Randomized clinical trial at a cl inical pharmacology unit (West Bend, Wisconsin) was conducted in 48 healthy participants. Systemic absorption and pharmacokinetics of six active ingredients (avobenzone, oxybenzone, octocrylene (OCR), homosalate, octisalate, and octinoxate) in four sunscreen products under single- and maximal-use conditions were assessed. Participants were randomized to one of four sunscreen products, formu- lated as lotion (n = 12), aerosol spray (n = 12), nonaerosol spray (n = 12), and pump spray (n = 12). The sunscreen product was applied at 2 mg/cm2 to 75% of the body surface area at 0 h on day 1 and three times on day 2 through day 4 at 2-h intervals, and 34 blood samples were collected over 21 d from each participant. In this study, all six of the tested active ingredients were systemically absorbed and had plasma concentrations that sur- passed the FDA threshold for potentially waiving some of the additional safety studies for sunscreens. Geometric mean maximum plasma concentrations of all six active ingredients were greater than 0.5 ng/mL, and this threshold was surpassed on day 1 after a single application for all active ingredients (33). Levels of UV fi lters measured in human seminal fl uid and comparisons to levels mea- sured in concurrently collected urine and serum samples were presented. In total, nine UV fi lters were analyzed by TurboFlow-LC–MS/MS (Thermo Fisher Scientifi c, San Jose, CA) in paired urine, serum, and seminal fl uid samples from 300 young Danish men from the general population each man collected one of each sample type within 1 h. Four of the examined UV fi lters could be detected in seminal fl uid sam- ples at levels above limit of detection in more than 10% of the samples. BP-1 and BP-3 were most frequently detected in, respectively, 18%, 19%, and 27% of the seminal fl uid samples albeit at levels one to two orders of magnitude lower than the levels observed in urine. 4-MBP was detectable in 11% of the seminal fl uid samples, whereas in 5% of the urine samples. Overall, 45% of the men had at least one of the UV fi lters present in their seminal fl uid at detectable levels. In conclusion, chemical UV fi lters are present in men’s seminal fl uid some of which can activate the human sperm-specifi c CatSper Ca2+ channel, and thereby potentially interfere with the fer- tilization process (34). Few human studies have investigated potential side effects of UV fi lters, although human exposure is high as UV fi lters in sunscreens are rapidly absorbed from the skin. One of the UV fi lters, BP-3, has been found in 96% of urine samples in the United States, and several UV fi lters have been found in 85% of Swiss breast milk samples. It seems pertinent to evaluate whether exposure to UV fi lters contributes to possible adverse effects on endo- crine disruption (35). BIOAVAILABILITY Bioavailability, in the case of the sensitization process, refers to the fact that the substance is able to permeate the skin and can also activate a weak or non-sensitizing substance into a sensitizer. A fi rst assessment is feasible by evaluating the chemical structure and the physical properties of a substance. The skin permeation potential of a substance would be allowed, e.g., in the case of low molecular weight compounds ( 500 Da) (35). The phys- icochemical properties of the active substance and the properties of the vehicle (polarity of the solvent, particle size, and type of vehicle), exposed to the sunscreen product, affect the degree of permeation into the skin (36). JOURNAL OF COSMETIC SCIENCE 306

Mathematical solution of Fick’s second law determines dermato-pharmacokinetic param- eters of UV fi lters, K, and D/L2, as follows (Crank, 1975): 2 1 2 veh veh 1 sin expž n x KC n x D C x KC n L n L L2 d  ｬ  ｬ  ｬ ž ž Q2tｭ, ｭ ｭ ž ž ž ｮ ｮ Ÿ ｮ Q œ where Cveh is the permeant’s concentration in the vehicle, K is the partition coeffi cient of the chemical between the SC surface and the vehicle, and L and D are the diffusion path- length and the coeffi cient of diffusion of the chemical across the SC, respectively. T he validity of equation https://www.sciencedirect.com/science/article/pii/S037851731400 9235?via%3Dihub - eq0015 also assumes that (i) all transport of chemical substance across the SC takes place by passive diffusion, (ii) the vehicle in which the chemical is presented to the SC does not modify the membrane or act as a carrier for the compound, and (iii) that no others skin layers contribute to the total barrier (37). P resently used sun fi lters are lipophilic molecules with relatively low molecular weight and because of their physicochemical characteristics possess a good potential to penetrate into the deep strata of the skin and to be systemically absorbed. I t has also been proven that there are some factors that designate differences between various formulations. These factors include penetration into the skin, permeation through it, and retention of UV fi lters in the skin from topical products. The formulation type infl uences the UV fi lter diffusion on the epidermis. Roussel et al. (38), conducted a study according to which they managed to predict and defi ne bioavailability of the following sunscreen agents: BP-3, 2-ethylhexyl salicylate (EHS), and OMC. The epidermis of four human volunteers was treated with petrolatum and emulsion-based formulations, which remained on the skin for 7 and 30 min. The composition of three sunscreen products ap- plied on human volunteers included a commercial Daylong 15 formulation (i.e., BP-3, 2-EHS, and OMC-loaded liposomes in oil/water emulsion gel, Galderma-Spirig, Egerkin- gen, Switzerland) and 2 laboratory-produced petrolatum jellies including BP-3, OS, and OMC. All sunscreen products respected the maximal concentrations authorized by the directive adopted by the European Union (Cosmetic Directive 76/768/EEC, Annex VII. Part I). Profi les of sunscreen agents through the SC, derived from the assessment of chem- ical amounts in SC layers collected by successive adhesive tape stripping, were success- fully fi tted to Fick’s second law of diffusion. Therefore, permeability coeffi cients of sunscreen agents were found lower with petrolatum than with emulsion-based formula- tions, confi rming the crucial role of vehicle in topical delivery. Although no signifi cant difference was shown for K values, likely because of the small number of volunteers, higher partition of chemicals between SC and emulsion-based vehicle was evidenced than petrolatum formulations, confi rming the crucial role of physicochemical properties of vehicle for the topical delivery of lipophilic compounds. This assumption was confi rmed by the comparison of permeability coeffi cients of UV fi lters showing higher values for emulsion than petrolatum formulations. M ARGIN OF SAFETY R esearchers calculated the margin of safety of UV fi lters by comparing the potential human SED with the NOAEL from in vivo toxicity studies DISTRIBUTION OF UV FILTERS ON THE SKIN 307