ICH Q3C Revisited Part I: Re-evaluation of Class 1 Residual Solvents.

In ICH Q3C five residual solvents are classified as "should be avoided" and are designated as Class 1 solvents. The solvents in question are: benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethene and 1,1,1-trichloroethane. Although multiple revisions to ICH Q3C have been made, PDE (permitted daily exposure) limits for Class 1 solvents remain unchanged from those originally proposed in 1997. Since that time, new toxicological data have become available, and additional expert assessments have been published. A detailed review of information currently available indicates that there is a case for a change to limits for all Class 1 solvents except benzene. Two of the solvents can be classified as mutagenic carcinogens making them eligible for determination of AI (acceptable intake) limits as described in ICH M7(R2). In addition, the concept of expressing limits as concentrations, based on the assumption of a daily drug-substance dose of 10 g, is challenged.