224 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS general, ranging in molecular weight from 18 to 750, and in lipophilicity with a log Poc• between - 3 to + 6. To test the validity of the Potts-Guy algorithm when it is applied to fragrance chem- icals, the values calculated according to Eq. (1) for 20 structures commonly encountered in fragrance compositions have been correlated with experimental Kps from the litera- ture, determined through human skin in vitro from aqueous solution under steady-state conditions. The multiple regression analysis by Potts and Guy, correlating the predicted with experimental log Kps, was also performed on the 20 fragrance chemicals, for direct comparison with the fit obtained for Flynn's much wider assortment of 93 chemicals (1). SAMPLE SELECTION The 20 compounds chosen for analysis of the predictive power of the Potts-Guy algo- rithm were selected based on the criteria that ß The measured log Poc• value does not exceed 4 ß An experimental permeability coefficient determined with human skin under steady- state conditions from aqueous solution is available from the literature ß The octanol-water partition coefficient has been determined experimentally ß They are listed in the standard reference on perfumery chemicals by S. Arctander (5). The list of chemicals selected for the validation of calculated versus measured log P values, on the other hand, was expanded to include 33 entries, as an experimental Kp is no longer a requirement there. All chemicals are listed in Table I. STATISTICS Statistical analysis was conducted using the Minitab TM statistical package (Minitab Release 6.1.1., Minitab Inc., State College, PA, 1987). RESULTS RELATIONSHIP BETWEEN EXPERIMENTAL AND PREDICTED Log P Linear regression analysis (Figure 1) shows near-perfect concordance between measured and calculated partition coefficients obtained from the PCMCP database for 33 common fragrance compounds (r 2 = 0.97, p 0.001), thereby legitimizing the use of calcu- lated values from that database in the Potts-Guy algorithm where measured values are not available. PREDICTIVE VALUE OF THE POTTS-GUY ALGORITHM Validity of the Potts-Guy algorithm predictive of skin permeability described in Eq. (1) was demonstrated when applied to fragrance chemicals in particular. Using measured log P values, the correlation of estimated permeability constants Kp with experimental values for 20 compounds, through human skin from an aqueous medium for steady-state

ABSORPTION IN HUMAN SKIN 225 Table I Measured and Predicted Log Po•t and Kp (cm/hr) Values for Fragrance Chemicals M log P(a) C log P(b) M Kp(c) Chemical MW (PCMCP) (PCMCP) (P-G) log M Kp (P-G) 3,4-Xylenol 122.17 2.23 2.42 1.3 le-02 3-Cresol 108.14 1.96 1.97 1.03e-02 4-Chloro- 3-xylenol 156.62 3.39 3.48 5.39e-02 4-Cresol 108.14 1.94 1.97 9.95e-03 4-Ethylphenol 122.17 2.58 2.50 2.33e-02 4-Methoxy acetophenone 150.17 1.74 1.80 3.98e-03 4-Methoxybenzyl alcohol 138.17 1.10 1.02 1.65e-03 4-Nitrophenol 139.11 1.91 1.85 6.13e-03 Benzophenone 182.22 3.18 3.18 2.67e-02 Benzyl acetate 150.17 1.96 1.96 5.70e-03 Benzyl alcohol 108.14 1.10 1.10 2.52e-03 Benzyl benzoate 212.25 3.97 3.88 6.37e-02 Cinnamic acid 148.16 2.13 2.09 7.74e-03 Cinnamic alcohol 134.18 1.95 1.41 7.01e-03 Cinnamic aidehyde 132.15 1.90 1.90 6.65e-03 Coumarin 146.15 1.39 1.41 2.37e-03 Cumene 120.20 3.66 3.57 1.40e-01 Heptanoic acid 130.19 2.50 2.41 1.82e-02 Heptanol 116.21 2.72 2.41 3.18e-02 Hexanoic acid 116.16 1.92 1.88 8.60e-03 Hexanol 102.18 2.03 1.88 1.25e-02 Indole 117.15 2.14 2.13 1.22e-02 Isoquinoline 129.16 2.08 1.82 9.3 le-03 Methyl-4-OH benzoate 152.14 1.96 1.98 5.54e-03 Methylsalicylate 152.14 2.34 2.44 1.03e-02 Nitrobenzene 123.11 1.85 1.88 6.96e-03 Octanoic acid 144.17 2.94 3.05 3.08e-02 Octanol 130.23 3.00 2.94 4.13 e-02 Pentanoic acid 102.14 1.39 1.35 4.40e-03 Pentanol 88.15 1.56 1.35 7.08e-03 Phenylethyl alcohol 122.17 1.18 1.36 2.36e-02 Resorcinol 110.11 0.80 0.81 1.50e-03 Thymol 150.22 3.30 3.40 5.09e-02 - 1.88 - 1.99 - 1.27 - 2.00 - 1.63 - 2.40 -2.78 -2.21 - 1.57 -2.24 -2.60 - 1.20 -2.11 -2.15 -2.18 -2.62 -0.85 - 1.74 - 1.50 - 2.07 - 1.90 - 1.92 -2.03 -2.26 - 1.99 -2.16 -1.51 - 1.38 -2.36 -2.15 -2.63 -2.82 - 1.29 C Kp(d) log CKp Chemical (P-G) (P-G) Lit. Kp(e) log lit. Kp Ref. 3,4-Xylenol 1.79e-02 3-Cresol 1.04e-02 4-Chloro-3-xylenol 6.24e-02 4-Cresol 1.04e-02 4-Ethylphenol 2.04e-02 4-Methoxy acetophenone 4.38e-03 4-Methoxybenzyl alcohol 1.45e-03 4-Nitrophenol 5.56e-03 Benzophenone 2.67e-02 Benzyl acetate 5.70e-03 Benzyl alcohol 2.52e-03 Benzyl benzoate 5.50e-02 Cinnamic acid 7.25e-03 Cinnamic alcohol 2.90e-03 - 1.75 - 1.98 - 1.20 - 1.98 - 1.69 -2.36 -2.84 -2.26 - 1.57 -2.24 -2.60 - 1.26 -2.14 -2.54 3.60e-02 - 1.44 1.50e-02 - 1.82 5.30e-02 - 1.28 1.80e-02 - 1.74 3.50e-02 - 1.46 5.60e-03 -2.25 6.00e-03 - 2.22