884 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS On the premise that skin sensitization occurs only when there is pene- tration through the skin we may conclude that the data reported here support the validity of these skin penetration tests. Skin sensitization in man occurs at 0.01-0.05% but not at 0.001%. Skin penetration like- wise occurs at the higher concentrations but not at the lower. Conservatively estimated from the data, at least 100 ng/cm2/hr or 2.4 t•g/cm2/day are expected to transfer into the body, following skin application of 3% ammoniated mercury cream. Since 20 t•g of mercury is estimated to be the daily intake of total mercury from food (17), this is equivalent in amount to that provided by daily application of mercury- containing bleach cream to less than 10 cm"of skin, assuming both to be in the same form. Generally, women apply these creams to at least 200 cm •, and often, as in the case of the 6 subjects of this report, much larger skin areas. Hence, one can expect the uptake of mercury during the use of a bleach cream to be at least 20 times that derived from food and many times more when applied by determined users of these preparations. Not considered in this evaluation is the real possibility that inadvertent ingestion occurs whenever a consumer applies a bleach cream to the hands and face prior to retiring. The literature contains one study of skin penetration of ammoniated mercury in man in vivo however, the results are not entirely quantitative because skin area was not given (18). Two normal subjects were treated for 7 days with 5% ammoniated mercury. They showed blood levels of 19-20 ng/g at the end of this period compared with 85-450 ng/g in 5 sub- jects similarly treated on psoriatic skin (50-60% of body surface). Erythrocyte levels were 15-18 ng/g in the normal subjects and 94-435 ng/g in the psoriatics. Thus, when applied to intact skin, the whole blood mer- cury remained within normal limits after 7 days however, the erythrocytes showed slightly elevated levels. The clinical signs and symptoms (19, 20) of inorganic mercury poison- ing have been described as tremors, weakness, sensory abnormalities, memory loss, emotion or intellect changes, dermatitis, spasticity, stoma- titis, gingivitis, paresthesia, mucle pains, neuralgia, and erethism. In- organic and aryl forms tend to be more quickly eliminated than alkyl forms. However, kidney damage from inorganic and aryl forms may eventually result in increased retention in chronic mercury poisoning. Eyl and others make the special point of distinguishing alkyl from aryl or inorganic mercury poisoning (19). Some of the cases studied here have reported symptoms that might be interpreted as signs of mercurialism.

HAZARDS OF TOPICALLY APPLIED MERCURIALS 885 There is a basic unawareness shared by many physicians that mercury penetrates skin in significant amounts, and could account for some patients being dismissed or misdiagnosed as psychotic, rather than as suffering from the effects of chronic elevated intake of mercury. In summary then, measurements have been presented regarding the penetration capacity of phenyl mercuric acetate and ammoniated mercury through skin. Although it is extremely slow, over a long period of time without excretion, it can build up to significant levels. It has been shown that urine, blood, or hair levels of mercury in chronic users of mercurial bleach creams were elevated above normal and were consistent with the experimental penetration data. In three cases the urinary mercury levels reported were within the range of values reported for inorganic mercury intoxication. Finally, we have indicated the possible usefulness of de- termining methyl mercury in hair when total mercury is elevated, as a means of finding out if exposure is due to inorganic or to alkyl mercury. Other related literature references involving topically applied mercurials include a unique technique for studying percutaneous absorption (21). two cases of nephrotic syndrome (edema, albuminuria, hypoproteinemia) from applying 5% ammoniated mercury (22, 23), a case of pink disease from 2% ammoniated mercury (24), and polyneuropathy from prolonged treatment with ammoniated mercury (25). ACKNO!NLEDGMENTS The authors are indebted to the 6 subjects in this study and to Robert F. Korns, M.D., Epidemiologist, Albany, N.Y., State Dept of Health, for their cooperation, to Dr. J. L. Tanner for neutron activation total mercury analyses, to L. R. Kamps for glc analyses of methyl mercury in hair sam- ples, to Dr. F. Demerj for determining mercury distribution coefficients, to R. J. Gajan for atomic absorption analyses of blood, and to Anne Amsie for statistical analyses. (Received June 12, 1972) REFERENCES (1) Marzulli, F. N., Barriers to skin penetration, J. Invest. Dermatol., 39• 387 (1962). (2) Marzulli, F. N., Callahan, J. F., and Brown, D. W. C., Chemical structure and skin penetrating capacity of a short series of organic phosphates and phosphoric acid, Ibid., 44, 339 (1965). (3) Marzulli, F. N., Brown, D. W. C., and Maibach, H. I., Techniques for studying skin penetration, Toxicol. Appl. Pharmacol., Suppl. No. 3, 76-83 (1969). (4) MerckIndex, 8th Ed., Merck & Co., Inc., Rahway, N.J., 1972, p. 818.