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The physico-chemical properties of manufactured nanomaterials (NMs) can be fine-tuned to obtain different functionalities addressing the needs of specific industrial applications. The physico-chemical properties of NMs also drive their biological interactions. Accordingly, each NM requires an adequate physico-chemical characterization and potentially an extensive and time-consuming (eco)toxicological assessment, depending on regulatory requirements. Grouping and read-across approaches, which have already been established for chemicals in general, are based on similarity between substances and can be used to fill data gaps without performing additional testing. Available data on "source" chemicals are thus used to predict the fate, toxicokinetics and/or (eco)toxicity of structurally similar "target" chemical(s). For NMs similar approaches are only beginning to emerge and several challenges remain, including the identification of the most relevant physico-chemical properties for supporting the claim of similarity. In general, NMs require additional parameters for a proper physico-chemical description. Furthermore, some parameters change during a NM's life cycle, suggesting that also the toxicological profile may change.This paper compares existing concepts for NM grouping, considering their underlying basic principles and criteria as well as their applicability for regulatory and other purposes. Perspectives and recommendations based on experiences obtained during the EU Horizon 2020 project NanoReg2 are presented. These include, for instance, the importance of harmonized data storage systems, the application of harmonized scoring systems for comparing biological responses, and the use of highthroughput and other screening approaches. We also include references to other ongoing EU projects addressing some of these challenges.

For perovskites with the general formula ACoO 3−δ (A = La, Pr, Nd, Sm, and Gd) the influence of the A-site cation on the electrical conductivity, electronic structure, thermodynamic stability, and oxygen stoichiometry was studied. The perovskite oxide powders were produced by a combined citric acid and ethylenediaminetetraacetic acid complexing method. Ceramic specimens sintered at 1100 • C in air were single-phase perovskites. With increasing temperature, the electrical conductivity shows three discrete regimes. All compositions show semiconductivity up to a transition temperature of ∼300 • C-450 • C and then behave like metallic conductors. The activation energies for the semiconductivity, as well as the transition temperatures to the metallic-like conduction, decrease monotonically with increasing pseudocubic lattice parameters, i.e., with increasing ionic radii of the A cation. This behavior correlates with decreasing oxygen nonstoichiometry and increased thermodynamic stability. The highest conductivity and the lowest activation energy of 0.66 eV were found for LaCoO 3−δ , which also had the lowest semiconductor-metal transition temperature at 269 • C, the lowest oxygen nonstoichiometry of δ = 0.008, and the highest Gibbs free energy change for the decomposition reaction of 42.37 kJ/mol at 850 • C. GdCoO 3−δ had the highest oxygen nonstoichiometry with δ = 0.032, a high activation energy of 1.19 eV for the semiconductivity with a high transition temperature at 452 • C, and the lowest Gibbs free energy change of 26.54 kJ/mol at 850 • C. X-ray absorption spectroscopy data imply an increasing Co low-spin character with decreasing cation radius from La to Gd, while an increase in temperature increases the number of holes or Co 3d bandwidth. This correlates well with the electrical conductivity data.

Understanding nanomaterial (NM)−protein interactions is a key issue in defining the bioreactivity of NMs with great impact for nanosafety. In the present work, the complex phenomena occurring at the bio/nano interface were evaluated in a simple case study focusing on NM−protein binding thermodynamics and protein stability for three representative metal oxide NMs, namely, zinc oxide (ZnO; NM-110), titanium dioxide (TiO 2 ; NM-101), and silica (SiO 2 ; NM-203). The thermodynamic signature associated with the NM interaction with an abundant protein occurring in most cell culture media, bovine serum albumin (BSA), has been investigated by isothermal titration and differential scanning calorimetry. Circular dichroism spectroscopy offers additional information concerning adsorption-induced protein conformational changes. The BSA adsorption onto NMs is enthalpy-controlled, with the enthalpic character (favorable interaction) decreasing as follows: ZnO (NM-110) > SiO 2 (NM-203) > TiO 2 (NM-101). The binding of BSA is spontaneous, as revealed by the negative free energy, ΔG, for all systems. The structural stability of the protein decreased as follows: TiO 2 (NM-101) > SiO 2 (NM-203) > ZnO (NM-110). As protein binding may alter NM reactivity and thus the toxicity, we furthermore assessed its putative influence on DNA damage, as well as on the expression of target genes for cell death (RIPK1, FAS) and oxidative stress (SOD1, SOD2, CAT, GSTK1) in the A549 human alveolar basal epithelial cell line. The enthalpic component of the BSA−NM interaction, corroborated with BSA structural stability, matched the ranking for the biological alterations, i.e., DNA strand breaks, oxidized DNA lesions, cell-death, and antioxidant gene expression in A549 cells. The relative and total content of BSA in the protein corona was determined using mass-spectrometry-based proteomics. For the present case study, the thermodynamic parameters at bio/nano interface emerge as key descriptors for the dominant contributions determining the adsorption processes and NMs toxicological effect.

This paper presents a comprehensive review of European Union (EU) legislation addressing the safety of chemical substances, and possibilities within each piece of legislation for applying grouping and read-across approaches for the assessment of nanomaterials (NMs). Hence, this review considers both the overarching regulation of chemical substances under REACH (Regulation (EC) No 1907/2006 on registration, evaluation, authorization, and restriction of chemicals) and CLP (Regulation (EC) No 1272/2008 on classification, labeling and packaging of substances and mixtures) and the sector-specific pieces of legislation for cosmetic, plant protection and biocidal products, and legislation addressing food, novel food, and food contact materials. The relevant supporting documents (e.g. guidance documents) regarding each piece of legislation were identified and reviewed, considering the relevant technical and scientific literature. Prospective regulatory needs for implementing grouping in the assessment of NMs were identified, and the question whether each particular piece of legislation permits the use of grouping and read-across to address information gaps was answered.ARTICLE HISTORY

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