Julia Hiller

Percutaneous penetration is an important human exposure route, but it is influenced by multiple factors and can vary greatly between different substances and exposure conditions. Furthermore, skin characteristics such as thickness of different anatomic sites may have an effect on percutaneous absorption. Despite a potential relevance for safety measures, little is yet known for occupationally relevant skin sites, like hands. We conducted a human in vivo study aiming to identify the effect of anatomic sites on percutaneous absorption of 2-phenoxyethanol. Two human volunteers were dermally exposed to 2-phenoxyethanol (loading dose: 0.2 mg/cm ² skin) at seven different anatomic skin sites with areas of 200 and 400 cm ² , respectively. Blood and urine samples were collected and analyzed for 2-phenoxyethanol and its two main metabolites up to 48 h post-exposure. Relative absorption ratios showed moderate site differences ranging from 0.89 to 1.64 (compared to the forearm) as the overall renal recovery was between 23 and 43% of applied 2-phenoxyethanol. Inter-individual variability was in a similar range. A notable influence of the exposed site could, however, be observed for the penetration speed which was highest at the forehead and neck, and slowest at the hand palms. Differing ratios of unmetabolized 2-phenoxyethanol and its main metabolite found in blood point to a site-depending intradermal metabolism. This study revealed major findings concerning the velocity of percutaneous penetration at different skin sites, which is relevant for adequate skin protection. The obtained data broaden the knowledge about site-related variations in percutaneous absorption and thus can improve future toxicological evaluations.

2-Phenoxyethanol (PhE) is an amphiphilic organic compound frequently used as a broad-spectrum preservative in cosmetic products and other consumer goods. PhE is also used as a biocidal component in occupational settings. A previous volunteer study by our working group following oral exposure to PhE showed that PhE is almost completely taken up into the human body followed by an extensive metabolization and fast urinary elimination. However, with respect to the importance of transdermal uptake, we now conducted another volunteer study applying dermal PhE exposure: five volunteers were dermally exposed with 0.4 mg/kg body weight of PhE each on a specified 800 cm² skin area using non-occlusive conditions. Subsequently, blood and urine samples were collected up to 48 h post-exposure. The present study illustrates the fast transdermal uptake of PhE. Following systemic resorption, PhE was extensively metabolized and rapidly eliminated in urine mainly in form of the metabolites PhAA (phenoxyacetic acid) and 4-OH-PhAA (4-hydroxyphenoxyacetic acid) accounting together for over 99% of the renally excreted PhE dose. The absolute urinary recovery rate of PhE was observed to be significantly lower following dermal exposure compared to oral uptake indicating a dermal resorption rate of PhE of about 45% in humans. The present study provides for the first time detailed insights into human biotransformation and toxicokinetics of PhE after dermal exposure, thus establishing a reliable strategy for human biomonitoring of PhE. The here presented results may thus be useful for further toxicokinetic modeling and forward dosimetry.

The chemical UV filter 2-ethylhexyl salicylate (EHS) is used in various personal-care products. The dermal and oral metabolism of EHS have already been targeted by different studies. However, toxicokinetic data after a single dermal exposure to EHS was missing. In our study, three volunteers were dermally exposed to a commercial EHS-containing sunscreen for 9 h with an application dose of 2 mg sunscreen per cm² body surface area. The exposure was performed indoors, and sunscreen was applied on about 75% of the total skin area. Complete urine voids were collected over 72 h and eight blood samples were drawn from each subject. Urine samples were analyzed for EHS and seven known metabolites (5OH-EHS, 4OH-EHS, 2OH-EHS, 6OH-EHS, 4oxo-EHS, 5oxo-EHS, and 5cx-EPS) by online-SPE UPLC MS/MS. The peaks of urinary elimination occurred 10–11 h after application. The elimination half-lives (Phase 1) were between 6.6 and 9.7 h. The dominant urinary biomarkers were EHS itself, followed by 5OH-EHS, 5cx-EPS, 5oxo-EHS, and 4OH-EHS. 2OH-EHS, 6OH-EHS, and 4oxo-EHS were detected only in minor amounts. An enhanced analysis of conjugation species revealed marginal amounts of unconjugated metabolites and up to 40% share of sulfate conjugates for 5OH-EHS, 5oxo-EHS, and 5cx-EPS. The results demonstrated a delayed systemic resorption of EHS via the dermal route. Despite an extensive metabolism, the parent compound occurred as main urinary parameter. The delayed dermal resorption as well as the slow elimination of EHS indicate an accumulation up to toxicological relevant doses during daily repeated dermal application to large skin areas.

2-Phenoxyethanol (PhE) is an aromatic glycol ether and is used in a variety of functions and applications, e.g., as preservative in pharmaceuticals, cosmetic and personal care products, as biocide in disinfectants (e.g. human hygiene), or as a solvent in formulations (e.g. coatings, functional fluids). Despite its widespread use, little is yet known on its biotransformation and toxicokinetics in humans. Therefore, a pilot study was conducted with oral administration of PhE (5 mg/kg body weight) to five volunteers. Blood and urine samples were collected and analyzed for PhE and three of its presumed metabolites up to 48 h post-exposure. Additionally, one volunteer was dermally exposed to PhE and monitored until 72 h post-exposure. PhE was rapidly resorbed following both oral and dermal application with t_max-levels in blood of about 1 h and 3 h, respectively. Metabolism of PhE was observed to be rather extensive with phenoxyacetic acid (PhAA) and 4-hydroxyphenoxyacetic acid (4-OH-PhAA) as the main metabolites found in blood and urine following oral and dermal exposure. PhE was excreted rapidly and efficiently via urine mostly in metabolized form: following oral exposure, on average 77% and 12% of the applied dose was excreted within 48 h as PhAA and 4-OH-PhAA, respectively. A similar metabolism pattern was observed following the single dermal exposure experiment. The obtained data on biotransformation and toxicokinetics of PhE in humans provide valuable information on this important chemical and will be highly useful for pharmacokinetic modelling and evaluation of human PhE exposure.