PREDICTING PERCUTANEOUS ABSORPTION 401 o o 30 t 2O 10 BENZOIC ACID LtJ 7' ß -J , --• 0 u• 0 (/) Lu 0 •u • 0 ß • • o 7' "• o n- • 0 • u_ :D -- 0 ',r' o T .• O2 "• • x PRODUCTS Figure 2. Percutaneous absorption levels of the test materials four days after their topical administration in the hairless rat. tion for the stratum corneum barrier effect. For a low reservoir capacity, we find low or minimal penetration and therefore a strong barrier effect. On the other hand, for a high reservoir capacity, we find substantial penetration and therefore a weak barrier effect. As a consequence, it is possible that barrier and reservoir functions of the horny layer may reflect the same physiological reality. From a practical viewpoint, the simple measurement of the amount of a chemical found in the stratum corneum at the end of a 30-rain application provides a good predictive assessment of the total amount penetrating within four days. As previously mentioned, the absorption level has been shown to be dependent on application conditions. It was therefore important to ascertain whether or not the "stripping method" was independent of the main factors capable of modifying the pen- etration level of a chemical, i.e., application time, dose applied, vehicle used, and anatomic site involved. PART II: INFLUENCE OF APPLICATION CONDITIONS ON THE RELATIONSHIP BETWEEN STRATUM CORNEUM CONCENTRATION AND PERCUTANEOUS ABSORPTION INFLUENCE OF APPLICATION TIME The duration of application of a compound may considerably influence the total

402 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS o o o o lO O. 1 J c B A STRIPPINGS Nr Figure 3. Distribution of the test materials within the horny layer of the dosed area, 30 minutes after their administration in the hairless rat. (A) dexamethasone, (B) hydrocortisone, (C) dehydroepiandrosterone, (D) testosterone, (E) mannitol, (F) thiourea, (G) caffeine, (H) sodium salicylate, (I) acetylsalicylic acid, (J) benzoic acid. amounts absorbed. Moreover, the time of application of a substance may be closely related to its field of use. Percutaneous absorption of four radiolabelled compounds (New England Nuclear) [(8-•4C) theophylline (specific activity 40 mCi/mmol, purity 98%) (Carboxyl 14C) ni- cotinic acid (specific activity 55 mCi/mmol, purity 97%) (Carboxyl 14C) acetylsalicylic acid (specific activity 60 mCi/mmol, purity 98%) was studied in the hairless rat. One thousand nmol of each compound were applied onto 1 cm 2 of dorsal skin during 0.5, 2, 4, and 6 hours, thus covering most of the usage conditions of materials topically applied. Total percutaneous absorption within four days for each molecule and each application time was carried out as described above (see Part I). Stratum corneum reser- voir was assessed for each compound after an application time fixed at 30 minutes by stripping the treated area. As shown in Table III and Figure 5, the amount of penetrated material is proportional to the duration of application (r = 0.98, p (0.001). From a theoretical viewpoint, this relation provides evidence that, as in vitro (15,16), a constant flux of penetration does really exist in vivo. This type of correlation was found on four ingredients with