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

THE PHARMACOLOGIST DELVES IN COSMETICS 131 skin and mucous membranes (7) are obtained in small laboratory animals. The albino rabbit has been found well suited for the bulk of the dermal toxicity studies. Experimental procedures in animals should yield data on the extent of injury, if such result, and a margin of safety in use. Pro- cedures for the study of local and systemic toxicity are given in brief outline below. I. Determination of dermal toxicity A. Acute (single exposure of 24 hours or less) 1. Intact skin 2. Damaged skin (a) Disease (b) Abrasion (mechanical) (c) Burn B. Subacute (multiple exposures) 1. Short or 20-day (a) Skin intact and abraded (b) Cosmetics, infrequently used 2. Long or 90-day (a) Skin, intact only (b) Majority of cosmetics (c) Dose levels employed (1) Determination of base line dose, depending on label directions (2) Demonstration of margin of safety II. Biochemical studies--analytical methods A. Excretion studies B. Tissue storage C. Organ function tests III. Hematology A. Hemoglobin determination B. Differential cell counts C. Abnormalities of formed elements D. Other tests as indicated, e.g., clotting time, fiocculation time, hematocrit, etc. IV. Pathology A. Gross examination of tissues, and recording of organ weights B. Detailed microscopic examination of tissues ¾. Local toxicity A. Primary irritation B. Sensitization 1. Guinea pig intracutaneous technique (shortcomings of method) 2. Man (a) Repeated insult technic (b) Shortcomings of limited exposure such as "prophetic tests" involving few or limited exposures •,•, C. Skin fatigue