PENETRATION OF SKIN--DEAD AND ALIVE 237 uncharged, can penetrate the skin. This property is enhanced if the sub- stance is also soluble in oil. It would even seem that preferentially a sub- stance should be both hydro- and oleophilic. Secondly, oleophilic substances can also be absorbed through the skin, their efficiency depending on the presence of polar groupings and their viscosity at about blood temperature, together with' the manner in which they are applied. Consider the cases of sodium and potassium chlorides. The mobility of the sodium ion is significantly less than that of the chloride ion, so that this substance in solution at a semi-permeable membrane will diffuse unevenly and set up a membrane potential which will retard and eventually prevent further passage of the sodium chloride. The potassium salt will continue to diffuse insomuch as the mobilities of the two ions are sensibly equal. This property is, of course, fully utilised when saturated potassium chloride solution is used as a bridge in potentiometric determinations. Equality of mobility of its ions makes water the centrepin of life. Substances which are completely ionised are not those which can penetrate unless some means is employed for preventing the ionisation. Prevention of ionisation can be accomplished in many instances by the use of a substance like ethylene diamine tetra-acetic acid. Unfortunately, this material, although assisting magnesium, calcium and other metals to pass through a membrane, if it reaches the blood stream it can pick up other metals and assist their passage through the membranes of the excretory organs.' To this extent, E.D.T.A. is a noxious substance and is not permitted for use in foodstuffs. It should not be employed as a means of increasing the permeability of skin. One of the substances which is outstanding in its power to penetrate tissues is ammonia, and yet ammonium salts have little power to do so. This is because the ammonium ion NH4 + will set up a membrane potential. It has to be remembered that in a solution of ammonia in water there are present NH3 and NH•OH in the equilibrium, NH3 q- H•O • NH40H • NH+• q- OH- but there is always some un-ionised ammonia. Being a small molecule it can pass through the membranes and its loss from the solution will be automatically made up by the liberation of more NH3 from the ammonium hydroxide in order to maintain the equilibrium. Iodine can also function in a somewhat similar fashion provided that the base in which it is dissolved is suitable. One of the ways in which substances can be made to penetrate is by means of esterification. One of the earliest substances to be investigated was salicylic acid. By itself, its penetrating powers are low, but when esterified

238 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS its rate of penetration is very high. This is partly because the ester does not set up an electrostatic barrier. It must, however, be mentioned that it is also more oleophilic than the acid. A most illuminating finding is, however, the instance of nicotinic acid. This substance, when applied as a dilute solution in water, will produce pinking of the skin due to its vaso-dilatory action on the surface capillaries. The effect varies from person to person. It was found that its action could be measured by using two thermo-couples separated at a small distance and measuring the differential temperature between the treated and the non- treated areas of the skin. When an ester of nicotinic acid, e.g., tetrahydro- furfuryl nicotinate, was applied, the reaction was considerably enhanced and also prolonged. This ester is soluble in oil as well as in water. It was subsequently dissolved in white mineral oil and on application to the skin the vaso-dilation was pronounced and prolonged. Some time later the experiment was repeated, but no reaction was observed. My colleague, Mr. Powell, fortunately recollected that at the time of the earlier work the conditions in the laboratory were distinctly hot and humid. He decided that the moisture on the skin might be a factor. After skipping for 15 minutes in order to induce sweating, he found that the application of an oil solution of the tetrahydrofurfuryl nicotinate produced a pink patch and an increase in the temperature of the surface of the skin. This was an important find- ing, and its implications will be discussed later. There has been much published work on the choice of the "oil" v•hich is most efficacious for "feeding" the skin. This was briefly discussed by the author.' It was pointed out that liquid paraffin was by no means the best substance with which to anoint the skin, for the simple reason that it does not spread over the surface of a water-wet material. If the surface is dry or is already wetted by fat then it will do so and, indeed, if massage be applied it will dissolve or blend with the fatty material, soften it and enable it to be removed by means of a tissue. For the purposes of cleansing it can function quite well, especially as it is not such a good solvent that the skin will be denuded of sebaceous fat. Nevertheless, the addition to the mineral oil of a polar fat-or even essential oils--will improve matters, and if the added materials are well chosen and in sufficient amount, they can imbue mineral oil with many desirable qualities, and approach those of fixed oils and certain esters. As in leather manufacture, the lower the viscosity at equal spreading power the better is the penetration. The penetration by oily material is probably a two-routed mechanism. It has long been known that greasy ointments require massage even though they be fluid at the temperature of the surface of the skin. This is because the dominant point of entry is via the hair follicles, and the act of massaging forces the oils down the hair follicle, the internal surface of which is fat-