FORMATION OF NDEIA 85 ACKNOWLEDGEMENT The authors wish to thank Dr. J. E. McCullough for his encouragement and Mr. J. L. Occolowitz for his helpful discussions on mass spectrometry. Thanks are also given to Messrs. H. F. Hugar and E. L. Pursell for their technical assistance. REFERENCES (1) H. Druckery, R. Preussman, S. Ivankovic and D. Schmaehl, Organotrope carcinogene Wirkungen bei 65 verschiedenen N-nitroso-Verbindungen an BD-Ratten, Z. Krebsforsch., 69, 103-201 (1967). (2) P. N. Magee and J. M. Barnes, Carcinogenic nitroso compounds, Adv. Cancer Research, 10, 163 (1967). (3) J. Hilfrich, I. Schmeltz and D. Hoffman, Effects of N-nitrosodiethanolamine and 1,1-diethanolhydra- zine in Syrian golden hamsters, Cancer Letters, 4, 55-60 (1977). (4) D. H. Fine, F. Rujeh, D. Lieb and D. P. Rounbehler, Description of the thermal energy analyzer (TEA) for trace determination of volatile and non-volatile N-nitroso compounds, Anal. Chem., 47, 1188-1191 (1975). (5) I. E. Rosenberg, J. Gross, T. Spears and U. Caterbone, Methodology development for the determination of nitrite and nitrosamines in cosmetic raw materials and finished products, J. Soc. Cosmet. Chem., 30, 127-135 (1979). (6) T. Y. Fan, U. Goff, L. Song, D. H. Fine, G. P. Arsenault and K. Biemann, N-nitrosodiethanolamine in cosmetics, lotions and shampoos, Food Cosmet. ToxicoL, 15,423-430 (1977). (7) G. S. Edwards, M. Peng, D. H. Fine, B. Spiegelhalder andJ. Kann, Detection of N-Nitrosodiethanol- amine in human urine following application of a contaminated cosmetic, Toxicol. Letters, 4, 217-222 (1979). (8) Anon., F.D.C. Reports, T G-8, July 30, 1979. (9) I. Schmeltz and A. Wenger, 2-Bromo-2-nitropropane-l,3-diol as a nitrosating agent for diethanoi- amine: a model study, Food Cosmet. ToxicoL, 17, 105-109 (1979). (10) J. T. H. Ong and B. S. Rutherford, Some factors affecting the rate of N-nitrosodiethanolamine formation from 2-bromo-2-nitropropane-l,3-diol and ethanolamines, J. Soc. Cosmet. Chem., 31, 153-159 (1980). (11) T. Y. Fan, R. Vita and D. H. Fine, C-nitro compounds: a new class of nitrosating agents, Toxicol. Letters, 2, 5-10 (1978). (12) R. Hamburger, E. Azaz and M. Donbrow, Autoxidation of polyoxyethylenic non-ionic surfactants and of polyethylene glycols, Pharm Acta Helv., 50, 10-17 (1975). (13) M. Donbrow, R. Hamburger and E. Azaz, Surface tension and cloud point changes of polyoxyethyl- enic non-ionic surfactants during autoxidation, J. Pharm. PharmacoL, 27, 160-166 (1975). (14) J. W. McGinity,J. A. Hill and A. L. Lavia, Influence of peroxide impurities in polyethylene glycols on drug stability,J. Pharm. Sci., 64, 356-357 (1975). (15) J. W. McGinity, T. R. Patel, A. H. Naqvi andJ. A. Hill, Implication of peroxide formation in lotion and ointment dosage forms containing polyethylene glycols, Drug Devel. Commun., 2, 505-519 (1976). (16) M. Donbrow, E. Azaz and A. Pillersdorf, Autoxidation of polysorbates, J. Pharm. Sci., 67, 1676-1681 (1978). (17) D. K. Banerjee and C. C. Budke, Spectrophotometric determination of traces of peroxides in organic solvents, Anal. Chem., 36, 792-796 (1964). (18) M.P. Gruber and R. W. Klein, Determination of benzoyl peroxide stability in pharmaceuticals, J. Pharm. Sci., 56, 505-508 (1967). (19) W. Fiddler, R. C. Doerr and E.G. Piotrowski, Observations on use of thermal energy analyzer as a specific detector for nitrosamines, in E. A. Walker, L. Griciute, M. Castegnaro and R. E. Lyle, "Environmental aspects of N-nitroso compounds," IARC Scientific Publications No. 19, Interna- tional Agency for Research on Cancer, Lyon, France, 1978, pp. 33-40. (20) K. Kahr and C. Berther, Katalytische oxydation von primaeren aminen zu oximen mit Wasserstoffpe- roxyd, Chem. Bet., 93, 132-136 (1960). (21) A. A. Oswald and D. L. Guertin, Organic nitrogen compounds. I. Peroxide intermediates of tertiary alkylamine oxidation by hydrogen peroxide, J. Org. Chem., 28, 651-657 (1963).

j. Soc. Cosmet. Chem., 32, 87-94 (March/April 1981) Effect of nonionic surfactants on penetration of dissolved benzocaine through hairless mouse skin UMESH G. DALVI, PH.D. and JOEL L. ZATZ, PH.D., College of Pharmacy, Rutgers University, P.O. Box 789, Piscataway, NJ 08854. Received November 14, 1980. Presented at the Society of Cosmetic Chemists Annual Scientific Meeting, December ! 1-12, 1980, New York, NY. Synopsis The penetration of benzocaine from solutions containing polyoxyethylene nonylphenols through hairless mouse skin was studied using an in vitro apparatus. Diffusion through STRATUM CORNEUM was the rate limiting step in benzocaine transport. Penetration flux in solutions containing a fixed benzocaine concentration was inversely related to surfactant concentration and polyoxyethylene chain length. In the case of solutions saturated with benzocaine, none of the surfactants had a significant effect on benzocaine flux. All experimental results could be reconciled by consideration of the concentration of free (not solubilized) benzocaine in solution. Bezocaine penetration was proportional to the free benzocaine concentration. Surface active agents are often included in topical formulations for a variety of purposes. However, possible effects on percutaneous absorption should be considered. Of the various surfactant classes, the nonionic have the least tendency to interact with the skin barrier and alter membrane permeability (1-4). In studies designed to probe the influence of nonionic surfactants on percutaneous penetration of chemical agents, penetration sometimes increased. Other studies showed a reduction in penetration while in some cases, no change in penetration was evident. Vinson and Choman (5) showed that nickel sulfate penetration into guinea pig skin was not affected by two nonionic surfactants. Chowhan and Pritchard observed enhanced penetration of naproxen through human and animal skin from aqueous gels containing methyldecyl sulfoxide (6). Polysorbate 80 increased chloramphenicol flux from aqueous solution through hairless mouse skin (7). Stolar, et al. (8) while studying the effect of nonionic surfactant on percutaneous absorption of salicylates from various ointment bases, found a marked reduction in the extent of percutaneous absorption of salicylic acid possibly due to the increased drug solubility and reduced partitioning into the stratum corneum. Hydrocortisone penetration from isopropanol-water solutions and gels through mouse skin was enhanced when polysorbate 80 was added to the vehicle (9). In sorting out possible mechanisms by which percutaneous absorption may be altered 87