Comparative in Vitro– in Vivo Percutaneous Penetration of the Fungicide ortho-Phenylphenol

• Published in: Regulatory toxicology and pharmacology Vol. 35; no. 2; pp. 198 - 208
• Main Authors: Cnubben, Nicole H.P., Elliott, Graham R., Hakkert, Betty C., Meuling, Wim J.A., van de Sandt, Johannes J.M.
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 01-04-2002; Elsevier
• Subjects: Administration, Cutaneous; Adult; Animals; Animals, Outbred Strains; Biological and medical sciences; Biphenyl Compounds - administration & dosage; Biphenyl Compounds - pharmacokinetics; Dose-Response Relationship, Drug; Epidermis - metabolism; Female; Fungicides, Industrial - administration & dosage; Fungicides, Industrial - pharmacokinetics; General aspects. Methods; Humans; In Vitro Techniques; Male; Medical sciences; Membranes - metabolism; Permeability; Rats; Rats, Wistar; Skin Absorption; Swine; Toxicology; risk assessment; ortho-phenylphenol; dermal penetration; in vitro– in vivo comparison; Human; Healthy subject; Rat; Interspecific comparison; Pesticides; Rodentia; Epidermis; Risk analysis; In vitro; Fungicide; Pig; Percutaneous route; Toxicokinetics; In vivo; Vertebrata; Mammalia; Absorption; Correlation analysis; Animal; Distribution; Models; Skin; Artiodactyla; Ungulata
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1006/rtph.2001.1530

The validity of
in vitro and
in vivo methods for the prediction of percutaneous penetration in humans was assessed using the fungicide
ortho-phenylphenol (OPP) (log
Po/
w 3.28, MW 170.8, solubility in water 0.7 g/L).
In vivo studies were performed in rats and human volunteers, applying the test compound to the dorsal skin and the volar aspect of the forearm, respectively.
In vitro studies were performed using static diffusion cells with viable full-thickness skin membranes (rat and human), nonviable epidermal membranes (rat and human), and a perfused pig ear model. For the purpose of conducting
in vitro/
in vivo comparisons, standardized experimental conditions were used with respect to dose (120 μg OPP/cm
2), vehicle (60% aqueous ethanol), and exposure duration (4 h). In human volunteers, the potentially absorbed dose (amount applied minus dislogded) was 105 μg/cm
2, while approximately 27% of the applied dose was excreted with urine within 48 h. In rats these values were 67 μg/cm
2 and 40%, respectively.
In vitro methods accurately predicted human
in vivo percutaneous absorption of OPP on the basis of the potential absorbed dose. With respect to the other parameters studied (amount systemically available, maximal flux), considerable differences were observed between the various
in vitro models. In viable full-thickness skin membranes, the amount systemically available and the potentially absorbed dose correlated reasonably well with the human
in vivo situation. In contrast the
K
p/maximal flux considerably underestimated the human
in vivo situation. Although epidermal membranes overestimated human
in vivo data, the species differences observed
in vivo were reflected correctly in this model. The data generated in the perfused pig ear model were generally intermedia te between viable skin membranes and epidermal membranes.