Skin permeation and metabolism of di(2-ethylhexyl) phthalate (DEHP)
Open accessAbstract
Phthalates are suspected to be endocrine disruptors. Di(2-ethylhexyl) phthalate (DEHP) is assumed to have low dermal absorption; however, previous in vitro skin permeation studies have shown large permeation differences. Our aims were to determine DEHP permeation parameters and assess extent of skin DEHP metabolism among workers highly exposed to these lipophilic, low volatile substances. Surgically removed skin from patients undergoing abdominoplasty was immediately dermatomed (800 μm) and mounted on flow-through diffusion cells (1.77 cm(2)) operating at 32°C with cell culture media (aqueous solution) as the reservoir liquid. The cells were dosed either with neat DEHP or emulsified in aqueous solution (166 μg/ml). Samples were analysed by HPLC-MS/MS. DEHP permeated human viable skin only as the metabolite MEHP (100%) after 8h of exposure. Human skin was able to further oxidize MEHP to 5-oxo-MEHP. Neat DEHP applied to the skin hardly permeated skin while the aqueous solution readily permeated skin measured in both cases as concentration of MEHP in the receptor liquid. DEHP pass through human skin, detected as MEHP only when emulsified in aqueous solution, and to a far lesser degree when applied neat to the skin. Using results from older in vitro skin permeation studies with non-viable skin may underestimate skin exposures. Our results are in overall agreement with newer phthalate skin permeation studies.
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The skin permeation rates from human in vitro studies are highly variable and reported to be 0.1-2.2 ug/cm2/h for DEHP, 0.07-0.59 ug/cm2/h for DBP, and 1.27-21 ug/cm2/h for DEP.
“The skin permeation rates from human in vitro studies are highly variable and reported to be: 0.1 -2.2 µ g/cm 2 /h for DEHP (Barber et al., 1992; Hopf et al., 2014; Scott et al., 1987), 0.07 -0.59 µ g/cm 2 /h for DBP (Beydon et al., 2010; Scott et al., 1987), and 1.27 -21 µ g/cm 2 /h for DEP (Barbero and Frasch, 2016; Mint et al., 1994; Scott et al., 1987).”
From Human skin absorption of three phthalates (2024) · cites this paper as Hopf et al., 2014
This citation is attached to the DEHP range, not the separately cited DBP and DEP ranges. The Introduction (p. 7) and Discussion (pp. 11–12) support substantial variability in DEHP permeation through human skin, but the passages available from our copy do not establish the stated 0.1–2.2 µg/cm²/h range; the numerical range quoted in the Discussion is for a different measure, the permeation coefficient (Kp). (LLM, conf=0.83)
Experimental — accuracy not yet measuredIn previous experiments with fresh skin, DEHP both neat and emulsified crossed the skin as MEHP, but overall DEHP permeated skin poorly.
“This result was the inverse of our previous experiments with fresh skin (Hopf et al., 2014) where we found that DEHP, both neat and emulsified, crossed the skin as MEHP; but overall DEHP permeated skin poorly.”
From Human skin absorption of three phthalates (2024) · cites this paper as Hopf et al., 2014
The Abstract (p. 3) and Discussion (p. 11) report that DEHP applied to viable human skin was detected in the receptor fluid as MEHP, with neat DEHP permeating far less than emulsified DEHP. They do not support the unqualified statement that DEHP permeated poorly overall: the paper describes permeation from the aqueous preparation as considerable or ready. (LLM, conf=0.88)
Experimental — accuracy not yet measuredReported skin permeation parameters for DEHP using human skin vary greatly across three published studies and might be explained by experimental design.
“Reported skin permeation parameters for DEHP using human skin vary greatly across three studies published (Barber et al., 1992; Hopf et al., 2014; Scott et al., 1987) and might be explained by experimental design (cadaver skin, heat separated, temperature ranges 32 -37 ◦ C, and others).”
From Human skin absorption of three phthalates (2024) · cites this paper as Hopf et al., 2014
The skin's ability to metabolize phthalates may alter their uptake rates.
“but the skin ' s ability to metabolize phthalates may alter their uptake rates (Hopf et al., 2014).”
From Human skin absorption of three phthalates (2024) · cites this paper as Hopf et al., 2014
Phthalate skin permeation decreases with increasing molecular weight / shorter alkyl chain length, with DEP > DBP > DEHP among the three phthalates tested.
“Our observation regarding the varying absorption rates for the different phthalates governed by their chain length supports previous studies (Chung et al., 2019; Hopf et al., 2014; Scott et al., 1987).”
From Human skin absorption of three phthalates (2024) · cites this paper as Hopf et al., 2014
The Abstract (p. 3) reports DEHP permeation under different application conditions, while the Discussion (p. 14) mentions separate DBP and DEP studies to illustrate effects of formulation. Our copy does not compare permeation rates across DEP, DBP, and DEHP or establish a molecular-weight or alkyl-chain-length trend; searches for those comparisons found no supporting passage. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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Cites
BARBER, E. (1992) · Fundamental and Applied Toxicology · doi:10.1016/0272-0590(92)90086-w · Cited by 119 · see citing works
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Research works printed but not linked: 6
- ATSDR, 1990. Toxicological Profile for Di(2-ethylhexyl)phthalate. U.S. Public Health Service, pp. 109 pp.
- Bronaugh, R.L., 2005. Chapter 2. In Vitro Diffusion Cell Studies in Dermal Absorption Models in Toxicology and Pharmacology. In: Riviere, J.E. (Ed.) Dermal Absorption Models in Toxicology and Pharmacology. CRC Press, Boca Raton, FL, USA, pp. 21-27. Bronaugh, R.L., Collier, S.W., Macpherson, S.E., Kraeling, M.E.K., 1994. Influence of metabolism in skin on dosimetry after topical exposure. Environ Health Perspect 102, 71-74. Bronaugh, R.L., Stewart, R.F., Congdon, E.R., Giles, A.L., 1982. Methods for in vitro percutaneous absorption studies. 1. Comparison with in vivo results. Toxicol Appl Pharmacol 62,
- Howes, D., Guy, R., Hadgraft, J., Heylings, J., Hoeck, U., Kemper, F., Maibach, H., Marty, J.P., Merk, H., Parra, J., Rekkas, D., Rondelli, I., Schaefer, H., Täuber, U., Verbiese, N., 1996. Methods for assessing percutaneous absorption, ECVAM Workshop Report n. 13. . Altern Lab
- IOM, 2004. CEFIC Workshop on methods to determine dermal permeation for human risk assessment. Held in Utrecht 13-15th June 2004. Research Report TM/04/07. Institute of Occupational Medicine, Riccarton, Edinburgh.
- SCCP, 2007. Opinion on phthalates in cosmetic products opinion adopted at the 11th plenary meeting of 21 March 2007, . In: SCCP (Ed.). Scientific Committee on Consumer Products, Brussels, p. 19.
- Scott, R.C., Dugard, P.H., Ramsey, J.D., Rhodes, C., 1987. In vitro absorption of some ophthalate diesters through human and rat skin. Environ Health Perspect 74, 223-227 Erratum in: Environ Health Perspect 1989;1979:1323.
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Weschler, C. J., Bekö, G., Koch, H. M., Salthammer, T., Schripp, T., Toftum, J., & Clausen, G. (2015) · Environmental Health Perspectives · doi:10.1289/ehp.1409151 · Cited by 209 · see citing works
Domínguez-Romero, E., & Scheringer, M. (2019) · Drug Metabolism Reviews · doi:10.1080/03602532.2019.1620762 · Cited by 86 · see citing works
Quinnies, K. M., Harris, E. P., Snyder, R. W., Sumner, S. S., & Rissman, E. F. (2017) · PLOS ONE · doi:10.1371/journal.pone.0171977 · Cited by 84 · see citing works
Human skin absorption of three phthalates
Hopf, N. B., De Luca, H. P., Borgatta, M., Koch, H. M., Pälmke, C., Benedetti, M., Berthet, A., & Reale, E. (2024) · Toxicology Letters · doi:10.1016/j.toxlet.2024.05.016 · Cited by 24 · see citing works
Self-citation
- Authors
- Hopf, N. B., Berthet, A., Vernez, D., Langard, E., Spring, P., & Gaudin, R.
- Affiliations
- Institute for Work and Health (CH)
- Institut National de Recherche et de Sécurité (FR)
- Centre Hospitalier Universitaire Vaudois (CH)
- Corresponding author
- Hopf, N.B.
- Venue
- Toxicology Letters
- Publisher
- Elsevier BV
- Published
- 2014-01
- Volume
- 224
- Issue
- 1
- Pages
- 47-53
- ISSN
- 0378-4274 (ISSN-L)
- OpenAlex
- W1971695130
- Cited by
- 72
- References
- 1
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 9 · 2023: 7 · 2022: 2 · 2021: 5 · 2020: 5 · 2019: 8 · 2018: 6 · 2017: 8 · 2016: 4 · 2015: 5 · 2014: 2 · 2013: 1
- FWCI
- 2.93
- Type
- journal article
- Language
- en
- Open access
- green
- serval.unil.ch
- Licence
- other-oa
- Locations
- Toxicology Letters (publishedVersion)
- PubMed (publishedVersion)
- SERVAL (Université de Lausanne) (acceptedVersion, other-oa)
- IRIS (submittedVersion)
- Funders
- U.S. Environmental Protection Agency
- European Food Safety Authority
- European Commission
- Swiss Centre for Applied Human Toxicology
- Topics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Pesticide Exposure and Toxicity
- Health Sciences › Medicine › Dermatology › Contact Dermatitis and Allergies
- Keywords
- DEHP, skin permeation, skin metabolism, mono(2-ethylhexyl) phthalate, percutaneous absorption, endocrine disruptors, phthalates, occupational exposure, flow-through diffusion cell
- MeSH terms
- Diethylhexyl Phthalate, Humans, Permeability, Skin
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