Safety and sustainability of animal feeds is a pillar of the safety of the entire food chain. Feed additive assessment incorporates consumer safety as well as animal health and welfare, which, in turn, can affect productivity and hence food security. The safety of feed users and the environment are other important components of the assessment process which, therefore, builds on a One Health perspective. In several instances the assessment entails a balanced assessment of benefits and risks for humans, animals and/or the environment. Three case studies are selected to discuss issues for a consistent framework on Risk-Benefit Assessment (RBA) of feed additives, based on EFSA opinions and literature: (a) Supplementation of feeds with trace elements with recognized human toxicity (cobalt, iodine) - RBA question: can use levels, hence human exposure, be reduced without increasing the risk of deficiency in animals?; (b) Aflatoxin binders in dairy animals - RBA question: can the use reduce the risk for human health due to aflatoxin M1, without unexpected adverse effects for animals or humans?; (c) Use of formaldehyde as preservative in feedstuffs to prevent microbial contamination - RBA question: is the reduction of microbiological risks outweighed by risks for the consumers, farmed animals or the workers? The case studies indicate that the safety of use of feed additives can involve RBA considerations which fit into a One Health perspective. As in other RBA circumstances, the main issues are defining the question and finding “metrics” that allow a R/B comparison; in the case of feed additives, R and B may concern different species (farm animals and humans). A robust assessment of animal requirements, together with sustainability considerations, might be a significant driving force for a RBA leading to a safe and effective use.