THE PHARMACOLOGIST DELVES IN COSMETICS 129 membrane at time of application. Animal experiments (7), both as to procedure and duration, are decided upon after the following factors have been carefully considered for the product in question: I. Extent of use on the body A. Area involved 1. Per cent of total skin area 2. Appendages (nails, hair, etc.) 3. Mucosae (oral or eye) B. Frequency of application 1. Number of times (several times daily, daily, weekly or less often) C. Duration of treatment 1. Daily throughout the year 2. Monthly or bimonthly (depilatories, hair waving) 3. Seasonal (sunscreen preparation) II. Physiological condition of the skin A. Normal skin 1. Age and sex differences 2. Race differences B. Pathological (damaged) skin 1. Eruptive conditions due to disease 2. Abrasions (mechanical) 3. Abnormal through weather effect (sun and wind burn) PH^R•a^eOI. O•¾ ^•rI• ToxieoI. o•¾ Although man is not excluded, moral considerations and jeopardy to human life would not permit the necessary experiments on this subject to yield the data required on pharmacology, biochemistry and pathology to permit a full appraisal of safety. It would be incorrect to state that all possible effects of a cosmetic can be predicted from the results of animal experimentation. However, thorough animal data should yield informa- tion on a margin of safety, seriousness and extent of possible injury, even to a prognosis for the repair of such injury. Reactions following exposure of the skin or mucous membranes to topical preparations may elicit (1) local effects and (2) systemic effects. The local effects are more properly termed "irritations," a general term used to describe an eczematous or contact dermatitis in case of skin, or of in- flammation in the case of mucous membranes. Skin irritation may result from contact with substances which are primary irritants, or with sub- stances producing sensitizations. A third type of local effect on the skin is recognized--it is termed "skin fatigue." LocAl. TOXICITY OR IRRITATION If a tissue is able to deal with an excitant (irritating substance), the reaction is normal and stimulation results. If the action of the excitant is

130 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS excessive, the reaction is pathological and irritation results. Irritation is an extreme reaction of tissues to an insult or injury and is best characterized as incipient inflammation. The inflammatory process may vary from a barely perceptible hyperemia to edema formation and vesiculation, and finally to an intensive suppurative process. Interestingly, what is meas- ured is not irritation, per se, but the result or consequence of irritation, that is, the injury reaction following irritation. A primary irritant may be defined as a substance capable of producing an injury reaction on first contact. The resultant injury will depend on: 1. Nature of irritant 2. Concentration of irritant 3. Total elapsed time of exposure Cutaneous sensitization represents an allergy to a chemical which is not obtained on first contact, but requires a number of prior exposures for de- velopment. The number of prior exposures required to produce reactions may vary greatly depending on the sensitizing potential of the agent. The sensitized tissue exhibits a greatly increased capacity to react to sub- sequent exposures of the offending agent. Indeed, subsequent exposures may produce severe reactions with little correlation to amounts of excitant involved. The human race is so heterogeneous in its reactions that few chemicals have not been incriminated at one time or another as producing sensitization. It is this heterogeneity of man which makes it difficult to establish a rigid criterion for experimental tests, whereby a substance should or should not be considered acceptable on the basis of its sensitizing propensities. Realistically, such criterion of acceptability must rest not only on the incidence of reactions observed experimentally, but on the seriousness of the reactions when such occur. "Skin fatigue" is a misnomer in that this term does not imply a condition in which the skin is no longer able to carry out its normal physiological functions. Chemicals capable of producing this phenomenon are well tolerated by the skin at first (and in this respect are unlike primary irri- tants) and quite abruptly in continued use may produce reactions not unlike cutaneous sensitization. However, such reactions differ from sensitization in that in a relatively short while (few days or weeks), the skin is again able to tolerate the substance as well as it did at the time of the original exposure. The mechanism of action for this phenomenon is not known it is more commonly observed during the hot summer months when it is conceivable the skin could be under greater environmental stress. SYSTEMIC TOXICITY Data on the systemic toxicity of substances applied topically to the