Towards harmonisation of testing of nanomaterials for EU regulatory requirements on chemical safety - A proposal for further actions.

Over the recent years, EU chemicals legislation, guidance and test guidelines have been developed or adapted for nanomaterials to facilitate safe use of nanomaterials. This paper provides an overview of the information requirements across different EU regulatory areas. For each information requirement, a group of 22 experts identified potential needs for further action to accommodate guidance and test guidelines to nanomaterials. Eleven different needs for action were identified, capturing twenty-two information requirements that are specific to nanomaterials and relevant to multiple regulatory areas. These were further reduced to three overarching issues: 1) resolve issues around nanomaterial dispersion stability and dosing in toxicity testing, in particular for human health endpoints, 2) further develop tests or guidance on degradation and transformation of organic nanomaterials or nanomaterials with organic components, and 3) further develop tests and guidance to measure (a)cellular reactivity of nanomaterials. Efforts towards addressing these issues will result in better fit-for-purpose test methods for (EU) regulatory compliance. Moreover, it secures validity of hazard and risk assessments of nanomaterials. The results of the study accentuate the need for a structural process of identification of information needs and knowledge generation, preferably as part of risk governance and closely connected to technological innovation policy.

Too advanced for assessment? Advanced materials, nanomedicine and the environment.

Advanced materials, and nanomaterials, are promising for healthcare applications and are in particular in the spotlight of medical innovation since rapidly developed nano-formulated vaccines provide relief in the SARS-CoV-2 pandemic. Further increased rapid growth is to be expected as more and more products are in development and reach the market, beneficial for human health. However, the human body is not a dead end and these products are likely to enter the environment, whereas their fate and effects in the environment are unknown. This part of the life-cycle of advanced medicinal products tends to be overlooked, if the perspective is human-centered and excludes the connectedness of human activity with, and consequences for our environment. Gaps are reviewed that exist in awareness, perspective taking, inclusion of environmental concerns into research and product development and also in available methodologies and regulatory guidance. To bridge these gaps, possible ways forward start to emerge, that could help to find a more integrative way of assessing human and environmental safety for advanced material medicinal products and nanomedicines.

Environmental Risk Assessment of Nanomaterials in the Light of New Obligations Under the REACH Regulation: Which Challenges Remain and How to Approach Them?

Within the European regulation on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH, EC No 1907/2006) specific provisions for nanomaterials were included, which have become effective on 1 January 2020. Although knowledge on the peculiarities of testing and assessing fate and effects of nanomaterials in the environment strongly increased in the last years, uncertainties about how to perform a reliable and robust environmental risk assessment for nanomaterials still remain. These uncertainties are of special relevance in a regulatory context, challenging both industry and regulators. The present paper presents current challenges in regulatory hazard and exposure assessment under REACH, as well as classification of nanomaterials, and makes proposals to address them. Still, the nanospecific considerations made here are expected to also be valid for environmental risk assessment approaches in other regulations of chemical safety. Inter alia, these proposals include a way forward to account for exposure concentrations in aquatic toxicity test systems, a discussion of how to account for availability of dissolving nanomaterials in aquatic test systems, and a pragmatic proposal to deduce effect data for soil organisms. Furthermore, it specifies how to potentially deal with nanoforms under the European regulation on Classification, Labelling and Packaging of substances and mixtures (CLP) and outlines the needs for proper exposure assessments of nanomaterials from a regulatory perspective. Integr Environ Assess Manag 2020;16:706-717. © 2020 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Nanopharmaceuticals: Tiny challenges for the environmental risk assessment of pharmaceuticals.

Many new developments and innovations in health care are based on nanotechnology. The field of nanopharmaceuticals is diverse and not as new as one might think; indeed, nanopharmaceuticals have been marketed for many years, and the future is likely to bring more nanosized compounds to the market. Therefore, it is time to examine whether the environmental risk assessment for human pharmaceuticals is prepared to assess the exposure, fate, and effects of nanopharmaceuticals in an adequate way. Challenges include the different definitions for nanomaterials and nanopharmaceuticals, different regulatory frameworks, the diversity of nanopharmaceuticals, the scope of current regulatory guidelines, and the applicability of test protocols. Based on the current environmental risk assessment for human medicinal products in the European Union, necessary adaptations for the assessment procedures and underlying study protocols are discussed and emerging solutions identified.

Test strategy for assessing the risks of nanomaterials in the environment considering general regulatory procedures.

BACKGROUND: Engineered nanomaterials (ENMs) are marketed as a substance or mixtures and are additionally used due to their active agent properties in products such as pesticides or biocides, for which specific regulations apply. Currently, there are no specific testing strategies for environmental fate and effects of ENMs within the different regulations. An environmental test and risk assessment strategy for ENMs have been developed considering the general principles of chemical assessment. RESULTS: The test strategy has been developed based on the knowledge of national and international discussions. It also takes into account the conclusions made by the OECD WPMN which held an expert meeting in January 2013. For the test strategy development, both conventional and alternative endpoints were discussed and environmental fate and effects were addressed separately. CONCLUSION: A tiered scheme as commonly used in the context of precautionary environmental risk assessment was suggested including the use of mathematical models and trigger values to either stop the procedure or proceed to the next tier. There are still several gaps which have to be filled, especially with respect to fate, to develop the test strategy further. The test strategy features a general approach. It is not specified to fulfil the information requirements of certain legislation (e.g. plant protection act, biocide regulation, REACH). However, the adaption of single elements of the strategy to the specific needs of certain legislation will provide a valuable contribution in relation to the testing of nanomaterials.

Structural engineering of nanoporous anodic aluminium oxide by pulse anodization of aluminium.

Nanoporous anodic aluminium oxide has traditionally been made in one of two ways: mild anodization or hard anodization. The first method produces self-ordered pore structures, but it is slow and only works for a narrow range of processing conditions; the second method, which is widely used in the aluminium industry, is faster, but it produces films with disordered pore structures. Here we report a novel approach termed "pulse anodization" that combines the advantages of the mild and hard anodization processes. By designing the pulse sequences it is possible to control both the composition and pore structure of the anodic aluminium oxide films while maintaining high throughput. We use pulse anodization to delaminate a single as-prepared anodic film into a stack of well-defined nanoporous alumina membrane sheets, and also to fabricate novel three-dimensional nanostructures.

Quantitative analysis of the grain morphology in self-assembled hexagonal lattices.

We present a methodology for the analysis of the grain morphology of self-ordered hexagonal lattices and for the quantitative comparison of the quality of their grain ordering based on the distances between nearest neighbors and their angular order. Two approaches to grain identification and evaluation are introduced: (i) color coding the relative angular orientation of hexagons containing a central entity and its six nearest neighbors, and (ii) incorporating triangles comprising three nearest neighbors into grains or repelling them from grains based on deviations of the side lengths and the internal angles of the triangles from those of an ideal equilateral triangle. A spreading algorithm with tolerance parameters allows single grains to be identified, which can thus be ranked according to their size. Hence, grain size distributions are accessible. For the practical evaluation of micrographs displaying self-ordered structures, we suggest using the size of the largest identified grain as a quality measure. Quantitative analyses of grain morphologies are key to the systematic and rational optimization of the fabrication of self-assembled materials.

Self-ordered anodic aluminum oxide formed by H2SO4 hard anodization.

The self-ordering of nanoporous anodic aluminum oxide (AAO) in the course of the hard anodization (HA) of aluminum in sulfuric acid (H2SO4) solutions at anodization voltages ranging from 27 to 80 V was investigated. Direct H2SO4-HA yielded AAOs with hexagonal pore arrays having interpore distances D(int) ranging from 72 to 145 nm. However, the AAOs were mechanically unstable and cracks formed along the cell boundaries. Therefore, we modified the anodization procedure previously employed for oxalic acid HA (H2C2O4-HA) to suppress the development of cracks and to fabricate mechanically robust AAO films with D(int) values ranging from 78 to 114 nm. Image analyses based on scanning electron micrographs revealed that at a given anodization voltage the self-ordering of nanopores as well as D(int) depend on the current density (i.e., the electric field strength at the bottoms of the pores). Moreover, periodic oscillations of the pore diameter formed at anodization voltages in the range from 27 to 32 V, which are reminiscent of structures originating from the spontaneous growth of periodic fluctuations, such as topologies resulting from Rayleigh instabilities.

Nondestructive mechanical release of ordered polymer microfiber arrays from porous templates.

The fabrication of one-dimensional (1D) nanostructures and microstructures inside the pores of porous templates is intensively investigated. The release of these structures is commonly accomplished by etching and destroying the templates. The 1D nanostructures and microstructures tend to condense because of the occurrence of capillary forces during drying of the specimens. It is shown that highly ordered arrays of polymer microfibers can be easily detached from silanized porous templates by mechanical lift-off. This procedure leaves the templates intact, thus allowing their recycling, and does not involve the use of solutions or solvents, thus circumventing condensation. Therefore, mechanical lift-off may enable the up-scaling of template-based approaches to the fabrication of highly ordered assemblies of 1D nanostructures and microstructures.