Calculation of a permitted daily exposure value for the solvent 2-methyltetrahydrofuran

In response to increasing concerns around the potential environmental impact of industrial chemicals, the pharmaceutical industry is seeking alternatives for traditional solvents used during the manufacturing process. Taking into consideration the principles of green chemistry, 2-methyltetrahydrofuran (2-MeTHF) is proposed as a suitable replacement for the structurally similar solvent tetrahydrofuran (THF). 2-MeTHF is derived from renewable sources and is more easily recovered thereby facilitating its reuse. However, 2-MeTHF is currently not included in the International Conference on Harmonisation (ICH) Q3C residual solvent guidelines and there is no Permitted Daily Exposure (PDE) limit proposed below which there would be negligible safety concerns for patients exposed to it as a residual impurity in a drug product. To enable the calculation of a PDE, a GLP compliant 3-month repeat-dose oral toxicity study in rats with a 1-month recovery period was conducted with doses of 2-MeTHF of 0, 80, 250, 500 and 1000 mg/ kg/day. Administration of doses of up to 1000 mg/kg/day was tolerated. Based upon minimal observed effects on the liver at >= 500 mg/kg/day, the NOAEL in this study was considered to be 250 mg/kg/day. Inclusion of this NOAEL, and a safety factor of 250 a PDE of 50 mg/day was derived to support the safe use of 2-MeTHF in the pharmaceutical industry. (C) 2017 Elsevier Inc. All rights reserved.