Toxicokinetic Characterization of Isopropyl Glycidyl Ether in Rat by a Validated LC-APCI-MS/MS Method Using In-Source...

Area of Science:

• Environmental Chemistry and Toxicology
• Analytical Chemistry
• Pharmacokinetics

Background:

• Isopropyl glycidyl ether (IPGE) is a reactive diluent in epoxy resin manufacturing.
• Limited toxicokinetic data exists for IPGE despite toxicity studies.
• Understanding systemic exposure is crucial for occupational health and safety.

Purpose of the Study:

• To develop and validate a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying IPGE in rat plasma.
• To investigate the toxicokinetics and systemic exposure of IPGE following oral administration in rats.
• To tentatively identify IPGE metabolites in rat plasma.

Main Methods:

• Development of an LC-MS/MS method using tert-butyl glycidyl ether as an internal standard.
• Application of in-source derivatization via the Meerwein reaction for enhanced sensitivity (LLOQ of 0.01 μg/mL).
• Analysis of rat plasma samples from a single-dose oral toxicity study across three dose levels (1000-2000 mg/kg).

Main Results:

• A validated LC-MS/MS method achieved high sensitivity for IPGE quantification.
• Dose-dependent superproportional systemic exposure to IPGE was observed in rats.
• Seven metabolites of IPGE were tentatively identified, including sulfate, glucuronide, and glutathione conjugates.

Conclusions:

• The developed method enables sensitive quantification of IPGE in rat plasma, aiding toxicokinetic studies.
• Observed superproportional exposure highlights the importance of dose considerations in toxicity assessments.
• Metabolite identification provides insights into IPGE's metabolic fate and supports biomonitoring strategies.