Toxicological Assessment of 2-Methyltetrahydrofuran and Cyclopentyl Methyl Ether in Support of Their Use in Pharmaceutical Chemical Process Development

Abstract

Herein we document our evaluation of the oral toxicity of MeTHF and CPME as determined in three month repeat-dose toxicity studies in rats as well as a battery of tests conducted under Good Laboratory Practice (GLP) to assess induction of micronuclei, microbial mutagenicity, and chromosomal aberrations. Based on the studies performed, human permitted daily exposure limits of 6.2 and 7.4 mg/day for MeTHF and CPME respectively have been established, with both of these solvents also considered negative for genotoxicity and mutagenicity. In addition, for future standard repeat-dose GLP animal studies a general limit of 20 mg/kg/day and a maximum concentration of 2% of MeTHF or CPME would not be expected to contribute to any toxicity potentially exhibited by an active pharmaceutical ingredient containing these solvents. By sharing these data, we hope to facilitate the use of these ethereal solvents within the pharmaceutical chemical process development community and contribute to the path to their potential ICH classification.