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Cited by 24Effects and risks of endocrine disrupting chemicalsPesticide Exposure and ToxicityContact Dermatitis and Allergies

Human skin absorption of three phthalates

Open access
Hopf, Nancy B., De Luca, Hélène P., Borgatta, Myriam, Koch, Holger M., Pälmke, Claudia, Benedetti, Manon, Berthet, Aurélie, Reale, Elena·2024·Toxicology Letters
DOI 10.1016/j.toxlet.2024.05.016
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Abstract

Population studies reveal widespread exposure to phthalates. Understanding their absorption, distribution, metabolism, and excretion is vital to reduce exposure. However, data on skin absorption remain limited. We thus aim to characterize the skin permeation of three phthalates in a mixture, neat or in emulsion; di(2-ethylhexyl) phthalate (d4-DEHP), dibutyl phthalate (d4-DBP), and diethyl phthalate (d4-DEP), by comparing in vitro human skin (800 µm) permeation (24 hours) results using flow-through diffusion cells with urine results obtained from volunteers exposed to the same mixture applied to a forearm (40 cm2). Metabolites were analyzed in receptor fluids and urine. Phthalates crossed the skin barrier and metabolized into monoesters before elimination. Increased permeation was observed for phthalates in emulsion compared to neat substances, with polyethylene glycol (PEG) in the receptor fluid enhancing emulsion permeation, but not affecting neat substances. In vitro results mirrored in vivo findings: DEP showed rapid permeation (J: ∼2 ug/cm2/h) and urinary excretion peaking at six hours post-application, whereas DBP exhibited slower kinetics (J: ∼0.1 ug/cm2/h), with a urinary peak at 15–17 hours post-application. DEHP had minimal permeation (J: ∼0.0002 ug/cm2/h) with no observable urinary peak. These findings underscore the importance of comprehending phthalate skin absorption for effective exposure mitigation strategies.

AI snapshot

Written from the paper’s full text.

TL;DR

This study compared in vitro human skin permeation of deuterated DEHP, DBP, and DEP with urinary metabolite excretion in five volunteers exposed to the same neat mixture on a forearm. Skin permeation decreased with increasing molecular weight (DEP > DBP > DEHP), and in vitro flow-through diffusion results broadly mirrored the in vivo urinary elimination patterns.

Key findings

  • In vitro, phthalates crossed human skin as monoester metabolites; permeation was higher for emulsion than neat application for DBP and DEP, while DEHP had minimal permeation. Reported permeation rates were approximately J ~2 µg/cm²/h for DEP, ~0.1 µg/cm²/h for DBP, and ~0.0002 µg/cm²/h for DEHP; in Table 2, neat DEP MEP J was 1.22 ± 0.59 µg/cm²/h, neat DBP MnBP J was 0.11 ± 0.04 µg/cm²/h, and neat DEHP MEHP J was 0.0002 ± 0.0001 µg/cm²/h.
  • In participants, the molar sum of urinary metabolites up to 30 h post-application was 3% ± 2% of the applied dose for DEP (MEP), 1% ± 0.5% for DBP (MBP + 3OH-MBP), and 0.01% ± 0.003% for DEHP (MEHP + 5OH-MEHP + 5oxoMEHP + 5cx-MEPP).
  • Urinary excretion peaked around 6 h for DEP, with an apparent half-life of about 8 h; DBP metabolites reached maximum concentrations 13–23 h post-application, with an estimated half-life of 2–9 h; DEHP metabolites showed a slow continued rise and no maximum within 30 h, so no half-life was reported.

Methods

  • In vitro: human abdominoplasty skin was dermatomed to 800 µm, frozen, and mounted in flow-through diffusion cells (1 cm² exposed area; receptor fluid saline with 0.006% or 6% PEG; 32°C; 24 h). Deuterated d4-DEHP, d4-DBP, and d4-DEP were applied neat (10 µL/cm²) or as an emulsion (847 µL/cm²), and metabolites were analyzed in receptor fluid and skin compartments; experiments used four skin donors with triplicates per donor (n = 3–9 per condition).
  • In vivo: five participants (mean BMI 21.9 ± 1.8; mean age 27.5 ± 10 years) received 400 µL of a neat deuterated phthalate mixture on a 40 cm² forearm area, left unwashed for 6 h. Urine was collected before exposure, every 2 h during exposure, and ad lib for the following 24 h; metabolites were quantified and expressed as percentage of applied dose and apparent urinary elimination half-lives.
  • Analysis: in vitro permeability parameters J, Tlag, and Kp were estimated from cumulative metabolite permeation curves; a semi-mass balance quantified metabolites in receptor fluid, skin, washes, and donor chamber; in vitro results were compared with participant urinary metabolite data.

Limitations

  • Stated in the paper: urine was not collected long enough to fully elucidate urinary elimination kinetics for all phthalate metabolites; the authors suggest 48 h post-exposure. In vitro diffusion samples were not collected beyond 24 h, limiting steady-state determination for high-molecular-weight phthalates, and a complete in vitro mass balance was not done because parent phthalates and unspecific metabolites could not be measured.
  • Stated in the paper: previously frozen skin has lower enzymatic activity than fresh skin, which may reduce metabolism-dependent permeation relative to in vivo conditions.
  • Evident from the text: the participant study included only five volunteers, and some in vitro conditions had small n (3–9 cells); the authors also describe the DEP skin permeation results as preliminary because steady state was not always reached.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.toxlet.2024.05.016

Cites

49 of 51 references verified1 citation errors · 1 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

19 of 38 cited sources checked · 6 supported · 0 flagged · accuracy not yet measured

  • Premisecitation
    § 4. Discussion · p. 5

    Dermal uptake is very modest for high molecular weight phthalates.

    “Dermal uptake is very modest for high molecular weight phthalates (Giovanoulis et al., 2020), as our DEHP results confirm”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Giovanoulis et al., 2020 source
  • Premisecitation
    § 4.1. In vitro skin permeation · p. 8

    Metabolism is far less in previously frozen skin kept on saline solution for 24 hours compared to in vivo.

    “Metabolism is known to be far less in previously frozen skin kept on saline solution for 24 hours compared to in vivo (Neil et al., 2020).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Neil et al., 2020 source

      The Conclusions (page unavailable) report a discrepancy in metabolic biomarkers between the cultured human skin explant model and skin in vivo. They do not say metabolism is far less in previously frozen skin, or assess skin kept in saline for 24 hours. The Methods describe tissue kept chilled before culture in modified Cornification medium, not previously frozen tissue held in saline. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
  • Premisecitation
    § [https://doi.org/10.1016/j.toxlet.2024.05.016](https://doi.org/10.1016/j.toxlet.2024.05.016) · p. 2

    The monoester metabolites have direct access to the systemic circulation and thus to target organs.

    “This is especially important for phthalates considering that the monoester metabolites have direct access to the systemic circulation and thus, the target organs (Hauser and Calafat, 2005; Sugino et al., 2017).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Hauser and Calafat, 2005 source

      The Routes of Exposure and Metabolism passage describes formation and excretion of phthalate monoesters, but does not say they have direct access to systemic circulation or target organs. Searches for “systemic circulation,” “target organs,” and monoester distribution found no passage in our copy establishing that point. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites Sugino et al., 2017 source

      The Introduction (page unavailable) says that metabolites formed in the skin can be absorbed into the body and links dermal blood vessels to systemic circulation. The Discussion reports that a phthalate monoester permeated rat skin. The paper does not establish that the metabolites reach target organs, so that extension is not supported by this source. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Premisecitation
    § [https://doi.org/10.1016/j.toxlet.2024.05.016](https://doi.org/10.1016/j.toxlet.2024.05.016) · p. 2

    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).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Hopf et al., 2014 source
  • Findingcitation
    § 4.2. Participant study · p. 9

    Urinary metabolites were almost equally distributed at all times post-exposure, similar to what was observed after inhalation.

    “Urinary metabolites were almost equally distributed at all times post-exposure, similar to what was observed after inhalation (Krais et al., 2018).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Krais et al., 2018 source

      Section 3.2 reports that some oxidised DEHP metabolites reached urinary levels comparable to the monoester after combined inhalation and dermal exposure. It does not establish that metabolites were almost equally distributed at all post-exposure times: their peak times differed, and one metabolite had a much lower peak level. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • May combine two claims. 39
  • Classified as probably not a substantial claim. 16

  • May combine two claims.

    Premisecitation
    § 4.1. In vitro skin permeation · p. 8

    In 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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Hopf et al., 2014 source

      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 measured

  • Classified as probably not a substantial claim.

    Premisecitation
    § 4.1. In vitro skin permeation · p. 8

    A recent review found that the very low aqueous solubility and vapor pressure of many plasticizers, such as DEHP, did not necessarily limit exposure because they have extensive binding and association with lipids.

    “A recent review (Gustafsson et al., 2020), found that the very low aqueous solubility and vapor pressure of many plas­ ticizers, such as DEHP, did not necessarily limit exposure, because they have extensive binding and association with lipids.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Gustafsson et al., 2020 source

  • May combine two claims.

    Findingown data
    § 4.2. Participant study · p. 9

    Urinary elimination of MEP was fast, with a mean apparent urinary elimination half-life of 8 hours, which was longer than the previously reported 2.7 (0.7-11) hours.

    “Urinary elimination of MEP was fast with a mean apparent urinary elimination half-life of 8 hours (Fig. 3), which was longer than previ­ ously reported in another study (2.7 (0.7 -11) hours (Krais et al., 2018)).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Krais et al., 2018 source

      Section 3.1 reports a mean D4-MEP urinary excretion half-life of 2.7 hours after dermal exposure, supporting the cited comparison value. The cited paper’s text does not report the accompanying 0.7–11-hour range. The 8-hour estimate belongs to the citing study, not the claim attributed to Krais et al. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation
    § [https://doi.org/10.1016/j.toxlet.2024.05.016](https://doi.org/10.1016/j.toxlet.2024.05.016) · p. 2

    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).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Barber et al., 1992 source
    • cites Hopf et al., 2014 source

      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 measured
    • cites Scott et al., 1987 source

  • May combine two claims.

    Interpretationown data
    § 4.1. In vitro skin permeation · p. 8

    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).”
    • Also stated in: § 4.3. Agreement of in vitro and participant results · p. 9 · plain
      “Our study also supports prior observations that phthalates with shorter alkyl chains have a greater skin permeation and shorter urinary elimination (Giovanoulis et al., 2020).”
    • Also stated in: § 5. Conclusion · p. 9 · plain
      “Our study showed that phthalate skin permeation decreased with increasing molecular weight among the three phthalates tested: DEP > DBP > DEHP.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Chung et al., 2019 source
    • cites Hopf et al., 2014 source

      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
    • cites Scott et al., 1987 source

      Table 1 (p. 225) shows DEP > DBP > DEHP for rat-skin absorption rates, but not for human skin: DEHP (1.06) exceeds DBP (0.07). The Discussion (pp. 225–226) relates absorption more closely to lipophilicity and aqueous solubility than to molecular weight alone. The claimed ordering therefore does not hold across both species studied. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisereasoning
    § 4.1. In vitro skin permeation · p. 8

    Reported 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).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Barber et al., 1992 source
    • cites Hopf et al., 2014 source
    • cites Scott et al., 1987 source

      Scott et al. report DEHP absorption measurements using human cadaver epidermis and describe heat separation in Materials and Methods. Their study therefore supplies one of the cited measurements and an experimental design, but it does not compare results across the three studies or explain between-study variation. Its diffusion cells were maintained at 30 ± 1°C, not within the stated 32–37°C range. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation
    § 4.2. Participant study · p. 9

    The inter-individual variation in half-lives could reflect inter-individual differences in oxidative metabolism of phthalates.

    “This could reflect inter-individual differences in oxidative metabolism of phthalates (Ito et al., 2014).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Ito et al., 2014 source

  • May combine two claims.

    Findingown data
    § 3.1. In vitro skin permeation of phthalates · p. 5

    DEP permeated the skin readily as MEP and was depleted when applied neat with 0.006% PEG and as emulsion with 6% PEG.

    “DEP permeated the skin readily as MEP and to the extent that it was depleted (as neat with 0.006 % PEG and emulsion with 6 % PEG).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given
    § 3.2.1. Urinary elimination · p. 5

    The intra-individual variability was considerable on the day of exposure.

    “The intra-individual variability was considerable on the day of the exposure.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § 3.1. In vitro skin permeation of phthalates · p. 5

    MEHP reached steady state only when applied neat and with 0.006% PEG in the receptor fluid; otherwise it was below the limit of detection.

    “MEHP reached steady state only when applied neat and with 0.006 %PEG in the receptor fluid, otherwise it was below the limit of detection.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § 1. Introduction · p. 1

    Polyethylene glycol in the receptor fluid enhanced emulsion permeation but did not affect neat substances.

    “with polyethylene glycol (PEG) in the receptor fluid enhancing emulsion permeation, but not affecting neat substances”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § 3.2.1. Urinary elimination · p. 5

    For DEHP, urinary elimination kinetics for MEHP, 5OH-MEHP, 5oxoMEHP, and 5cx-MEHP were rather similar, and concentrations were very low compared to metabolites of the other two phthalates.

    “For DEHP, urinary elimination kinetics for MEHP, 5OH-MEHP, 5oxoMEHP, and 5cx-MEHP were rather similar, and concentrations were very low (Figs. 3C and 3F), compared to the metabolites of the other two phthalates.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § 1. Introduction · p. 1

    Phthalates crossed the skin barrier and were metabolized into monoesters before elimination.

    “Phthalates crossed the skin barrier and metabolized into monoesters before elimination.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § 3.1. In vitro skin permeation of phthalates · p. 5

    Steady state was reached for neat DEP with 6% PEG in receptor fluid after doubling the dose, while emulsified DEP did not reach steady state.

    “We reached steady state in the experiment with neat DEP and 6 % PEG in the receptor fluid after doubling the dose, while emulsified DEP did not.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § 3.2.1. Urinary elimination · p. 5

    Most of MBP and 3OH-MBP had eliminated within 30 hours post-application, but their presence was still measurable.

    “Although, most of MBP and 3OH-MBP had eliminated within 30 hours post-application their presence was still measurable.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § 3.2.1. Urinary elimination · p. 5

    The predominant urinary DBP metabolite was the monoester MBP, at concentrations more than an order of magnitude higher than 3OH-MBP.

    “The predominant urinary metabolite was the monoester MBP, at concentrations more than an order of magnitude higher than 3OH-MBP (Figs. 3B and 3E).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data
    § 3.2.1. Urinary elimination · p. 5

    One participant started eliminating all DEHP urinary metabolites two hours post-application.

    “One participant started eliminating all DEHP urinary metabolites two hours post-application.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § 4.1. In vitro skin permeation · p. 8

    MEP had the highest concentration of the three phthalates in the receptor fluid, showing that DEP crossed the skin barrier readily compared to DBP and DEHP.

    “MEP had the highest con­ centration of the three phthalates in the receptor fluid showing that DEP crossed the skin barrier readily compared to DBP and DEHP.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation
    § 4.2. Participant study · p. 9

    The calculated elimination half-life range for the sum of two urinary DBP metabolites was 2-9 h in urine, in line with other human data showing ranges from 2 to 4 h.

    “Therefore, the calculated elimination half-life range was 2 -9 h in urine, which is in line with other human data showing ranges from 2 to 4 h (Domínguez-Romero and Scheringer, 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Domínguez-Romero and Scheringer, 2019 source

  • May combine two claims.

    Findingown data
    § 4.2. Participant study · p. 9

    Two participants had very long half-lives (13-14.5 hours) while the three others had half-lives from 3.8 to 6.6 hours.

    “Interestingly, two of our participants had very long half-lives (13 -14.5 hours) while the three others had half-lives from 3.8 to 6.6 hours.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning
    § 4.1. In vitro skin permeation · p. 8

    The difference between the current study and the previous study was that the current study used human viable skin and previously frozen skin.

    “The difference between our current study and former was that we used human viable skin and this time previously frozen skin.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § 4.1. In vitro skin permeation · p. 8

    The study's DEHP skin permeation rates were lower than previously reported (0.002 μg/cm2/h, <LOQ-0.005, versus literature 0.0013-5.59 μg/cm2/h), and its permeation coefficient (Kp) varied a few thousand fold (0.00002*10^5 cm/h versus literature 0.011*10^5-15.1*10^5 cm/h).

    “Our DEHP skin permeation rates were lower than previously reported (0.002 µ g/cm 2 /h ( &lt; LOQ-0.005) in our study compared to literature ranges 0.0013 -5.59 µ g/cm 2 /h) and this was also true for the permeation coefficient (Kp), which varied a few thousands fold (0.00002*10 5 cm/h in our study compared to literature ranges 0.011*10 5 - 15.1*10 5 cm/h).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § 4.1. In vitro skin permeation · p. 8

    When applied neat with 0.006% PEG in the receptor fluid, DEHP barely crossed the skin as MEHP and did not permeate when emulsified.

    “When applied neat with 0.006 % of PEG in the receptor fluid, DEHP barely crossed the skin as MEHP and did not permeate when emulsified.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § 4.1. In vitro skin permeation · p. 8

    DEHP metabolites were quantified when DEHP was applied neat to the skin but were not detected in any parts of the in vitro diffusion system when DEHP was applied as an emulsion.

    “The DEHP metabolites were quantified for the experiments where DEHP was applied neat to the skin but were not detected in any parts of the in vitro diffusion system when applied as an emulsion.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § 4.1. In vitro skin permeation · p. 8

    With a greater amount of DEP applied to the skin, MEP reached steady state when DEP was applied neat, but not when it was applied emulsified.

    “With a greater amount of DEP applied to the skin, MEP reached steady state when DEP was applied neat, but not when it was applied emulsified.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation
    § 4.1. In vitro skin permeation · p. 8

    The vehicles water or neat had an influence on the skin permeation of the phthalates, with phthalates emulsified in water having a faster rate compared to neat application.

    “The vehicles in our study, water or neat, had an influence on the skin permeation of the phthalates. Phthalates emulsified in water had a faster rate compared to neat application.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § 4.1. In vitro skin permeation · p. 8

    DEHP did not permeate skin when emulsified, and DBP permeation rates were similar for both PEG concentrations (J: 0.38 versus 0.24 μg/cm2/h).

    “DEHP did not permeate skin when emulsified and the DBP permeation rates were similar for both PEG concentrations (J: 0.38 versus 0.24 µ g/cm 2 /h) (Table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § 4.3. Agreement of in vitro and participant results · p. 9

    The in vitro skin permeation experiments showed that dermal absorption was very slow and continued after 24 hours for DBP and DEHP experiments.

    “The in vitro skin permeation experiments showed that dermal absorption was very slow and continued after 24 hours for DBP and DEHP experiments.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § 4.3. Agreement of in vitro and participant results · p. 9

    The maximum urinary DEP, DBP, and DEHP concentrations were reached 11, 17, and 22 hours post-application, respectively.

    “The maximum urinary DEP, DBP, and DEHP concentrations were reached 11-, 17-, and 22-hours post-application, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § 5. Conclusion · p. 9

    All tested phthalates permeated skin as their respective monoester metabolite in vitro and were further metabolized in the body before being eliminated in urine in participants.

    “All the tested phthalates permeated skin as their respective monoester metabolite ( in vitro data) and were further metabolized in the body before being eliminated in urine in participants (human participant data).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § 4.2. Participant study · p. 9

    The study observed very low urinary DEHP metabolite concentrations and was unable to elucidate elimination kinetics.

    “We observed very low urinary DEHP metabolite concentrations and were unable to elucidate elimination kinetics.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § 4.3. Agreement of in vitro and participant results · p. 9

    Although DEHP metabolites were not detected in any parts of the in vitro diffusion system, urinary elimination kinetics were observed for MEHP, 5OH-MEHP, 5oxo-MEHP, and 5cx-MEHP post-application on the participants' skin.

    “Although, DEHP me­ tabolites were not detected in any parts of the in vitro diffusion system, we observed urinary elimination kinetics for MEHP, 5OH-MEHP, 5oxo-MEHP, and 5cx-MEHP post-application on the participants ' skin.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation
    § 2.2.5. Skin permeation parameters · p. 4

    The study complies with OECD guideline 428 in describing skin origin and preparation, proof of skin integrity using TEWL, temperature (32°C), choice of a suitable receptor fluid, description of the diffusion cells used, actual area of skin dosed, and duration of sampling period (24 h).

    “Our study complies with the OECD guideline 428 in describing the skin origin and preparation, and the proof of skin integrity using the TEWL, temperature (32 ◦ C), the choice of a suitable receptor fluid, the description of the diffusion cells used, the actual area of skin dosed, the duration of sampling period (24 h).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites OECD guideline 428

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation
    § [https://doi.org/10.1016/j.toxlet.2024.05.016](https://doi.org/10.1016/j.toxlet.2024.05.016) · p. 2

    Skin absorption in human volunteers has been demonstrated for DEHP dissolved in ethanol and for DEP and DBP in a cream formulation.

    “Skin absorption in human volunteers has been demonstrated for DEHP dissolved in ethanol ([ 14 C]DEHP) (Wester et al., 1998) as well as DEP and DBP (2 % (w/w) in a cream formulation over a week (Janjua et al., 2007).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Wester et al., 1998 source
    • cites Janjua et al., 2007 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation
    § 2.2.3. Experimental design · p. 3

    Skin discs with TEWL reading above 11 g/m2/h were deemed damaged and replaced.

    “If the TEWL reading was above 11 g/m 2 /h (Pinnagoda et al., 1990), the skin disc was deemed damaged and replaced.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pinnagoda et al., 1990 source

  • May combine two claims.

    Interpretationcitation
    § 4.1. In vitro skin permeation · p. 8

    The secondary oxidation products are formed in viable human skin with active enzyme activity or elsewhere in the body, most likely the liver.

    “we conclude that these oxidation products are formed in viable human skin with active enzyme activity or elsewhere in the body, most likely the liver (Isobe et al. 2023).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Isobe et al. 2023 source

  • Classified as probably not a substantial claim.

    Premisecitation
    § 4.1. In vitro skin permeation · p. 8

    Others have observed a phthalate accumulation in skin.

    “Others have observed a phthalate accumula­ tion in skin (e.g., Ng et al., 1992 used mice and pig full thickness skin with a receptor medium of 40 % ethanol and determined the parent compounds; Pan et al., 2014 used hairless guinea pigs and quantified both parent compounds and metabolites).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Ng et al., 1992

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Pan et al., 2014 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given
    § 4.1. In vitro skin permeation · p. 8

    Kp could only be provided for experiments that reached steady state.

    “We could only provide Kp for experiments that reached steady state (Table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § 4.1. In vitro skin permeation · p. 9

    DEHP is highly lipophilic and would favor the longer intercellular route in either neat or emulsion, as DEHP does not readily stay emulsified in water.

    “On the contrary, DEHP is highly lipophilic and would favor the longer inter­ cellular route in either neat or in emulsion, as DEHP does not readily stay emulsified in water.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given
    § 1. Introduction · p. 1

    The significance of dermal uptake is usually governed by molecular weight and water solubility according to Fick's law of diffusion.

    “The significance of dermal uptake is usually governed by molecular weight and water solubility according to Fick ' s law of diffusion.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § [https://doi.org/10.1016/j.toxlet.2024.05.016](https://doi.org/10.1016/j.toxlet.2024.05.016) · p. 2

    Phthalates are metabolized once absorbed into the body; the first step is hydrolysis by esterases yielding a monoester phthalate.

    “Phthalates are also metabolized once absorbed into the body. The first step is hydrolysis by esterases (in lungs, skin, and the digestive system), which yields the primary metabolite, a monoester phthalate (Frederiksen et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Frederiksen et al., 2007 source

  • May combine two claims.

    Interpretationreasoning
    § [https://doi.org/10.1016/j.toxlet.2024.05.016](https://doi.org/10.1016/j.toxlet.2024.05.016) · p. 2

    The in vitro quantitative results were highly variable between studies, probably due to differences in anatomical origin and thickness of skin used as well as experimental conditions.

    “The in vitro quantitative results were highly variable between studies, and this is probably due to differences in the anatomical origin and thickness of skin used as well as experimental conditions (exposure duration, concentration, vehicle, and experimental apparatus).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § [https://doi.org/10.1016/j.toxlet.2024.05.016](https://doi.org/10.1016/j.toxlet.2024.05.016) · p. 2

    Once phthalates have been absorbed into the stratum corneum, they diffuse through and gain access to viable epidermis, where esterases can metabolize the parent compound to monoesters.

    “Once phthalates have been absorbed into the stratum corneum (outer layer of the skin), they diffuse through and gain access to viable epidermis, where the esterases can metabolize the parent compound to monoesters (B ¨ atz et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites B ¨ atz et al., 2013

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § 2.2.4. Semi-mass balance experiments · p. 3

    The total mass balance for substances that are not radiolabeled has an acceptable range of 80-120%.

    “The total mass balance for substances that are not radiolabeled has an acceptable range 80 -120 % (OECD GD28, par. 77; GN156, par. 95).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites OECD GD28, par. 77

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites GN156, par. 95

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning
    § 4.1. In vitro skin permeation · p. 8

    Previously frozen skin is less hydrated than fresh skin and therefore reacts differently to oily neat DEHP compared to a small amount of DEHP in water.

    “Previously frozen skin is less hydrated than fresh skin and therefore reacts differently to the oily neat DEHP compared to a small amount of DEHP in water.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Previously frozen skin is less hydrated than fresh skin.

  • Classified as probably not a substantial claim.

    Premisecitation
    § 1. Introduction · p. 1

    The relative importance of skin exposure compared to ingestion is lower.

    “This is because the relative importance of skin exposure compared to ingestion is lower (Giovanoulis et al., 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Giovanoulis et al., 2018 source

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given
    § 2.3.2. Study design · p. 4

    Urine sampling cups used to collect urine samples were without phthalates and any other potential background contamination was avoided by dosing deuterated phthalates.

    “Urine sampling cups used to collect urine samples were without phthalates and any other potential (background) contamination was avoided by dosing deuterated phthalates.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data
    § 4.3. Agreement of in vitro and participant results · p. 9

    The slow in vitro dermal absorption continuing after 24 hours corroborated the urinary elimination kinetics that showed a continued rise in urinary phthalate metabolite concentrations after 24 hours post-application.

    “This corroborated the urinary elimination kinetics that showed a continued rise in urinary phthalate metabolite concentrations after 24 hours post-application.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning
    § 4.4. Study limitations · p. 9

    The study used human skin in the in vitro experiments and human participants in the toxicokinetic study, and thus was able to contrast the findings from the two approaches.

    “Furthermore, we used human skin in the in vitro experiments and human participants in the toxicokinetic study, and thus, were able to contrast the findings from the two ap­ proaches.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data
    § 4.4. Study limitations · p. 9

    The study did not complete an in vitro mass balance because it was not able to measure the parent phthalate nor the unspecific metabolites.

    “Furthermore, we did not complete an in vitro mass balance as we were not able to measure the parent phthalate nor the unspecific metabolites.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning
    § 4.4. Study limitations · p. 9

    The strength of the study is that it used two approaches to further understand the importance of skin absorption of phthalates in humans.

    “Overall, the strength of this study is that we used two approaches to further understand the importance of skin absorption of phthalates in humans.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given
    § 4.4. Study limitations · p. 9

    Another related limitation was that flow-through diffusion samples were not collected after 24 hours in the in vitro experiments to reach steady state for the high molecular weight phthalates.

    “Another related limitation is that we did not collect flow-through diffusion samples after 24 hours in the in vitro experiments to reach steady state for the high molecular weight phthalates.”
    Quote in the paperNot a substantial claim
52 of 52

  • The authors state this as an assumption.

    Highly lipophilic substances, such as phthalates, have low skin absorption.

    “Highly lipophilic substances, such as phthalates, are assumed to have low skin absorption”

  • The paper relies on this without support.

    Data on skin absorption of phthalates remain limited.

    “However, data on skin absorption remain limited.”

  • The paper relies on this without support.

    The stratum corneum absorbs phthalate, justifying leaving a substance on top of the skin for more than 24 hours.

    “The relevance of leaving a substance on top of the skin more than 24 hours, which is outside of the OECD guidelines, is justified for phthalate exposures, we believe, because the stratum corneum (SC) absorbs the phthalate.”

  • The paper relies on this without support.

    DEP is the phthalate with the smallest molecular weight in the mixture and has the lowest hydrophobicity.

    “DEP is the phthalate with the smallest molecular weight in our mixture and has the lowest hydrophobicity.”

  • The paper relies on this without support.

    Water can disrupt the structure of the stratum corneum and enhance the absorption of certain substances.

    “as water can disrupt the structure of the stratum corneum and enhance the absorption N.B. Hopf et al. of certain substances.”

  • The paper relies on this without support.

    Ingested phthalates undergo first-pass liver metabolism, whereas phthalates absorbed through the lungs or across skin do not, so phthalate monoesters are directly distributed into the blood after skin absorption and inhalation.

    “Ingested phthalates get into the blood from the intestines where phthalates are broken down by liver enzymes, known as the first pass effect. Phthalates absorbed through the lungs or across skin do not succumb to the first pass effect. Conse­ quently, the phthalate monoesters are directly distributed into the blood after skin absorption and inhalation.”

  • The paper relies on this without support.

    Phthalate exposures via the skin route contribute far less to the internal dose compared to inhalation and ingestion.

    “Even though phthalate exposures via the skin route contributes far less to the internal dose compared to inhalation and ingestion”

  • The paper relies on this without support.

    Previously frozen skin is less hydrated than fresh skin.

    “Previously frozen skin is less hydrated than fresh skin and therefore reacts differently to the oily neat DEHP compared to a small amount of DEHP in water.”
8 of 8

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • DEHP maximum reported at 22 hours despite not being reached by 30 hours

    Major

    The discussion says maximum urinary DEHP concentration occurred 22 hours after application, while the results say maximum concentrations had not been reached after 30 hours.

  • Two different higher PEG concentrations are specified

    Minor

    The methods say the receptor fluid contained either 0.6% or 0.006% PEG, whereas the study description and results identify the higher concentration as 6%.

2 of 2

Cites

Flagged first, then by citations

3 of the 54 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Hopf, N. B., De Luca, H. P., Borgatta, M., Koch, H. M., Pälmke, C., Benedetti, M., Berthet, A., & Reale, E.
Affiliations
  • Centre universitaire de médecine générale et santé publique, Lausanne (CH)
  • Institute for Prevention and Occupational Medicine (DE)
Corresponding author
Hopf, Nancy B.
ORCID
Venue
Toxicology Letters
Publisher
Elsevier BV
Published
2024-07
Volume
398
Pages
38-48
ISSN
0378-4274 (ISSN-L)
DOI
10.1016/j.toxlet.2024.05.016
OpenAlex
W4399662040
Semantic Scholar
118a1e37243c901f9eac74007a994cd5b981eae9
Cited by
24
References
54
Citations by year
2026: 10 · 2025: 11 · 2024: 3
FWCI
3.86
Type
journal article
Language
en
Open access
Licence
Locations
  • Toxicology Letters (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • IRIS (submittedVersion, cc-by)
  • SERVAL (Université de Lausanne) (submittedVersion, cc-by)
Funders
SCAHT (AP20\u20132)
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
phthalates, skin permeation, DEHP, dibutyl phthalate, diethyl phthalate, human skin, emulsion formulation, polyethylene glycol, urinary excretion, flow-through diffusion cell, in vitro-in vivo correlation, phthalate exposure
MeSH terms
Administration, Cutaneous, Adult, Dibutyl Phthalate, Diethylhexyl Phthalate, Emulsions, Female, Humans, Male, Middle Aged, Phthalic Acids, Skin, Skin Absorption, Young Adult

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-12.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-12.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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