Moving towards safe and sustainable innovations is an international policy ambition. In the on-hand manuscript, a concept combining safe by design and sustainability was implemented through the integration of human and environmental risk assessment, life cycle assessment as well as an assessment of the economic viability. The result is a nested and iterative process in form of a decision tree that integrates these three elements in order to achieve sustainable, safe and competitive materials, products or services. This approach, embedded into the stage-gate-model for safe by design, allows to reduce the uncertainty related to the assessment of risks and impacts by improving the quality of the data collected along each stage. In the second part of the manuscript, the application is shown for a case study dealing with the application of nanoparticles for Li-Ion batteries. One of the general conclusions out of this case study is that data gaps are a key aspect in view of the reliability of the results.

In line with the 3R concept, nanotoxicology is shifting from a phenomenological to a mechanistic approach based on in vitro and in silico methods, with a consequent reduction in animal testing. Risk Assessment (RA) and Life Cycle Assessment (LCA) methodologies, which traditionally rely on in vivo toxicity studies, will not be able to keep up with the pace of development of new nanomaterials unless they adapt to use this new type of data. While tools and models are already available and show a great potential for future use in RA and LCA, currently none is able alone to quantitatively assess human hazards (i.e. calculate chronic NOAEL or ED50 values). By highlighting which models and approaches can be used in a quantitative way with the available knowledge and data, we propose an integrated pathway for the use of in vitro data in RA and LCA. Starting with the characterization of nanoparticles' properties, the pathway then investigates how to select relevant in vitro human data, and how to bridge in vitro dose-response relationships to in vivo effects. If verified, this approach would allow RA and LCA to stir up the development of nanotoxicology by giving indications about the data and quality requirements needed in risk methodologies.

Microplastics are ubiquitous in ecosystems and a lot of research is being performed to understand their environmental fate and effects on organisms. However, the release and impact of MP has so far not been considered in LCA studies. This is due to missing information on the inventory side about microplastic releases and missing Characterization Factors to quantify the effects of MP. The goal of this study was to elucidate the relevance of MP release into freshwaters from an LCA perspective, by using worst-case assumptions. In accordance with the USEtox framework, an interim and simplified Characterization Factor for the impact category of freshwater ecotoxicity was calculated to be 3231 PAF·m³·d·kg⁻¹. Applying this Characterization Factor, two LCA case studies were conducted, one on a polyester T-Shirt and one with a shower gel containing microplastics. The results show a small contribution of microplastics to the freshwater ecotoxicity for a scenario with state-of-the-art wastewater treatment. Different scenarios varying in microplastic release and removal during wastewater treatment and a sensitivity analysis of the Characterization Factor allowed identifying the potential range of the microplastic contribution to the overall ecotoxicity. In conclusion, the inclusion of microplastic release into LCA only marginally influences the overall environmental effects of the two products in the LCA case studies.

The major theme of the NRC report “Toxicity Testing in the Twenty-first Century” is to replace animal testing by using alternative in vitro methods. Therefore, it can be expected that in the future in vivo data will be replaced with in vitro data. Hence, there is a need for new strategies to make use of the increasing amount of in vitro data when developing human toxicological effect factors (HEF) to characterize the impact category of human toxicity in life cycle assessment (LCA). Here, we present a new approach for deriving HEF for manufactured nanomaterials (MNMs) based on the combined use of in vitro toxicity data and a relative potency factor (RPF) approach. In vitro toxicity tests with nano-CuO, nano-Ag and nano-ZnO and their corresponding ions were performed on THP-1, CaCo-2 and Hep-G2 cell lines. The ratio of the here calculated EC₅₀ of the ionic form and the nanoform corresponds to the Relative Potency Factor (RPF). Using this approach, HEFs (case/kg_intake) for the aforementioned nanoparticles were obtained. Non-carcinogenic HEFs (case/kg_intake) for exposure via ingestion of 5.9E-01, 7.5E-03 and 2.5 E-02 were calculated for nano-Ag, nano-CuO and nano-ZnO, respectively. The HEF values here proposed were compared with HEF values extrapolated from in vivo toxicity data reported in the literature. The here presented procedure is the most appropriate approximation currently available for using in vitro toxicity data on MNM for application in the field of LCIA.