ECETOC’s Scientific Committee. 


Robert Landsiedel

Robert Landsiedel

I am Vice President at the experimental toxicology and ecology department of BASF and associate professor (Privatdozent) for pharmacology and toxicology at the Free University of Berlin. I am the vice-chairperson of the German Toxicology Society.


Wendel Wohlleben 

 Wendel Wohlleben

I am Senior Principal Scientist at BASF, Dept. of Material Physics, second affiliation with Dept. of Experimental Toxicology and Ecology. I work on research projects on advanced materials development and on the safety of particles.


Simon Rafael Luederwald

Simon Rafael Luederwald

I am a lab team leader for experimental ecology at BASF. I received my PhD in environmental sciences from the University of Koblenz-Landau, Germany. During my doctoral research I was focusing on engineered inorganic nanomaterials, their transformation by environmental processes and resulting ecotoxicological potential towards aquatic invertebrates. 


Olivier de Matos

Olivier de Matos

I am the Secretary General of ECETOC a platform established in 1978 to advance the scientific knowledge of chemical safety for both human health and the environment. All of our work is based on the collaboration of leading scientists from industry, academia and regulatory bodies. These experts develop peer-reviewed, practical and trusted tools and frameworks that address scientific challenges with the ultimate goal of delivering a benefit to society. 



Arts, Josje H. E., Mackenzie Hadi, Muhammad-Adeel Irfan, Athena M. Keene, Reinhard Kreiling, Delina Lyon, Monika Maier, et al. 2015. “A Decision-Making Framework for the Grouping and Testing of Nanomaterials (DF4nanoGrouping).” Regulatory Toxicology andPharmacology : RTP 71 (2 Suppl): S1–S27. doi:10.1016/j.yrtph.2015.03.007.

Drew, N. M., E. D. Kuempel, Y. Pei, and F. Yang. 2017. “A Quantitative Framework to Group Nanoscale and Microscale Particles by Hazard Potency to Derive Occupational Exposure Limits: Proof of Concept Evaluation.” Regulatory Toxicology and Pharmacology89: 253–267. doi:10.1016/j.yrtph.2017.08.003.

ECHA. 2019a. Appendix for Nanoforms Applicable to the Guidance on Registration and Substance Identification.

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Janer, Gemma, Robert Landsiedel, and Wendel Wohlleben. "Rationale and decision rules behind the ECETOC NanoApp to support registration of sets of similar nanoforms within REACH." Nanotoxicology (2020): 1-22.

Oomen, A. G., E. A. Bleeker, P. M. Bos, F. Van Broekhuizen, S. Gottardo, M. Groenewold, D. Hristozov, et al. 2015. “Grouping and Read-Across Approaches for Risk Assessment of Nanomaterials.” International Journal of Environmental Research and Public Health 12 (10):13415–13434. doi:10.3390/ijerph121013415.

Wohlleben, Wendel, Bryan Hellack, Carmen Nickel, Monika Herrchen, Kerstin Hund-Rinke, Katja Kettler, Christian Riebeling, et al. 2019. “The nanoGRAVUR Framework to Group (nano)materials for their occupational, consumer, environmental risks based on a harmonized set of material properties, applied to 34 case studies.” Nanoscale 11 (38): 17637–17654. doi:10.1039/c9nr03306h.


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1 Comment

Highly informative article! We all hope NanoApp will provide better assessment of nanomaterials within REACH and reduce animal testing. I'm curious if the App could feature a list of gold-standard reference nanoforms to select from when submitting the comparison between novel and the currently existent and ECHA recognized valid nanomaterials.