Current regulatory guidelines call for the identification and quantification of chemical compounds which may migrate out of a medical device, combination product, or a drug container closure system, and into an individual. Compounds that migrate from these devices often have little available toxicity data resulting in a major challenge in performing an adequate assessment of biological or toxicological risks and thus potentially compromising patient safety. These limited toxicity data may exist by alternative routes. Therefore, route-to-route extrapolation of the available data may be considered for use in these instances. Here we discuss the factors to consider when performing route-to-route extrapolations for L&E compounds beginning with historic and regulatory approaches. This will be followed by a review of pharmacokinetic and pharmacodynamic considerations regarding the applicability of route-to-route extrapolation. Finally, we will discuss route-specific considerations and the derivation of safe exposure limits.