j. Cosmet. Sci., 54, 251-261 (May/June 2003) N, N', N' '-trisl d i hyd roxyp h osp h oryl m ethyl)-'l, 4,7- triazacyclononane (DeofixT•A)--A high-affinity, high-specificity chelator for first transition series metal cations with significant deodorant, antimicrobial, and antioxidant activity KARL LADEN, HAIM ZAKLAD, ELLIOT D. SIMHON, JOSEPH Y. KLEIN, and ROSA L. CYJON, Complexx R&D Services, Keren Hayesod St., Bldg. 6, Tirat Carmel 39026, Israel,' and HARRY S. WINCHELL, LLC, 3205 Northwood Drive, Bldg. 5, Concord, CA 94520. Accepted for publication April 29, 2002. Synopsis Deofix TM, N,N',N"-tris(dihydroxyphosphorylmethyl)-l,4,7-triazacyclononane, is a high-affinity, high- specificity chelator for first transition series cations such as iron, zinc, manganese, and copper. A 1% solution in 50% ethanol was found to be significantly better at reducing underarm malodor than a solution of 0.3% Triclosan in 50% ethanol. Compared to a 50% alcohol control, Deofix TM was found to produce a significant reduction in malodor for at least 48 hours. Deofix TM appears to work by reducing the concentration of first transition series metal ions below the levels needed for microbial cell reproduction and by inhibiting oxidative processes by interfering with catalytic formation of free radicals. Deofix TM has very low levels of toxicity when measured via a number of screening techniques. INTRODUCTION Since the introduction of the first axillary deodorant product in 1888 (1), deodorant products have grown to become one of the largest HBA categories in terms of number of users, frequency of use, and total sales. Over 50 years ago, hexachlorophene, a halogenated phenolic antimicrobial agent was launched into the market. It represented one of the first truly effective and potent deodorant ingredients and quickly became the ingredient of choice in a wide range of deodorant products. Concerns about its safety resulted in it being banned by the FDA from use in OTC products in 1972 (2). Since then, a wide range of agents, mostly antimicrobial, have been explored as deodor- ant ingredients (3). Of these, Triclosan (Irgasan DP300) has found the greatest use in 251

252 JOURNAL OF COSMETIC SCIENCE deodorant products. However, in spite of numerous safety studies, it is not universally accepted as a deodorant ingredient. Deofix TM represents a new approach to deodorancy. A non-halogenated, non-phenolic compound, it controls microbial growth by limiting the bioavailability of first transition series elements that are essential for microbiological replication and by inhibiting oxi- dative processes on the skin. MATERIALS DeofixTM is an amino phosphonate, N,N',N"-tris(dihydroxyphosphorylmethyl)-l,4,7- triazacyclononane. It's formula is shown in Figure ! (4). DeofixT• is an extremely strong and highly specific chelating agent for first transition series elements such as iron, zinc, manganese, and copper. As an example, it has a thermodynamic equilibrium constant with iron of 10 -30 and with zinc of 10 -25, but a much higher Keq with calcium (10-6). The complex formed between DeofixT• and iron is at least 103 times more stable than that of the iron complex of deferoxamine and 109 times more stable than that of the iron complex of EDTA (5). Triclosan, (2,4,4'-trichloro-2'-hydroxydiphenyl ether), is a synthetic, nonionic antibac- terial agent developed by Ciba Geigy in the late 1960s (6,7). It is active against a wide range of gram-positive and gram-negative bacteria and particularly against microorgan- isms commonly found in the axilla. Its mode of action is believed to involve perturbation of the cytoplasmic membrane (8). DEODORANCY STUDIES Deodorancy studies were performed by Hill Top Research, Inc. (Miamiville, OH) using OH NOH o Figure 1. The chemical structure of Deofix TM, N,N',N"-tris(dihydroxyphosphorylmethyl)-l,4,7- triazacyclononane.