Major accident regulations aim at protecting the population and the environment from possible accidental releases of chemicals. To achieve this goal, the regulations need to be reassessed in light of the development of new technologies. A currently rapidly growing new technology is nanotechnology, and engineered nanomaterials (ENM) are already produced and used in commercial products. The aim of this work was therefore to evaluate the current knowledge on human and ecotoxicology of ENM and their release and behavior in the environment in the context of major accident prevention. Nano-specific release paths are not to be expected. The established safety standards in the chemical industry are also applicable to ENM, especially the separate storage of flammable solvents and detention reservoirs. The potential of a release to the environment of ENM in powder form is larger than for suspensions; however, it can be minimized by safety measures established for conventional dusts. The considered human toxicology studies show that to date not conclusive enough answers regarding the toxicity of ENM can be made. The effects are dependent not only on the material itself but more on the functionalization, surface reactivity, size, and form. The acute ecotoxicity of ENM seems to be similar to the one of the corresponding microparticles (TiO2) or the respective dissolved ions (Ag, Zn) with the exception of photocatalytically active nano-TiO2, which has an increased toxicity. In order to guarantee that all ENM are included in the existing major accident regulations, different classification options are possible and the advantages and disadvantages are discussed. An important step will be the compulsory inclusion of nano-specific data in the Material Safety Data Sheets that serve as the basic medium to transfer information from the manufacturer to downstream users and authorities. We also call for a regular monitoring of the production and uses for ‘high production volume ENM’ that could have the largest implications for major accident regulations.