Human metabolism and excretion kinetics of the surfactant 2,4,7,9-tetramethyl-5-decyne-4,7-diol (TMDD) after oral and dermal administration.

2,4,7,9-Tetramethyl-5-decyne-4,7-diol (TMDD) is a non-ionic surfactant with a wide range of applications. TMDD is considered a high-production chemical and, due to its low biodegradation rate, possesses a potentially high prevalence in the environment. However, despite its widespread use, toxicokinetic data and data on internal exposure to TMDD in the general population are completely lacking. Hence, we developed a human biomonitoring (HBM) method for TMDD. Our approach included a metabolism study with four subjects, who were administered an oral dose of 75 µg TMDD/kg body weight and a dermal dose of 750 µg/kg body weight. Terminal methyl-hydroxylated TMDD (1-OH-TMDD) was previously identified as the main urinary metabolite in our lab. The results of the oral and dermal applications were used to determine the toxicokinetic parameters of 1-OH-TMDD as a biomarker of exposure. Finally, the method was applied to 50 urine samples from non-occupationally exposed volunteers. Results show that TMDD was rapidly metabolized, with an average tmax of 1.7 h and a rapid and almost complete (96%) excretion of 1-OH-TMDD until 12 h after oral dosage. Elimination was bi-phasic, with half-lives of 0.75-1.6 h and 3.4-3.6 h for phases 1 and 2, respectively. The dermal application resulted in a delayed urinary excretion of this metabolite with a tmax of 12 h and complete excretion after about 48 h. The excreted amounts of 1-OH-TMDD represented 18% of the orally administered TMDD dose. The data of the metabolism study demonstrated a fast oral as well as substantial dermal resorption of TMDD. Moreover, the results indicated an effective metabolism of 1-OH-TMDD, which is excreted rapidly and completely via urine. Application of the method to 50 urine samples revealed a quantification rate of 90%, with an average concentration of 0.19 ng/mL (0.97 nmol/g creatinine). With the urinary excretion factor (Fue) derived from the metabolism study, we estimated an average daily intake of 1.65 µg TMDD from environmental and dietary sources. In conclusion, 1-OH-TMDD in urine is a suitable biomarker of exposure to TMDD and can be applied for biomonitoring of the general population.

Determination of a specific metabolite for the non-ionic surfactant 2,4,7,9-Tetramethyl-5-decyne-4,7-diol (TMDD) by UPLC-MS/MS.

2,4,7,9-Tetramethyldec-5-yne-4,7-diol (TMDD) is a non-ionic surfactant commonly used as defoaming agent and numerous other applications. Effluents of wastewater treatment plants have been identified as one of the main sources of TMDD emissions into the environment. Due to its broad application in various fields, TMDD was selected for the development of a biomonitoring method for assessing human exposure within the frame of the cooperation project of the German Federal Ministry for the Environment, Nature Conservation, Building and Nuclear Safety (BMUB) and the German Chemical Industry Association (VCI) in 2020. This study aimed to identify a urinary metabolite for TMDD by UPLC-Q-Orbitrap-MS which can be used as a biomarker of TMDD exposure. Monohydroxylated TMDD (1-OH-TMDD) was deciphered as the most prominent metabolite of TMDD in humans in a series of in vitro and in vivo experiments. In a next step, a quantitative method for the determination of 1-OH-TMDD was developed and validated. Quantification was achieved by isotope dilution using D3-1-OH-TMDD as internal standard. The method is characterized by a simple sample clean-up procedure and an enzymatic hydrolysis of possible metabolite conjugates with ß-glucuronidase. Method validation was performed according to international guidelines for bioanalytical method validation. The method proved its robustness, precision, accuracy and sensitivity for the intended purpose, i.e. the assessment of TMDD exposure in the general population by means of human biomonitoring.