Human metabolism and excretion kinetics of the fragrance lysmeral after a single oral dosage

2-(4-tert-Butylbenzyl)propionaldehyde, also known as lysmeral, lilial or lily-aldehyde (CAS No 80-54-6) is a synthetic fragrance used in a variety of consumer products like perfumes, after shave lotions, cosmetics and others. Due to its broad application, lysmeral was selected for the development of a biomonitoring method for the general population within the frame of the cooperation project of the Federal Ministry for the Environment (BMUB) and the German Chemical Industry Association (VCI). The project also comprises the identification of suitable biomarkers of exposure in human urine as well as basic toxicokinetic data after defined, experimental exposure. For this purpose, 5 healthy subjects were orally dosed once with 5.26 mg lysmeral. Urine was collected immediately before and for 48 h after administration of the fragrance. The lysmeral metabolites lysmerol, lysmerylic acid, hydroxylated lysmerylic acid and 4-tert-butylbenzoic acid (TBBA) were determined in all urine samples by a newly developed UPLC-MS/MS (ultra-high pressure liquid chromatography combined with tandem mass spectrometry) method. Peak excretion for all metabolites occurred between 2 and 5 h after oral application, with the primary metabolites (lysmerol and lysmerylic acid) being excreted about 1 h earlier than the secondary metabolites (hydroxylated lysmerylic acid and TBBA). More than 90% of all measured lysmeral metabolites were excreted after 12 h, with the renal excretion being virtually complete after 48 h. After this time period, TBBA, lysmerol, lysmerylic acid and hydroxyl-lysmerylic acid represent on average 14.3, 1.82, 0.20 and 0.16%, respectively, of the dose administered. In total, the 4 metabolites determined represent about 16.5% of the dose. With the conversion factors derived from the controlled human study, we estimated median exposure doses for lysmeral in a group of 40 human volunteers from the general population of approximately 140-220 μg per day.In conclusion, the lysmeral metabolites lysmerol, lysmerylic acid, hydroxyl-lysmerylic acid and TBBA in urine are suitable biomarkers of exposure and can be applied, either single or in any combination, for biomonitoring of the general population.