Here we describe the generation of hypotheses for grouping nanoforms (NFs) following inhalation exposure and the tailored Integrated Approach to Testing and Assessment (IATA) with which each specific hypothesis can be tested. This is part of a state-of-the-art framework to support the hypothesis-driven grouping and read-across of NFs, as developed by the EU-funded Horizon 2020 project GRACIOUS. Respirable NFs, depending on their physicochemical properties, may either dissolve in lung lining

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... d, or in acidic lysosomal fluid after uptake by cells. Alternatively, NFs may also persist in particulate form. Dissolution in the lung is therefore a decisive factor for the toxicokinetics of NFs. This has led to the development of four hypotheses broadly grouping NFs as instantaneous, quickly, gradually and very slowly dissolving NFs. For instantaneously dissolving NFs, hazard information can be derived by read-across from the ions. For quickly dissolving particles, as accumulation of particles is not expected, ion toxicity will drive the toxic profile. However, the particle aspect influences the location of the ion release. For gradually dissolving and very slowly dissolving NFs, particle-driven toxicity is of concern. These NFs may be grouped by their reactivity and inflammation potency. The hypotheses are substantiated by a tailored IATA which describes the minimum information and laboratory assessments of NFs under investigation required to justify grouping. The GRACIOUS hypotheses and tailored IATA for respiratory toxicity of inhaled NFs can be used to support decision making regarding Safe(r)-by-Design product development or adoption of precautionary measures to mitigate potential risks. It can also be used to support read-across of adverse effects such as pulmonary inflammation and subsequent downstream effects like lung fibrosis and lung tumor formation after long-term exposure.