600 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS N2 and N20, respectively, which are not reoxidized by molecular oxygen. These in- hibitors are not as innocuous as some of the weaker reducing agents, however. Cosmetics are frequently in the form of emulsions. Mirvish has shown that lipids readily extract nitrosating species from water. Under these conditions, nitrosation reactions are very fast. Since amines are also more soluble in the oil phase of emul- sions, it is appropriate to incorporate oil soluble inhibitors, such as ascorbyl palmitate and g-tocopherol, into such products for maximum inhibition of nitrosamine forma- tion. REFERENCES (1) 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 (1977). (2) H. Druckrey, R. Preussmann, S. Ivankovic, D. Schmlihl, J. Afkham, G. Blum, H. D. Mennel, H. Mfiller, P. Petropoulos and H. Schneider, Organotrope carcinogene Wirkungen bei 65 verschiedenen N-Nitroso-Verbindungen an BD-Ratten, Z. Krebsforsch., 69, 103 (1967). (3) H. Druckrey, Chemical carcinogenesis on N-nitroso derivatives, GANN Monogr. Cancer Res., n. 17, 107 (1975). (4) P. N. Magee, R. Montessano and R. Preussman, N-Nitroso Compounds and Related Carcinogens, in C. E. Searle, "Chemical Carcinogens" (ACS Monograph 173), The American Chemical Society, 1976, pp 491-625. (5) P. N. Magee andJ. M. Barnes, Carcinogenic N-nitroso compounds, Adv. Cancer Res., 10, 163 (1967). (6) P. N. Magee andJ. M. Barnes, The production of malignant primary hepatic tumors in the rat by feed- ing dimethylnitrosamine, Br. J. Cancer, 10, 114 (1956). (7) Later studies showed that as little as 2 to 5 ppm fed over a lifetime produced liver tumors (8). (8) B. Terracini, P. N. Magee and J. M. Barnes, Hepatic pathology in rats on low dietary levels of dimethylnitrosamine, Br. J. Cancer, 21,559 (1967). (9) C. L. Walters, Nitrosamines--environmental carcinogens?, Chem. Br., 13,140 (1977). (10) Another analysis of nitrosamine carcinogenicity is presented by Druckrey et al. (2). They show that the total dose required for carcinogenesis in rats becomes smaller with decreasing daily doses and longer induction times. The log of the induction time is directly proportional to the log of the daily dose, ruling out a recovery process. They conclude that ihe carcinogenic effect is due to a summation of irreversible primary effects. (11) J. S. Wishnok, M. C. Archer, A. S. Edelmann and W. M. Rand, Nitrosamine carcinogenicity: a quanti- tative Hansch-Taft structure-activity relationship, Chem. Biol. Interact., 20, 43 (1978). (12) M. Greenblatt and W. Lijinsky, Carcinogenesis and chronic toxicity of nitrilotriacetic acid in Swiss mice, J. Nat. CancerInst., 52, 1123 (1974). (13) J. S. Wishnok and M. C. Archer, Structure-activity relationships in nitrosamine carcinogenesis, Br. J. Cancer, 33,307 (1976). (14) W. Lijinsky, How nitrosamines cause cancer, New Sci., 27, 216 (1977). (15) D. Seebach and D. Enders, Umpolung of amine reactivity. Nucleophilic a-(secondary amino)-alkyla- tion via metalated nitrosamines, Angew. Chem. Int. Ed. EngL, 14, 15 (1975). (16) J. E. Baldwin, S. E. Branz, R. F. Gomez, P. L. Kraft, A. J. Sinskey and S. R. Tannenbaum, Chemical ac- tivation of nitrosamines into mutagenic agents, Tetrahedron Lett., 333 (1976). (17) J. Venulet and R. L. Van Etten, Biochemistry and Pharmacology of the Nitro and Nitroso Groups in H. Feuer, "The Chemistry of the Nitro and Nitroso Groups," Part 2, Wiley Interscience, New York, New York., 1970, Chapter 4, pp 201-287. (18) B. Singer, All oxygens in nucleic acids react with carcinogenic alkylating agents, Nature, 264, 333 (1976). (19) B.C. Challis and A. R. Butler, Substitution at an Amino Nitrogen in S. Patai, "The Chemistry of the Amino Group," Wiley Interscience, New York, New York, 1968, Chapter 6, pp 277-345. (20) G. B. Neurath, M. Dfinger and F. G. Pein, Nitrosation of Nornicotine and Nicotine in Gaseous Mix- tures and Aqueous Solutions, in E. A. Walker, P. Bogovski and L. Griciute, "Environmental N-Ni- troso Compounds: Analysis and Formation," IARC Scientific Publications no. 14, International Agency for Research on Cancer, Lyon, France, 1976, pp 227-236.
NITROSAMINE CHEMISTRY 601 (21) W. Rolle, P. Gehlert and E. Renner, Kinetische Untersuchungen fiber die Bilding von Diethyl- nitrosamin aus Stickstoffoxiden und Diethylamin in der Gasphase, Z. Chem., 18, 99 (1978). (22) J. H. Ridd, Nitrosation, diazotization and deamination, Q. Rev. Chem. Soc., 15,418 (1961). (23) S.S. Mirvish, Formation of N-nitroso compounds. Chemistry, kinetics and in vivo occurrence, Toxicol. Appl. Pharmacol., 31,325 (1975). (24) S.S. Mirvish, Kinetics of dimethylamine nitrosation in relation to nitrosamine carcinogenesis, J. Nat. CancerInst., 44, 633 (1970). (25) B.C. Challis and S. A. Kyrtopoulos, Nitrosation under alkaline conditions, J. Chem. Sac., Chem. Cam- mun., 877 (1976). (26) B.C. Challis and S. A. Kyrtopoulos, Rapid formation of carcinogenic N-nitrosamines in aqueous al- kaline solutions, Br. J. Cancer, 35,693 (1977). (27) B.C. Challis, A. Edwards, R. R. Hunma, S. A. Kyrtopoulos and J. R. Outram, Rapid Formation of N- Nitrosamines from Nitrogen Oxides Under Neutral and Alkaline Conditions, in E. A. Walker, M. Castegnaro, L. Griciute and R. E. Lyle, "Environmental Aspects of N-Nitroso Compounds," IARC Scientific Publications no. 19, International Agency for Research on Cancer, Lyon, France, 1978, pp 127-142. (28) E. H. White, The chemistry of the N-alkyl-N-nitrosamides. I. Methods of preparation, J. Amer. Chem. Sac., 77, 6008 (1955). (29) E. H. White and W. R. Feldman, The nitrosation and nitration of amines and alcohols with nitrogen tetroxide, J. Amer. Chem. Sac., 79, 5832 (1957). (30) P. Gehlert and W. Rolle, Formation of diethylnitrosamine by reaction of diethylamine with nitrogen dioxide in the gas phase, Experientia, 33,579 (1977). (31) E. Boyland, The Effect of Some Ions of Physiological Interest on Nitrosamine Synthesis, in P. Bogovski, R. Preussman and E. A. Walker, "N-Nitroso Compounds: Analysis and Formation," IARC Scientific Publications no. 3, International Agency for Research on Cancer, Lyon, France, 1972, pp 124-126. (32) E. Boyland, E. Nice and K. Williams, The catalysis of nitrosation by thiocyanate from saliva, Food Cosmet. TaxicoL, 9, 639 (1971). (33) T. ¾. Fan and S. R. Tannenbaum, Factors influencing the rate of formation of nitrosomorpholine from morpholine and nitrite: acceleration by thiocyanate and other anions, J. Agr. Food Chem., 21,237 (1973). (34) S.S. Mirvish, J. Sams, T. ¾. Fan and S. R. Tannenbaum, Kinetics of nitrosation of the amino acids proline, hydroxyproline and sarcosine, J. Nat. Cancer Inst., 51, 1833 ( 1973). (35) F. Schweinsberg, Catalysis of Nitrosamine Synthesis, in P. Bogovski and E. A. Walker, "N-Nitroso Compounds in the Environment," IARC Scientific Publications no. 9, International Agency for Re- search on Cancer, Lyon, France, 1974, pp 80-85. (36) D. L. H. Williams, S-Nitrosation of thiourea and thiocyanate ion. Nitrosyl thiocyanate and the S-ni- troso-adduct of thiourea as nitrosating agents, J. Chem. Sac. Perkin Trans. 2,128 (1977). (37) E. Boyland and S. A. Walker, Thiocyanate Catalysis of Nitrosamine Formation and Some Dietary Im- plications, in P. Bogovski and E. A. Walker, "N-Nitroso Compounds in the Environment," IARC Scientific Publications no. 9, International Agency for Research on Cancer, Lyon, France, 1974, pp 132-136. (38) E. Kalatzis and J. H. Ridd, Nitrosation, diazotization and deamination. Part XII. The kinetics of N-ni- trosation ofN-methylaniline, J. Chem. Soc., B, 529 (1966). (39) S.S. Mirvish, Kinetics of nitrosamide formation from alkylureas, N-alkylurethans, and alkylgua- nidines. Possible implications for the etiology of human gastric cancer, J. Nat. Cancer Inst., 46, 1183 (1971). (40) S.S. Mirvish, Kinetics of N-Nitrosation Reactions in Relation to Tumorigenesis Experiments with Ni- trite Plus Amines or Ureas, in P. Bogovski, R. Preussmann and E. A. Walker, "N-Nitroso Com- pounds: Analysis and Formation," IARC Scientific Publications no. 3, International Agency for Re- search on Cancer, Lyon, France, 1972, pp 104-108. (41) R. C. Weast, "Handbook of Biochemistry, Selected Data for Molecular Biology," The Chemical Rub- ber Co., Cleveland, Ohio, 1968, p J131. (42) J. Tummavuori and P. Lumme, Protolysis of nitrous acid in aqueous sodium nitrate and sodium nitrite solutions at different temperatures, Acta Chem. Scand., 22, 2003 (1968). (43) J. D. Okun and M. C. Archer, Kinetics of nitrosamine formation in the presence of micelie-forming surfactants, J. Nat. Cancer Inst., 58,409 (1977). (44) J. D. Okun and M. C. Archer, Micellar Catalysis of Nitrosamine Formation, in E. A. Walker, P. Bogovski and L. Griciute, "Environmental N-Nitroso Compounds: Analysis and Formation," IARC
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