PERCUTANEOUS ABSORPTION 511 According to Draize (23) 'the rabbit is the most popular choice because it is generally more susceptible than man to the action of most substances'. This opinion was also expressed by Brown (34). He considered the rabbit more sensitive than other species and cited the work of Stevenson (175) with Telodrin in support. The percutaneous LD50 for a xylene solution of, Telodrin was 25 mg kg 4 in rats but only 5.8 mg kg 4 in rabbits. There are however, important exceptions to this general rule. For example, the per- cutaneous LD50 for parathion is lower for rats than it is for the rabbit (176). Because of their low toxicity, it is doubtful whether the LD,0 estimation is applicable to the cosmetic chemicals commonly in use. In any case, the wide difference in species sensitivity to toxic substances makes the LD,0 an unreliable index of percutaneous absorption. The experiments conducted by McCreesh (48) in which he compared the sensitivity of a variety of species to a toxic dose of two organophosphorus compounds with their passage in vitro through the epidermis of the same species serves to illustrate this point. McCreesh (48) determined the percutaneous LD50 of two organo- phosphorus compounds (formula not given) in the rabbit, pig, dog, monkey, goat, cat, mouse and rat. He found that the rabbit and cat were the most sensitive followed in order by the dog, the goat, the monkey, the mouse, the pig and the rat. The dog, goat and monkey were about two to four times less sensitive than the rabbit and the cat, the mouse about six times, and the pig and rat about 10 and 20 times respectively. Measurement in vitro of the penetration of the labelled organophosphorus compound through the excised skin from dorsal thorax of these eight animal species revealed that there was no correlation between penetration and toxicity. The fastest rate of penetration was recorded in the case of rabbit and the rat, followed by that of the guinea-pig, cat and goat, monkey, dog and slowest of all, that of the pig. If one assumes the diffusion rate across the pig's skin to be unity, the rates of diffusion of the skin of the respective species are 9, 18, 18, 18, 27, 35, and 35 (rabbit and rat) times that of the pig. For an objective assessment of the rate of absorption, in vivo tests are essential although valuable data may be obtained from in vitro work. A number of authors have conducted comparative tests of this sort. Employing the technique of measuring radio-activity in blood, urine and selected internal organs, N6rgaard (177) found that when 10 [tl of an aqueous solu- tion of*7Ni was applied to the shaved skin of rabbits, and guinea-pigs, the degree of radio-activity after 24 h in the blood, kidney, and liver of the rabbit was approximately 5, 10 and 2 times those of the guinea-pig respec- tively. When 56Co was applied in the same way it was found that the radio-

'512 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS activity, measured 1-20 h after application, of the blood and urine from the rabbit were six to eight times greater than those of the guinea-pig. These experiments indicated that the rabbit skin was more permeable to Ni and Co ions than guinea-pig skin. This same author found that human skin was impermeable to cobalt and that both human and rabbit skin were imper- meable to sodium. The permeability of rabbit skin was also shown to be greater than that of guinea-pig in the work conducted by McDermot, Murray and Heggie (178). These authors applied a solution of a quaternary oxime (1-methyl-2- hydroximinomethylpyridinium methane sulphonate) in DMSO to the entire area of clipped skin (except head and legs) of rabbits and guinea-pigs. Hourly measurement of the plasma concentration of the oxime revealed a peak at 2 h in both species which was approximately 60 ¾ ml -• in the case of rabbits and 40 ¾ ml -x in the case of guinea-pigs. These differences are greater than they appear since the rabbit received approximately 0.5 g kg -x of the oxime applied topically while the guinea-pigs received double this amount. The relationship of the rate of absorption from human skin to that of rabbit or guinea-pig is not certain. According to Wahlberg (179) human skin is less permeable than that of the guinea-pig to sodium chromate, cobaltous chloride and mercuric chloride when tested in vitro. This author employed radio-active isotopes and calculated the mean absorption rates for labelled compounds. He found that the absorption of 0.034 M Na•COa, 0.085 M CoCI• and 0.005, 0.239 M HgCI• was approximately three times greater through freshly excised guinea-pig skin compared to stored, human abdominal skin. The difference was less but still appreciable when freshly excised human skin was employed. Thus, the mean absorption rate for 0.08 M HgCI• was 1.8 times greater through freshly excised guinea-pig skin when compared with freshly excised human mammary skin. If one excludes results from LD50 studies it would seem that percutaneous absorption takes place much more readily through skin of the rabbit than that of any of the other species studied. Guinea-pig skin appears to be less permeable than that of the rabbits and human skin is less permeable than either. ACTIVE TRANSPORT AND METABOLIC TRANSFORMATION According to Tregear (180) there is no evidence to support the presence of a system in the skin that actively transports water and electrolytes into