Di-n-butyl adipate (DnBA) is an alternative to the anti-androgenic and strictly regulated di-n-butyl phthalate (DnBP) used as a cosmetic ingredient, plasticizer, and in various articles of everyday life. Hence, exposures of the general population have to be expected. Currently, biomarkers of DnBA exposure and methods for their determination are not available. Here, we describe a sensitive, rugged and precise analytical method for the determination of the DnBA monoester metabolite mono-n-butyl adipate (MnBA), as well as its potential downstream metabolites 3-hydroxy-mono-n-butyl adipate (3OH-MnBA) and 3-carboxy-mono-n-propyl adipate (3cx-MnPrA) in human urine. Glucuronic acid conjugates present in urine were deconjugated using a pure β-glucuronidase. The metabolites were then analyzed by liquid chromatography on a C18 column with superficially porous particles coupled to electrospray ionization-triple quadrupole-tandem mass spectrometry, applying online turbulent flow chromatography for analyte enrichment and matrix depletion (online-SPE-LC-MS/MS). The metabolites were quantified using stable isotope dilution analysis with limits of quantification of 0.05 µg/L (MnBA), 0.1 µg/L (3OH-MnBA), and 0.5 µg/L (3cx-MnPrA). Method imprecision in urinary matrix was below 7% (coefficient of variation) for all analytes. Mean relative recoveries were between 93% and 107%. The suitability of the DnBA metabolites as biomarkers of exposure was demonstrated after dermal application of a commercially available sunscreen containing DnBA. Maximum concentrations were reached 6.5 h after dose (219 µg/L 3cx-MnPrA, 91 µg/L MnBA, and 3.9 µg/L 3OH-MnBA). Elimination kinetics were similar for all three metabolites. We were able to quantify 3cx-MnPrA and MnBA until 4 d after sunscreen application. In a sample set of 35 urine samples from the general German population, 3cx-MnPrA was quantified in 94% (median 2.54 µg/L, maximum 78.3 µg/L) and MnBA in 3% (median < LOQ, maximum 0.18 µg/L) of the samples. The method will be applied in future human metabolism and human biomonitoring population studies.

中文翻译：

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通过在线SPE-LC-MS / MS测定己二酸二正丁酯（DnBA）代谢物可能是人尿中暴露的可能生物标志物。

己二酸二正丁酯（DnBA）是抗雄激素和严格管制的邻苯二甲酸二正丁酯（DnBP）的替代品，用作化妆品成分，增塑剂以及各种日常生活用品。因此，必须预期到一般人群的暴露。目前，尚无DnBA暴露的生物标志物及其确定方法。在这里，我们描述了一种灵敏，坚固，精确的分析方法，用于测定DnBA单酯代谢物己二酸正丁酯（MnBA）及其潜在的下游代谢物3-羟基己酸正丁酯（3OH- MnBA）和人尿中的3-羧基-单-正丙基己二酸酯（3cx-MnPrA）。使用纯的β-葡萄糖醛酸苷酶将尿液中存在的葡萄糖醛酸结合物解偶联。然后在C18柱上通过液相色谱法分析代谢产物，并将表面多孔颗粒与电喷雾电离三重四极杆串联质谱联用，应用在线湍流色谱法进行分析物富集和基质消耗（在线SPE-LC-MS / MS） 。使用稳定的同位素稀释分析法对代谢产物进行定量，定量限为0.05 µg / L（MnBA），0.1 µg / L（3OH-MnBA）和0.5 µg / L（3cx-MnPrA）。所有分析物在尿液基质中的方法不准确度均低于7％（变异系数）。平均相对回收率在93％至107％之间。在皮肤上应用含有DnBA的市售防晒霜后，证明了DnBA代谢物作为暴露生物标志物的适用性。给药后6.5小时达到最高浓度（219 µg / L 3cx-MnPrA，91 µg / L MnBA和3.9 µg / L 3OH-MnBA）。所有三种代谢物的消除动力学均相似。在涂完防晒霜后4天，我们能够定量3cx-MnPrA和MnBA。在一组来自德国普通人群的35个尿液样本中，对3cx-MnPrA的定量为94％（中值2.54 µg / L，最大78.3 µg / L），对MnBA的定量为3％（中值<LOQ，最大0.18 µg / L）。 ）的样本。该方法将用于未来的人类代谢和人类生物监测人群研究。18 µg / L）的样品。该方法将用于未来的人类代谢和人类生物监测人群研究。18 µg / L）的样品。该方法将用于未来的人类代谢和人类生物监测人群研究。