Today, the FDA published the eighth revision of a guidance titled Part VI: Impurities: Residual Solvents (Maintenance): PDES For 2-Methyltetrahydrofuran, Cyclopentyl Methyl Ether, and Tertiary-Butyl Alcohol (here). This revision adds the three residual solvents named above and provides permitted safe daily exposure (PDE) limits for patients.
The guidance provides information on the solvents themselves, the results of genotoxicity, reproductive and developmental toxicity, and repeat dose toxicity studies, and, in one case, the carcinogenicity evaluation that supports the classification of the solvent, as well as the recommended PDE for each of the three residual solvents.
The conclusion for each of the three solvents is reproduced below.
Conclusion: The calculated PDE for 2-MTHF is 50 milligrams per day (mg/day) based upon the no observable effect level (NOEL) of the rat sub-chronic oral study. Since the PDE is 50 mg/day, it is recommended that 2-MTHF be placed into class 3 “Solvents with Low Toxic Potential” in Table 3 in the ICH Q3C guidance.
CYCLOPENTYL METHYL ETHER
Conclusion: The calculated PDE for CPME is 15 mg/day based upon the NOEL from the 28-day oral toxicity study. Therefore, it is recommended that CPME be placed into class 2 “Solvents To Be Limited” in Table 2 in the ICH Q3C guidance.
Conclusion: The calculated PDE for TBA is 35 mg/day based upon the Lowest Observed Effect Level (LOEL) for nephropathy in females from the two-year rat carcinogenicity study. It is recommended that TBA be placed into class 2 “Solvents To Be Limited” in Table 2 in the ICH Q3C guidance.
The guidance also provides a discussion of the key findings and the references upon which the decisions were evaluated.