Permitted Daily Exposure Values: Application Considerations in Toxicological Risk Assessments.

ABSTRACT

Permitted daily exposure (PDE) values are used by some toxicologists to support the safety qualification of various types of impurities found in a drug substance (DS) or drug product (DP). Permitted daily exposure values are important tools for the toxicologist, but one must be aware of their limitations to ensure that they are used appropriately and effectively in the risk assessment process. First, a toxicologist must always perform a comprehensive analysis of all available animal and human safety data for an impurity, including identifying any data gaps that may exist. Second, if adequate data are available and there are no genotoxicity concerns, an appropriate well-designed repeat-dose toxicity study in animals should be chosen to calculate the PDE. It is important to note that PDE values qualify general systemic toxicity and not necessarily local toleration end points such as irritation and sensitization that are more concentration than dose dependent. In addition, a PDE value calculated from a general toxicity study in animals may not necessarily qualify for reproductive toxicology end points. Lastly, PDE values should never be thought of as analytical limits for or acceptable levels of an impurity in a DS or DP, as this ignores quality considerations. Using safety information from several chemicals as proxy impurities, this article serves as an educational primer to facilitate a better understanding of the development and use of PDE values in the risk assessment process.