878 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Time (heurs) Figure I. Idealized representation of penetration of phenyl mercuric acetate through isolated stratum corneum as related to time. (Cum. Pen. = cumulative penetration) Ammoniated Mercury AMM is used in skin bleach creams at 1 to 5% concentrations. It is practically insoluble in all useful solvent systems. A test with 2øaHg- labeled AMM showed its solubility to be about 0.6 t•g/ml in isotonic saline at 22 øC. A benzene-water partition coefficient was Ka 25 = 0.004. The penetration test used a commercial bleach cream containing 0.9% AMM by chemical analysis to which 2øaHg-labeled AMM was added to produce concentrations of 3.9, 5.4, and 9.9% total AMM. Results, al- though exploratory (Table III), show that 50-200 ng AMM/cm2/hr in these test concentrations penetrated skin during the first 24 hr that pene- tration decreased during the period 24-72 hr and that penetration ap- peared to be inversely related to concentration in this test range.* The decrease in rate, as a function of time, is likely to be related to a reaction between AMM and the skin tissue. * An inverse relation of this type also occurs with phenol. Table III Maximum Steady Penetration Rates of :øaHg Ammoniated Mercury a Through Stripped Human Stratum Corneum Penetration Rate Test Material, % No. (ng/cm2/hr) Samples Test Initial Added b Total Skin Tissue 0-24 hr 24-72 hr 140 0.9 3.0 3.9 4 200 100 144 0.9 4.5 5.4 4 100 50 141 0.9 9.0 9.9 5 50 20 a Contains 79.6% mercury, as found in a commercial mercury-containing bleach cream base. b Radiolabeled.

HAZARDS OF TOPICALLY APPLIED MERCURIALS 879 The overall results of these skin penetration studies conducted on PMA and AMM suggest that at their use concentrations, AMM repre- sents more than a 10-fold greater absorption, with its attendant potential hazard of mercury poisoning, than PMA, if applied to the same size area of skin surface. The results are surprising in view of the far greater aqueous and lipid solubility of the PMA-mercury.* The variability in results may partly explain the well-known great range in individual sus- ceptibility to mercurial exposure. RETROSPECTIVE STUDY Clinical Findings Data were collected on 6 women who had used mercurial skin bleach creams for 2 years or more. Four of these (Subjects 1, 2, 3, and 4) had used creams containing 1% AMM. Two of them (Subjects 5 and 6) had used creams containing 3% AMM. According to hospital and physician records, all subjects displayed symptoms consistent with mercurialism. These consisted of numbness or aching of extremities, weakness, and ataxia. Some subjects also experienced nervousness and had difficulties in speech, vision, or hearing, according to the medical records. Classi- cally, chronic mercurialism (inorganic) is characterized by erethism, tremors, ataxia, paresthesia, muscle pain, speech, vision or hearing diffi- culties, and kidney injury. Urinary and blood levelsl' of Hg were obtained, mostly from hospital records, at various times after use of bleach creams ceased. In some cases, blood was analyzed at FDA (7). Mercury in the hair was analyzed at FDA, after samples were washed to remove any external Hg contami- nation, by neutron activation analysis for total mercury (8) and glc for methyl and phenyl mercury (9). Table IV is a compilation of the total findings. Inorganic mercury is excreted mainly in the urine. The normal urinary volume is 1 to 2 1./24 hr, and the normal mercury excre- tion is about 8 /•g/24 hr (10). Signs suggestive of mercury poisoning have been reported to occur at urinary excretion levels ranging from 80 to 197/•g/liter (10). In the present group of women, Subjects 1, 3, and 6 displayed clearly elevated urinary mercury excretion rates of 945, 634, and 251 /•g/24 hr. The latter two values were determined many months after cessation of use of the bleach cream. * Molecular size may be a factor. • Correlation between blood and urinary mercury following exposure to inorganic mercury is rarely found in individuals (6).