Systematic Evaluation of ICH Guidelines Q3C, Q3D, Q3E, and M7 with Comparative Analysis of Permitted Daily Exposure Limits and Occupational Exposure Limits.

Permitted Daily Exposure (PDE) limits established by ICH guidelines and Occupational Exposure Limits (OELs) adopted in the European Union are central to controlling human exposure to pharmaceutical impurities and industrial chemicals, yet they are derived for different exposure scenarios, target populations, and protection goals. We compiled data for 90 chemicals with both PDEs (Q3C, Q3D, Q3E, M7) and EU OELs, normalized PDEs to a 70 kg worker, and converted them to airborne equivalents assuming 10 m3 inhalation over an 8-hour workday. OEL/PDE ratios ranged from 0.04 to 8,929, with an overall geometric mean of 57.1, indicating that OELs are generally several-fold higher (less stringent) than airborne PDE equivalents; eleven substances exceeded ratios of 1,000, most of them M7 mutagenic impurities. Five substances, however, showed more stringent OELs than the corresponding PDE-derived values. These patterns reflect systematic differences in risk-assessment objectives and support structured, Threshold of Toxicological Concern (TTC)- and hazard-banding-based approaches for deriving default OELs where none exist.