Safety is not the issue. Ability to feed the rounds might be? Some guns will accept any size of regular rimfire except mags, of course. Some might have issues with cartridges of varying lengths, and might still fire fine single shot with any cartridge, BB, CB, Short, LR. I guess if you closed the bolt on a misfed cartridge and it crushed the rim, it could set it off outside the chamber. That is just a wild guess. And of course they claim that firing shorts in a long rifle chamber causes buildup or crud to make loading a LR into the chamber a problem. Therefore a good scrubbing is in order after shooting alot of them. And of course autos will not function with different power level carts. But I think you can get a 10-22 modified to work with shorts. Just that no one much bothers because the smaller cartridges are no longer cheaper than the LR.