A Physiological-Based Pharmacokinetic Model For The Broad Spectrum Antimicrobial Zinc Pyrithione: II. Dermal Absorption And Dosimetry In The Rat

ABSTRACT

The broad spectrum antimicrobial/antifungal zinc pyrithione (ZnPT) is used in products ranging from antifouling paint to antidandruff shampoo. The hazard profile of ZnPT was established based upon comprehensive toxicological testing, and products containing this biocide have been safely used for years. The purpose of this study was to create a dermal physiologically based pharmacokinetic (PBPK) model for ZnPT in the rat for improving dose–response analysis of ZnPT-induced toxicity where reversible hindlimb weakness was the endpoint used as the basis for ZnPT risk assessments. Previously, we developed a PBPK model which simulated the kinetics of pyrithione (PT) and its major metabolites 2-(methylsulfonyl)pyridine and S-glucuronide conjugates in blood and tissues of rats following oral ZnPT administration. The dermal model was optimized utilizing in vitro dermal penetration investigations conducted with rat skin and with historical data from a dermal repeat dose study using rats. The model replicated the observed temporal patterns and elimination kinetics of [¹⁴C]PT equivalents in blood and urine during and following repeated dermal dosing and replicated the observed dose-dependencies of absorption, blood [¹⁴C]PT equivalents and plasma PT concentrations. The model provided internal dosimetry predictions for a benchmark dose analysis of hindlimb weakness in rats that combined dermal, gavage and dietary studies into a single internal dose–response model with area-under-the-curve (AUC) for plasma PT, the toxic moiety in the rat, as the internal dose metric. This PBPK model has predictive validity for calculating internal doses of PT and/or [¹⁴C]PT equivalents from different routes of exposure in the rat.

KEYWORDS:

• Benchmark dose
• dermal absorption
• dermal physiological-based pharmacokinetic model
• hindlimb weakness
• zinc pyrithione

Acknowledgments

The studies were funded by Lonza (formerly Arch Chemical) and The Procter & Gamble Company. The authors thank Drs. Sheppard Martin, Harald Schlatter, Corie Ellison, and Jennifer Rhoades-Hamacher for their thoughtful comments and assistance.

Disclosure

J Frank Nash is an employee of the Procter & Gamble Company, Nicholas Skoulis is employed by SFA Toxicology & Risk Management Services and a consultant to Lonza, and Gary Diamond is an independent consultant.

Additional information

Funding

This work was supported by the The Procter & Gamble Company.