THE PHARMACOLOGIST DELVES IN COSMETICS 127 material is obtained. On the other hand, some substances produce a pre- cipitant or coagulative effect on the skin, resulting in a lessened capacity for absorption with subsequent applications. Both artificial and natural membranes have been used to simulate skin in studies of percutaneous absorption. No such membrane can represent the entire physico-chemical properties of the living skin, or its electrical properties, or such other additional differences as may be inherent in the penetration of the living cell membrane, the keratins, cell detritus and secre- tion and excretions of the appendages. NATURE OF THE SUBSTANCE During the past eighteen years, the Skin Toxicity Branch of our Division of Pharmacology, has had occasion to acquire data on the percutaneous absorption of several hundred compounds. Review of these data in at- tempts to correlate, if possible, the percutaneous absorption of compounds with their molecular characteristics, such as molecule size, presence of molecular side chains or the length of molecular side chains, has failed to reveal much pertinent information. It is remarkable, for example, that the skin is relatively impervious to simple molecules, such as water, or to simple electrolytes, such as sodium chloride, or to simple organic molecules, such as carbon monoxide and carbon bisulfide, when it readily absorbs, and with apparent ease, complex molecules of which the following are cited as examples: CH, I CH• CH• CHa• /CH2--CH • / / )c )CHO--CU--Cm--O--Cm--C-- CHa xCH•--CH• • OH 3, 3, 5-Trimethylcyclohexyldipropylene glycol ether or or C2H• CH•--CH•--C• H--CH•OH 2-ethyl Butyl alcohol //o --CH•-CH--C--0C•H• Ethyl cinnamate Until more is known of the molecular structure of compounds in their relationship to the structural elements of the skin cells, it is believed that it will be impossible to predict either the manner or the extent of the per- cutaneousabsorption of a compound by mere inspection of molecular struc- ture. •

128 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS ROLE OF VEHICLE There is little doubt that a vehicle may play a significant, although not a direct, role in percutaneous absorption. It may not be considered direct in the sense that it carries a material directly into the cell, or that it accom- plishes an action which would not occur in the absence of the vehicle. The role of the vehicle in percutaneous absorption has been overemphasized. One must understand that some vehicles in themselves are skin irritants and are capable of producing damage or an unphysiological condition in the skin. The presence of organic solvents or surface-active agents may affect per- cutaneous absorption. The action in these cases may be: (1) permitting better physical contact between skin and the material to be absorbed or (2) reducing surface tension of materials and skin and thereby producing better wettability of the skin with the material to be absorbed or (3) permitting better physical solution of the material to be absorbed and there- fore easier and more complete access into the lumen of the ducts of the ap- pendages. Aside from these, however, there is no evidence that a vehicle, per se, can actually promote absorption of substances in or through the dermal cells. EXTENT OF USE AND DESIGN OF EXPERIMENT During the course of conferences with members of technical staffs of concerns and by direct inquiry, the Food and Drug Administration is often asked the type and nature of pharmacological and toxicological tests on products to develop data which would be adequate to demonstrate safety for use. The requirements or extent of such tests will vary and will be dependent on the manner, condition and extent of use of the product itself. Some cosmetics are used infrequently examples are hair wave lotions, depilatories and hair dyes. The majority of cosmetic products are em- ployed often daily to several times a day, and over the greater portion of the individual's lifetime, not infrequently by persons in various conditions of health. The cosmetic itself may vary in its inherent toxicity. Although many cosmetic preparations are relatively inert or nontoxic, some may exert profound local or systemic effects. A substance which can alter hair struc- ture to permit waving, or one capable of rapid keratolysis, as in the case of depilatories, may exert profound local or systemic effects on absorption. In such cases their toxicology and limitations in use must be well under- stood, and such products must bear adequate label directions to prevent harm to the prospective user. The proper planning of experiments to be undertaken must take into consideration the extent of the total body area involved, frequency of application, amounts administered and condition of the skin and mucous