The applicability of the Safe-by-Design (SbD) concept was investigated during development of oxygen carriers (OCs) for Chemical Looping Combustion (CLC) installations; the newly developed OCs are complex, fluidizable metal-oxides. SbD assesses Health Safety and Environmental (HSE) risks at an early stage of product development. Hereto, the impact of the key parameters on safety of future industrial units were estimated with exposure simulations (solid pouring tests and modelling by similarity with commercial refining technology). The likelihood of health effects for workers exposed via inhalation was examined with in vitro tests, showing that particles of Mn-based OC have the potency to initiate an allergic reaction (concentration-dependent increase of cytokines). The manufacturing process showed impact on the ecotoxicological properties of Cu-based OC (EC50 algae <6.5 to 68 % of the soluble fraction). The following characteristics were identified as key parameters for the assessment: powder particle size (mean diameter 4.24-175.4 mu m) and airborne size distribution (PM10 fraction 8-62% in PM100), dustiness (201-1370 PM100 mu g/m(3)), chemical composition (Mn, Fe, Cu) and manufacturing process. This multidisciplinary study demonstrates the relevance of the SbD approach to assess and manage HSE risks at an early stage of OC development for future energy production. (C) 2021 Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.