Archives of Toxicology

, Volume 93, Issue 9, pp 2565–2574 | Cite as

Toxicokinetics of urinary 2-ethylhexyl salicylate and its metabolite 2-ethyl-hydroxyhexyl salicylate in humans after simulating real-life dermal sunscreen exposure

  • Julia HillerEmail author
  • Katrin Klotz
  • Sebastian Meyer
  • Wolfgang Uter
  • Kerstin Hof
  • Annette Greiner
  • Thomas Göen
  • Hans Drexler
Toxicokinetics and Metabolism


Chemical UV filters are common components in sunscreens and cosmetic products. The question of adverse health risks is not completely resolved, partly owing to lacking human data from dermal exposure, which are essential for sound risk assessment. Therefore, we investigated the urinary toxicokinetics of 2-ethylhexyl salicylate (EHS) after a 1-day dermal real-life sunscreen application scenario. Twenty human volunteers were dermally exposed to a commercial sunscreen for 9 h under real-life conditions (2 mg/cm2 body surface area; double re-application; corresponding to 3.8 g EHS). Urine samples were analyzed for EHS and one of its specific metabolites 2-ethyl-5-hydroxyhexyl salicylate (5OH-EHS) using a two-dimensional liquid chromatographic electrospray–ionization tandem mass spectrometric procedure. EHS and 5OH-EHS were excreted after sunscreen application and reached up to 525 µg/g and 213 µg/g creatinine, respectively. The toxicokinetic models showed concentration peaks between 7 and 8 h after first application. First-phase terminal half-lives were 8–9 h. For 5OH-EHS, a second-phase terminal half-life could be determined (87 h). EHS and 5OH-EHS showed a faster elimination with 70–80% of the overall excretion occurring within 24 h after application compared to more lipophilic UV filters. Cumulative excreted amounts over 24 h reached up to 334 µg EHS and 124 µg of 5OH-EHS. Simulated real-life sunscreen use for 1 day leads to the bioavailability of the UV filter EHS in humans. The kinetic profiles with a prolonged systemic availability indicate a skin depot and make accumulation during consecutive multi-day exposure likely.


UV filter 2-Ethylhexyl salicylate Biomonitoring Sunscreen Bioaccumulation 



The authors thank the Bavarian State Office for Health and Food Safety for the determination of the UV filter concentrations of the sunscreen product and all study subjects for their participation. We would also like to take this opportunity to thank the staff of the Institute of Occupational, Social and Environmental Medicine, Erlangen, for their support during the conduct of the field study.


This study was carried out with financial support by the Bavarian State Ministry for Health and Care. The sponsor was not involved in the study design, collection, analysis or interpretation of data and in the publication of the results.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study protocol was approved by the local ethics committee of the University of Erlangen-Nürnberg (No. 122_17B) in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Informed written consent was obtained from each participant prior to inclusion.

Supplementary material

204_2019_2537_MOESM1_ESM.pdf (361 kb)
Supplementary material 1 (PDF 365 kb)


  1. Bakdash JZ, Marusich LR (2017) Repeated measures correlation. Front Psychol 8:456CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bens G (2014) Sunscreens. Adv Exp Med Biol 810:429–463PubMedGoogle Scholar
  3. Bury D, Bruning T, Koch HM (2019a) Determination of metabolites of the UV filter 2-ethylhexyl salicylate in human urine by online-SPE-LC-MS/MS. J Chromatogr B 1110–1111:59–66CrossRefGoogle Scholar
  4. Bury D, Griem P, Wildemann T, Bruning T, Koch HM (2019b) Urinary metabolites of the UV filter 2-ethylhexyl salicylate as biomarkers of exposure in humans. Toxicol Lett 309:35–41CrossRefPubMedGoogle Scholar
  5. Chatelain E, Gabard B, Surber C (2003) Skin penetration and sun protection factor of five UV filters: effect of the vehicle. Skin Pharmacol Physiol 16(1):28–35CrossRefGoogle Scholar
  6. Destatis (2018) press release No. 19. Wiesbaden, Germany, Federal Statistical OfficeGoogle Scholar
  7. Diffey BL (2001) When should sunscreen be reapplied? J Am Acad Dermatol 45(6):882–885CrossRefPubMedGoogle Scholar
  8. DuBois D, DuBois EF (1989) A formula to estimate the approximate surface area if height and weight be known. Nutrition 5(5):303–311Google Scholar
  9. Duracher L, Blasco L, Abdel Jaoued A, Vian L, Marti-Mestres G (2009) Irradiation of skin and contrasting effects on absorption of hydrophilic and lipophilic compounds. Photochem Photobiol 85(6):1459–1467CrossRefPubMedGoogle Scholar
  10. Emilson A, Lindberg M, Forslind B (1993) The temperature effect on in vitro penetration of sodium lauryl sulfate and nickel chloride through human skin. Acta Derm Venereol 73(3):203–207PubMedGoogle Scholar
  11. European Chemicals Agency (2019) ECHA disseminated dossier CAS 118-60-5 (2-ethylhexyl salicylate). Accessed 19 July 2019
  12. Fitzpatrick TB (1988) The validity and practicality of sun-reactive skin types I through VI. Arch Dermatol 124(6):869–871CrossRefPubMedGoogle Scholar
  13. Gilbert E, Pirot F, Bertholle V, Roussel L, Falson F, Padois K (2013) Commonly used UV filter toxicity on biological functions: review of last decade studies. Int J Cosmet Sci 35(3):208–219CrossRefPubMedGoogle Scholar
  14. Göen T, von Helden F, Eckert E, Knecht U, Drexler H, Walter D (2016) Metabolism and toxicokinetics of 1,4-dioxane in humans after inhalational exposure at rest and under physical stress. Arch Toxicol 90(6):1315–1324CrossRefPubMedGoogle Scholar
  15. Hiller J, Klotz K, Meyer S, Uter W, Hof K, Greiner A, Göen T, Drexler H (2019) Systemic availability of lipophilic organic UV filters through dermal sunscreen exposure. Environ Int. CrossRefGoogle Scholar
  16. ISO 24444:2010 (2010) Cosmetics—sun protection test methods—in vivo determination of the sun protection factor (SPF). International Organization for Standardization, GenevaGoogle Scholar
  17. Jiang R, Roberts MS, Collins DM, Benson HA (1999) Absorption of sunscreens across human skin: an evaluation of commercial products for children and adults. Br J Clin Pharmacol 48(4):635–637CrossRefPubMedPubMedCentralGoogle Scholar
  18. Jungman E, Laugel C, Kasselouri A, Baillet-Guffroy A (2012) Study of the potential of stratum corneum lipids and exogenous molecules interaction by fluorescence spectroscopy for the estimation of percutaneous penetration. Int J Pharm 434(1–2):183–190CrossRefPubMedGoogle Scholar
  19. Kerr AC (2011) A survey of the availability of sunscreen filters in the UK. Clin Exp Dermatol 36(5):541–543CrossRefPubMedGoogle Scholar
  20. Khemiri R, Cote J, Fetoui H, Bouchard M (2018) Kinetic time courses of lambda-cyhalothrin metabolites after dermal application of Matador EC 120 in volunteers. Toxicol Lett 296:132–138CrossRefPubMedGoogle Scholar
  21. Klemsdal TO, Gjesdal K, Bredesen JE (1992) Heating and cooling of the nitroglycerin patch application area modify the plasma level of nitroglycerin. Eur J Clin Pharmacol 43(6):625–628CrossRefPubMedGoogle Scholar
  22. Klotz K, Hof K, Hiller J, Göen T, Drexler H (2019) Quantification of prominent organic UV filters and their metabolites in human urine and plasma samples. J Chromatogr B 1125:121706. CrossRefGoogle Scholar
  23. Kunz PY, Fent K (2006) Multiple hormonal activities of UV filters and comparison of in vivo and in vitro estrogenic activity of ethyl-4-aminobenzoate in fish. Aquat Toxicol 79(4):305–324CrossRefPubMedGoogle Scholar
  24. Larsen K (1972) Creatinine assay by a reaction-kinetic principle. Clin Chim Acta 41:209–217CrossRefPubMedGoogle Scholar
  25. Lopes LB, Garcia MT, Bentley MV (2015) Chemical penetration enhancers. Ther Deliv 6(9):1053–1061CrossRefPubMedGoogle Scholar
  26. Mancuso JB, Maruthi R, Wang SQ, Lim HW (2017) Sunscreens: an update. Am J Clin Dermatol 18(5):643–650CrossRefPubMedGoogle Scholar
  27. Manova E, von Goetz N, Hauri U, Bogdal C, Hungerbuhler K (2013) Organic UV filters in personal care products in Switzerland: a survey of occurrence and concentrations. Int J Hyg Environ Health 216(4):508–514CrossRefPubMedGoogle Scholar
  28. Matta MK, Zusterzeel R, Pilli NR, Patel V, Volpe DA, Florian J, Oh L, Bashaw E, Zineh I, Sanabria C, Kemp S, Godfrey A, Adah S, Coelho S, Wang J, Furlong LS, Ganley C, Michele T, Strauss DG (2019) Effect of sunscreen application under maximal use conditions on plasma concentration of sunscreen active ingredients: a randomized clinical trial. JAMA 321(21):2082–2091. CrossRefPubMedPubMedCentralGoogle Scholar
  29. Petersen B, Wulf HC (2014) Application of sunscreen–theory and reality. Photodermatol Photoimmunol Photomed 30(2–3):96–101CrossRefPubMedGoogle Scholar
  30. Pinheiro JC, Bates DM (2000) Mixed-effects models in S and S-plus. Springer-Verlag, New YorkCrossRefGoogle Scholar
  31. Pirotta G (2015) An overview of sunscreen regulations in the world. Househ Pers Care Today 10(4):17–22Google Scholar
  32. Rehfeld A, Dissing S, Skakkebaek NE (2016) Chemical UV filters mimic the effect of progesterone on Ca(2+) signaling in human sperm cells. Endocrinology 157(11):4297–4308CrossRefGoogle Scholar
  33. Rehfeld A, Egeberg DL, Almstrup K, Petersen JH, Dissing S, Skakkebaek NE (2018) EDC IMPACT: chemical UV filters can affect human sperm function in a progesterone-like manner. Endocr Connect 7(1):16–25CrossRefPubMedGoogle Scholar
  34. Rom WN, Markowitz S (2007) Environmental and occupational medicine. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  35. Roussel L, Gilbert E, Salmon D, Serre C, Gabard B, Haftek M, Maibach HI, Pirot F (2015) Measurement, analysis and prediction of topical UV filter bioavailability. Int J Pharm 478(2):804–810CrossRefPubMedGoogle Scholar
  36. Sarveiya V, Risk S, Benson HA (2004) Liquid chromatographic assay for common sunscreen agents: application to in vivo assessment of skin penetration and systemic absorption in human volunteers. J Chromatogr B 803(2):225–231CrossRefGoogle Scholar
  37. Schlumpf M, Schmid P, Durrer S, Conscience M, Maerkel K, Henseler M, Gruetter M, Herzog I, Reolon S, Ceccatelli R, Faass O, Stutz E, Jarry H, Wuttke W, Lichtensteiger W (2004) Endocrine activity and developmental toxicity of cosmetic UV filters—an update. Toxicology 205(1–2):113–122CrossRefPubMedGoogle Scholar
  38. Seite S, Del Marmol V, Moyal D, Friedman AJ (2017) Public primary and secondary skin cancer prevention, perceptions and knowledge: an international cross-sectional survey. J Eur Acad Dermatol Venereol 31(5):815–820CrossRefPubMedPubMedCentralGoogle Scholar
  39. Silva ESD, Tavares R, Paulitsch FDS, Zhang L (2018) Use of sunscreen and risk of melanoma and non-melanoma skin cancer: a systematic review and meta-analysis. Eur J Dermatol 28(2):186–201PubMedGoogle Scholar
  40. Stoeckelhuber M, Krnac D, Pluym N, Scherer M, Peschel O, Leibold E, Scherer G (2018) Human metabolism and excretion kinetics of the fragrance 7-hydroxycitronellal after a single oral or dermal dosage. Int J Hyg Environ Health 221(2):239–245CrossRefPubMedGoogle Scholar
  41. Treffel P, Gabard B (1996) Skin penetration and sun protection factor of ultra-violet filters from two vehicles. Pharm Res 13(5):770–774CrossRefPubMedGoogle Scholar
  42. Uter W, Goncalo M, Yazar K, Kratz EM, Mildau G, Liden C (2014) Coupled exposure to ingredients of cosmetic products: III. Ultraviolet filters. Contact Dermat 71(3):162–169CrossRefGoogle Scholar
  43. Walters KA, Brain KR, Howes D, James VJ, Kraus AL, Teetsel NM, Toulon M, Watkinson AC, Gettings SD (1997) Percutaneous penetration of octyl salicylate from representative sunscreen formulations through human skin in vitro. Food Chem Toxicol 35(12):1219–1225CrossRefPubMedGoogle Scholar
  44. WHO (1996) Biological monitoring of chemical exposure in the workplace. World Health Organization, GenevaGoogle Scholar
  45. Wickham H (2016) ggplot2: Elegant graphics for data analysis. Springer Verlag, New YorkCrossRefGoogle Scholar
  46. Williams AC, Barry BW (2004) Penetration enhancers. Adv Drug Deliv Rev 56(5):603–618CrossRefPubMedGoogle Scholar
  47. Yap FH, Chua HC, Tait CP (2017) Active sunscreen ingredients in Australia. Australas J Dermatol 58(4):e160–e170CrossRefPubMedGoogle Scholar
  48. Young AR, Claveau J, Rossi AB (2017) Ultraviolet radiation and the skin: photobiology and sunscreen photoprotection. J Am Acad Dermatol 76(3S1):S100–S109CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Institute and Outpatient Clinic of Occupational, Social and Environmental MedicineFriedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany
  2. 2.Institute of Medical Informatics, Biometry and EpidemiologyFriedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany

Personalised recommendations