COSMETIC PRESERVATION 671 after washing. The recent FDA action making hexachlorophene a prescription drug is well known. The disadvantages of hexachlorophene have been recog- nized for some time, and are common to phenolic antimicrobials in general. Phenolics are moderately-to-highly toxic and can be hazardous on damaged skin. In general, the antimicrobial activity of phenolics is limited to gram-pos- itive bacteria. They are poor preservatives for cosmetics, in part because they are often inactivated by nonionics, anionics, or proteins. Phenolics usually have low solubility in water, and are somewhat pH-dependent. With hexa- chlorophene, for example, when the solution pH is raised from 6 to 8, the anti~ microbial activity drops by 75%. Phenolics also tend to develop color in the presence of ferric salts. Although parabens are also phenols, they will be dis- cussed separately. Halogenated Salicylanilides These compounds are derivatives of salicylic acid, which is phenolic. Many of the problems of phenolics are therefore present: sparingly soluble in water, sometimes deactivated by nonionics, etc. The halogenated salicylanilides are substantive to skin and reportedly synergistic with hexachlorophene. They have therefore been used in deodorant soaps. Some of these derivatives are photosensitizers: they become toxic or allergenic when irradiated by ultra- violet light. As with most water-insoluble germicides used in antiseptic soaps, they make poor cosmetic preservatives. Formaldehyde Formaldehyde is cheap and has high antimicrobial activity. Although it has been used for mm)y years, it is now banned in Japan, Sweden, and several other countries. It is being phased out of almost all cosmetics in the United States. deNavarre (4) has pointed out the disadvantages of formaldehyde: "The undesirability of formaldehyde is manifold. It is volatile. It is highly re- active with many perfumery and cosmetic ingredients. It is irritating to skin. Its effectiveness decreases with age. It has an undesirable odor." Formaldehyde is chemically reactive, and it is not likely to remain un- changed over a period of weeks or months. Bryce and Smart (5) reported that when formaldehyde was put into a shampoo base (pH 5.5) at 0.12%, its concentration dropped to 0.031% after 10 weeks at 30øC. The loss of anti- bacterial power at pH 8, where formaldehyde has strong reducing properties, vas even more severe. Bronopol* (2-Bromo-2-nitro-l,3-propanediol) Bronopol, a water-soluble preservative with good antimicrobial activity, has several disadvantages. It is reasonably stable at pH 5.5 and can be used suc- *Trade name, Boots Pure Drug Co. Ltd., Nottingham, England.

672 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS cessfully at low pH's, but it breaks down at neutral or alkaline pH's to give formaldehyde and one or more bromo compounds. It develops a yellow or brown color on exposure to light, especially in alkaline solution. Solutions of Bronopol should not be heated. Bronopol tends to migrate into certain oil phases. Dowicil©* 200 Dowicil 200 is a water-soluble antimicrobial which is active against bac- teria. It is somewhat less effective against yeast and mold. Solutions of Dowi- cil 200 become yellow on aging and sometimes cause color changes in the cosmetic. The powder decomposes when heated above 60øC, and solutions containing Dowicil 200 should not be held at elevated temperatures. Dioxin©t (6-Acetoxy-2,4,-dimethyl-m-dioxane) Dioxin is soluble in water, and is reported to have good activity against gram-negative organisms as well as gram-positive organisms. Unfortunately, it has a powerful mustard-like odor which is almost impossible to mask. Be- cause of this odor, it is seldom used in cosmetics. Dioxin hydrolyzes slowly in xvater to form acetic acid, which tends to lower the pH. Also, it is quite solu- ble in oils and organic solvents so it can migrate out of the water phase into an oil phase. Organic Mercurials The most common organic mercurials are the phenyl mercuric salts: ace- tate, benzoate, chloride, and nitrate. Mercurials attack both the cell membrane and thiol groupings on enzymes within the cell. The strong affinity of mer- cury for sulfur means that sulfur-containing components of a cosmetic, such as certain proteins, sulfides, amino acids, can inactivate the mercurial. Anionic surfactants diminish the activity of mercurials, and an irritating hydroxide precipitates at pH's above 8.5. Barring such inactivation, mercurials are effec- tive at low concentrations against a broad spectrum of microorganisms. The problem of toxicity (mercury is toxic at 10 mg/kg) has led to its recent elimi- nation as a preservative from all cosmetics except eye cosmetics. A recent survey by the Cosmetic, Toiletries and Fragrances Association found that, except for eye products, virtually no mercurial preservatives are now in use. Parabens (p-Hydroxybenzoatcs) The parabens are the most widely used cosmetic preservatives. They are p- hydroxybenzoic acid esters, and the name of the paraben reflects the alkyl *Registered trademark of Dow Chemical Company, Mid]and, Mich. tRegistered trademark of Givaudan Corporation, New York, N.Y.