1:20 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS able for persorptive purposes. _rn vitro tests with isolated skin tissue may prove useful in certain instances (26). The prevention of cutaneous disturbances has also been used to estimate percutaneous penetration. Thus, histamine solutions applied to the skin either directly or by iontophoresis, produce the usual response however, antihistamine preparations when applied to the skin may interfere with or prevent this action (27). Incidentally, iontophoresis is an excellent method for enabling certain ions to pass the epidermal barrier. Usually it is more applicable with cations applied at the anode it was used over fifty years ago for introducing the iodide ion into the neck for the successful treatment of deficiency goiter. Histamine, because of its biological importance, has been widely tested for percutaneous absorption. The base will penetrate from most solutions and ointments, but it is such a potent drug that only very •small quantities are needed to elicit vascular responses. The salts of histamine are less easily petsorbed. An attempt was made to inunct "48-80" (28), a potent histamine liberator, into the skin of several species of animals. A water washable ointment containing 1 per cent of "48-80" was rubbed vigorously into the skin of the backs of a rabbit, rat, guinea pig and dog from which the hair had been removed with an electric clipper. No cutaneous effects or temperature changes were observed in any of the animals, and no drop in blood pressure was found in the dog. Later a 1 per cent aqueous solution was applied on the same regions with still no effects except for a slight blister on the dog, possibly due only to the rubbing. Administered intravenously, 25 to 50 micrograms of "48-80" will produce a 50 per cent reduction in the dog's blood pressure. Thus the above data indicate that a polymer (formaldehyde' with N-methylhomoanisylamine) of large molec- ular weight (about 471 or more), will not rapidly pass the epidermal mem- brane barrier and reach the mast cells where much of the skin histamine is located. In order to determine the persorption of chlorocyclizine hydrochloride from a water washable ointment* the amount of drug actually found in the blood was biologically measured (29). This was accomplished by taking blood samples from the inuncted dog at various time intervals and deter- mining the inhibition of histamine induced contractions of the isolated guinea pig ileum following the addition of plasma samples to the tissue bath. During this procedure it was discovered that an appreciable amount of chlorocyclizine became bound in the plasma and did not exhibit full activity in this type of assay. Control samples of standards in plasma were thus made necessary in order to evaluate the actual amount passing through the skin and found in the blood. * Supplied as "Perazil" brand Chlorcyclizine Hydrochloride Cream, Burroughs Wellcome & Co. (U.S.A.), Inc., Tuckahoe, N.Y.

PERSORPTION 121 Boric acid powders, solutions and ointments have been investigated but no persorption could be detected through normal skin, as determined by an increase of boron content in blood by chemical assay (30). The passage of cortisone through the skin of adrenalectomized mice has been measured by the eosinopenic response (31). Most vitamins have been found to pene- trate the skin enough to relieve the various deficiency symptoms in rats when vigorous application and special ointments are used (32). With human skin, similar activities (33) have been reported and in one instance actual recovery of vitamin B-6 in the urine has been recorded (34). Nico- tinic acid derivatives, used for peripheral vasodilation when applied locally, have been found to raise the blood level of the vitamin (35). Tetraethyl- pyrophosphate certainly passed through the skin when it almost caused the death of a child by its blocking action on the heart (36). In a high con- centration, DDT exhibits toxicity when placed in contact with the skin especially when chlorinated solvents are present (37). Of the war gases, the mustard type at low concentration appears to penetrate uniformly through the epidermal barrier, whereas lewisite has been found more in the cellular lining of the hair follicles. Both have much less effect in cold weather (38). Local anesthetic action is also a unique but valuable way of observing the passage of compounds through the skin (39). A polyethylene glycol ointment base permits the dye, phenolsulfonphthalein, to pass through the skin much better than a petrolatum base (40). Radioactive tracers are now being used to determine the amounts and the pathways of persorption. Mercuric chloride with radioactive mercury has been found to have no penetrative ability (41). On the other hand C TM hydrocortisone was easily followed through the skin and into the blood system by autoradiography (42). Sodium retention has also been meas- ured following the application of fluorohydrocortisone lotion (43). Hair growth has been inhibited in rats by application of both cortisone and es- trogens (44) but this does not necessarily indicate that persorption has taken place. However, in other tests, it was found that the sex hormones exhibited their respective actions on the rat, estradiol being catabolic and methyl testosterone anabolic (45). With humans, it has been reported that an estrogen lotion applied to male scalps has reduced the amount of falling hair (46). These examples could possibly involve persorption. When the applied material has passed through the epidermal barrier its continued movement largely depends on the vascularity and circulation in the underlying tissues (47). This has been increased by the use of periph- eral vascular dilators such as salicylic acid, nicotinic acid, benzedrine and their derivatives (48). Some of these may be administered orally or by inunction. Benzyl nicotinate has been shown to increase the rapidity with which S :•5 may be excreted in the urine following inunction (49). Besides blood flow, the size of the molecule may affect the passage of the material.