Dermal absorption, skin retention and urinary elimination of bisphenol S in rats: in vitro, in vivo and intravenous comparative analysis

Bisphenol S (BPS) is widely used as a substitute for bisphenol A (BPA) in industrial applications, but concerns have been raised about its dermal absorption and potential systemic toxicity. Here, we investigated the toxicokinetics of BPS following dermal and intravenous (i.v.) exposure in rats, and performed complementary in vitro dermal absorption studies. A single dose of 20 µg/cm² [¹⁴C]-BPS was applied (50 µL/cm²) in vitro and in vivo to rat skin. Maximum systemic exposure was achieved by administering 0.05, 0.5, or 5 mg/kg i.v. In vitro percutaneous absorption depended on the solvent, with the highest uptake measured in artificial sebum (~ 5000 ng/cm² over 40 h). Most absorbed BPS remained unmetabolised (78–85%), with a significant skin reservoir (25–60% of the applied dose). In vivo dermal exposure resulted in low systemic absorption (~ 10%), with BPS persisting in the skin for more than 72 h. The primary excretion route was in urine (60–70%), mainly as BPS-glucuronide. Systemic i.v. exposure confirmed rapid metabolisation, with BPS-G dominating in the plasma and urinary profiles. Applying the Triple-Pack approach, by integrating in vitro and in vivo rat data with prior human in vitro findings, human in vivo dermal absorption was estimated at 1.4% of the applied dose. The results presented highlight prolonged skin retention and slow systemic release of BPS, raising concerns about chronic low-level exposure following dermal contact. Further studies are needed to refine risk assessments, particularly to enhance toxicokinetic modelling and forward dosimetry to improve exposure prediction and regulatory decision-making.