?ERCUTANEOUS ABSORPTION 495 technique. They determined the permeability constants of each of the seven alcohols and found that there was, on an average, a 10-fold increase in the permeability constant for each alcohol, as the temperature rose from 10 øC to 50øC. A five-fold increase in the rate of absorption of salicylic acid and carbinoxamine was also found in vivo when the skin temperature of the abdomen of guinea-pigs was raised from 20øC to 38 øC (106). These effects of temperature demonstrated by in vivo and in vitro techniques are not due to skin circulatory effects of heat and cold. State of ionization Before the advent of radio-isotope labelling techniques it was generally held that electrolytes applied to the mammalian skin in aqueous solutions either do not penetrate at all, or if they do, they enter only in small amounts (21). In several experiments 'non-physiologic' cations, such as Li, Hg, Cs, Sr and Ba or of 'physiological' cations such as Na and Ca were applied to the skin of several species including man. No transepidermal passage could be detected by the analytical techniques employed (107-111). With the isotope tracer technique Loeffier and Thomas (112) were able to demon- strate the percutaneous absorption of aqueous radio-active strontium solutions (89SrC1•) through the shaved skin of rats. Johnston and Lee (113), applying an aqueous solution of •aNaC1 incorporated in an ointment base to the right arm of man, showed that radio-activity appeared in the left hand and in the urine. Others (96, 114, 115) have confirmed that electrolytes penetrate mammalian skin and in a recent experiment Wahlberg (56) showed that in the guinea-pig approximately 20•o of the amount of HgCI• and NaC1 applied to the skin was absorbed via the skin appendages, the remaining 80•o passed via the stratum corneum. It is of some interest that the rate of diffusion of water estimated by Scheuplein (39) on human epidermis in vitro is of the same order as that of the electrolytes employed by Wahlberg (56) on guinea-pig skin. This indicates that the rate of penetration of these electrolytes is not appreciably different from that of water. It would seem reasonable to expect other electrolytes to penetrate the skin at similar rates. Skog and Wahlberg (114) applied the chlorides of Co, Zn, Cd and Hg, sodium chromate and silver nitrate in equimolar concentrations (0.002 M) to the skin of guinea-pigs. With the exception of HgCI• these salts are present in an ionized form and their rate of absorption on a molar basis was of the same order as that of water. Some variation in the percutaneous absorption, expressed as disappearance constant was, however, found. The mercury compounds were absorbed twice as rapidly as those of Co,

496 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Zn and Hg, while cadmium occupied an intermediate position. Non- electrolytes are influenced by other factors which will be dealt with in a subsequent section. pH The pH of the solution influences percutaneous absorption principally by determining the state of ionization of a particular compound. Samitz et al (97) found that the absorption of chromium from chloride, sulphate or nitrate solutions in vitro was less at a pH of 7 than at pH 5 or pH 9. Later studies in vivo by Arita et al (106) confirmed that altering the pH of the skin to either side of neutrality increased absorption. Thus, absorption of salicylic acid was less at a pH 5 or higher than that at more acidic pH values while with carbinoxamine, absorption was lowest at pH 7 and increased as the pH became more alkaline. In both these investigations the authors attribute the low absorption at neutral pH to a higher degree of ionization at this pH than at more acid or alkaline pH values. If the solution is strongly acid or alkaline an irreversible destructive effect on the keratin occurs which will render the skin more permeable (1). Water/lipid solubility A much wider variation in the rate of absorption has been demonstrated in studies of some non-electrolytes. Skin permeability to a homologue series of normal primary alcohols CwC8 applied in dilute aqueous solutions were studied by Blank (46). He found that methanol and ethanol (0.1-0.4 s0 penetrated the epidermal barrier in vitro to the same extent as water. The rate of penetration of propanol was greater than that of water by a factor of 1.4. The higher alcohols in this series penetrated the skin much more rapidly octanol, the alcohol with the highest molecular weight in the series, passed through the barrier 52 times as fast as water. The lipid solu- bility of these alcohols also increased with increasing molecular weight, and according to Scheuplein (39) the increased rate of absorption is accounted for by the increased lipid solubility. At higher concentrations, the rate of penetration of the alcohols is greatly increased, and does not follow the pattern of absorption from weak solutions. According tO Blank and Scheuplein (116) this may be due to one or other of two reasons: at high concentrations, the alcohol content of the stratum corneum increases and this 'acts as an added pathway'. Secondly, high concentrations may damage the stratum corneum impairing its 'barrier' properties.