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

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.

Lens cholesterol biosynthesis inhibition: A common mechanism of cataract formation in laboratory animals by pharmaceutical products.

CJ-12,918, a 5-lipoxygenase (5-LO) inhibitor, caused cataracts during a 1-month safety assessment studies in rats whereas the structurally similar ZD-2138 was without effect. For CJ-12,918 analogs, blocking different sites of metabolic liability reduced (CJ-13,454) and eliminated (CJ-13,610) cataract formation in both rats and dogs. Using this chemical series as a test set, models and mechanisms of toxicity were first explored by testing the utility of ex vivo rat lens explant cultures as a safety screen.

Calculation of a permitted daily exposure value for the solvent 2-methyltetrahydrofuran.

In response to increasing concerns around the potential environmental impact of industrial chemicals, the pharmaceutical industry is seeking alternatives for traditional solvents used during the manufacturing process. Taking into consideration the principles of green chemistry, 2-methyltetrahydrofuran (2-MeTHF) is proposed as a suitable replacement for the structurally similar solvent tetrahydrofuran (THF). 2-MeTHF is derived from renewable sources and is more easily recovered thereby facilitating its reuse.