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A framework for chemical hazard assessments under Safe and Sustainable by Design using multiple in silico tools

Publication Date
Authors
Author Name
Joanke van Dijk
Author Organization
Empa - Swiss Federal Laboratories for Material Science and Technology, St Gallen, Switzerland
Author Name
Anna Agalliadou
Author Organization
Aristotle University of Thessaloniki, Thessaloniki, Greece
Author Name
Chiara Laura Battistelli
Author Organization
Istituto Superiore di Sanita, Rome, Italy
Author Name
Emilio Benfenati
Author Organization
Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
Author Name
Cecilia Bossa
Author Organization
Istituto Superiore di Sanita, Rome, Italy
Author Name
Maja Halling
Author Organization
IVL, Swedish Environmental Research Institute, Stockholm, Sweden
Author Name
Spyros Karakitsios
Author Organization
Aristotle University of Thessaloniki, Thessaloniki, Greece & HERACLES Research Center on the Exposome and Health, Thessaloniki, Greece
Author Name
Achilleas Karakoltzidis
Author Organization
Aristotle University of Thessaloniki, Thessaloniki, Greece & HERACLES Research Center on the Exposome and Health, Thessaloniki, Greece
Author Name
Fotini Nikiforou
Author Organization
Aristotle University of Thessaloniki, Thessaloniki, Greece & HERACLES Research Center on the Exposome and Health, Thessaloniki, Greece
Author Name
Dimosthenis A. Sarigiannis
Author Organization
Aristotle University of Thessaloniki, Thessaloniki, Greece & HERACLES Research Center on the Exposome and Health, Thessaloniki, Greece & National Hellenic Research Foundation, Athens, Greece & School for Advanced Study (IUSS), Pavia, Italy
Author Name
Gianluca Selvestrel
Author Organization
Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
Author Name
Anezka Sharma
Author Organization
Masaryk University, Brno, Czechia
Author Name
Kirsi M. Siivola
Author Organization
Finnish Institute of Occupational Health, Helsinki, Finland
Author Name
Ziye Zheng
Author Organization
Swedish Environmental Research Institute, Stockholm, Sweden

The hazard identification of chemicals is a key step of the “Safe and Sustainable by Design” (SSbD) framework introduced by the European Commission, aiming to eliminate hazardous substances early in innovation. In this context, in silico methods such as (Quantitative) Structure–Activity Relationship ((Q)SAR) models offer rapid, cost-effective, and animalfree alternatives for early-stage hazard screening. The Partnership for the Assessment of Risks from Chemicals (PARC) is developing a toolbox to facilitate SSbD assessments containing numerous (Q)SAR models. Challenges, however, exist in using and combining multiple in silico tools. Here, we developed a workflow to assess chemical hazards using multiple in silico tools within the PARC toolbox. The workflow consists of three phases: (1) the preparation stage, (2) running the models, and (3) the evaluation stage. To demonstrate the approach, we applied it to a case study comparing bisphenol A, isosorbide, and bisphenol AP. Tools from the PARC toolbox were screened for relevance, transparency, and open access availability. Only models aligned with SSbD-required endpoints and adequately documented via (Q)SAR Model Reporting Formats were retained. The properties assessed in this study cover carcinogenicity, germ cell mutagenicity, reproductive toxicity, endocrine disruption, persistence, bioaccumulation, and aquatic toxicity. Predictions were filtered using applicability domain criteria and reliability scores. Next, three strategies were applied for integrating different model outputs. Model agreement varied across endpoints and integration methods. This emphasizes the possibility of different SSbD assessment outcomes and thus the need for transparent documentation of the chosen strategy and explicit handling of uncertainty. Our study demonstrates how multiple models can systematically and transparently be integrated via the developed workflow. Key areas for improvement are to refine integration strategies, harmonize the definition and communication of applicability domains across tools, expand in silico coverage for currently underrepresented endpoints, and develop approaches to consider data gaps in SSbD assessments.

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Integrated Environmental Assessment and Management
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Safe and Sustainable by Design
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