ICH: ICH Q3C(R8) Guideline for Residual Solvents contains new PDEs

ICH published the revised version (Step 4) of the ICH Q3C(R8) Guideline on Impurities: Guideline for Residual Solvents on 22 April 2021.

The Permitted Daily Exposure (PDE) values for the following substances were added:  

• 2-Methyltetrahydrofuran (50 mg/day) 
• Cyclopentyl methyl ether (15 mg/day)  
• Tertiary butyl alcohol (35 mg/day) 

The PDE values were developed by the relevant Expert Working Group (EWG). On 25 March 2020, ICH already published the document for public consultation under Step 2 (we reported). The values proposed then have been adopted as final and the Step 4 version has not been changed compared to the draft document. This allows implementation to take place in the ICH regions. This ICH process, which is conducted under "Step 5", concludes the revision. 

Toxicity details:  

• Methyltetrahydrofuran was found to be non-genotoxic in a mutation assay with bacteria, human lymphocytes and rats. No data are available on carcinogenicity. Reproductive toxicity and repeated-dose toxicity were not observed. The product was classified in solvent class 3.  
• For cyclopentyl methyl ether, no toxicity in humans was found. Likewise, no genotoxic potential was found. Again, no data are available on carcinogenicity. No statements could be made on reproductive and developmental toxicity on the basis of data available to date. The product was classified as a class 2 solvent.  
• For tertiary butyl alcohol, no genotoxicity was found either. The data on carcinogenicity do not allow any precise conclusions to be drawn with regard to the effect on humans, while changes in the renal tubules were found in rats. No precise statements could be made on reproductive toxicity either, but moderate transient systemic toxicity was found in rats. The product was classified as a class 2 solvent.  

In a revision process, further PDE values are to be gradually added as new toxicological data for solvents become known.