Development of an LC–MS/MS Assay and Toxicokinetic Characterization of Hexamethylenetetramine in Rats

Hexamethylenetetramine, an aldehyde-releasing agent, is used as a preservative in various food, cosmetics, and medical treatments, such as a treatment for urinary tract infections. It has been reported to be allergenic on contact with the skin, with the additional possibility of causing toxicity once absorbed systemically. Despite its potential toxicity, there are no reports on the in vivo bioavailability of hexamethylenetetramine following oral or dermal administration. In this study, we developed a new simple and sensitive LC–MS/MS method for the determination of hexamethylenetetramine in plasma and applied this method to characterize the toxicokinetics. The developed assay had a sufficient specificity and sensitivity for toxicokinetic characterization, and its accuracy and precision were verified. Following iv injection, the plasma concentration of hexamethylenetetramine showed mono exponential decay, with an elimination half-life of about 1.3 h. Following oral administration, the T(max) reached an average of 0.47 h and bioavailability was estimated as 89.93%. After percutaneous administration, it reached C(max) on average at 2.9–3.6 h. Although the absorption rate was relatively slow, its average bioavailability was calculated as 77.19–78.91%. Overall, most of the orally and percutaneously administered hexamethylenetetramine was absorbed into systemic circulation. The derived results in this study are expected to be utilized as the scientific evidence for further toxicokinetic study and risk assessment.