Oxide-perovskites designed for automotive catalysts contain multiple metal elements whose presence is crucial to achieving the targeted performance. They are highly stable in exhaust operating conditions; however, little is known about their stability under physiological conditions. As some of the metallic components are hazardous to humans and the environment, perovskite benefits in cleaner air must be balanced with risks in a Safe and Sustainable Design (SSbD) approach. New approach methodologies (NAMs), including in chemico and in silico methods, were used for testing hazards and benefits, including catalytic activity and tolerance for temporary excess of oxygen under dynamic driving conditions. The composition and surface properties of six different lanthanum-based oxide-perovskites compromised their stability under lung physiological conditions, influencing the oxidative damage of the particles and the bioacessibility of leaching metals. We found consistent biotransformation of the oxide-perovskite materials at pH 4.5. The leached lanthanum ions, but not other metals, respeciated into lanthanum phosphate nanoparticles, which increased the overall oxidative damage in additive synergy. The NAM results in the presented SSbD approach were challenged by in vivo studies in rats and mice, which confirmed multicomponent clearance from lungs into urine and supported the comparative ranking of effects against well-characterized spinel materials. Among the perovskites, the version with reduced nickel content and doped with palladium offered the best SSbD balance, despite not improving the conventional benchmark catalytic performance and related sustainability benefits. Redesign by industry may be necessary to better fulfill all SSbD dimensions.