The fundamental chemical principles of blocking inadvertent nitrosamine formation and contamination through the recognition of structural features which predispose compounds toward rapid nitrosation as well as the development of new blocking agents are reviewed. Rapid nitrosamine formation from tertiary nitrogen compounds such as amines, amidines, and gem. diamines is shown to occur through an electron pair assisted nitrosative solvolysis type mechanism. The rapid production of nitrosamines from amdinocillin, an amidine containing antibiotic, and hexetidine, a widely used antimicrobial agent, are presented as examples of new findings. The development and assay of new monomeric and polymeric blocking agents is described. An advantage of the latter blocking agent is its ability to be removed from mixtures by physical means. This knowledge and these measures permit significant reductions in nitrosamine contamination to be realized.Nitrosamine formation in the human environment continues to be a significant problem despite the widespread recognition of the possible carcinogenic role of nitrosamines and other N-nitroso compounds. Many effective measures have been taken to eliminate or significantly reduce the level of nitrosamines in foods and other commercial products (7). In many instances, successful steps to block nitrosamine formation have been based upon an elucidation of the mechanisms by which they are formed and/or the use of specific blocking agents. These numerous individual successes, however, have not eliminated the problem of nitrosamine contamination. Moreover, there is now good evidence that nitrosamines form in vivo from several types of precursors, heightening concern that many tumors could have their origin in endogenous nitrosation (2).

The acidic nitrosation of hexetidine and hexedine, common antimicrobial agents and drug constituents, leads to a mixture of nitrosamines. The major nitrosamine product, "HEXNO", forms rapidly in yields as high as 60% over the pH range 1-4.8 at incubation times of 1 h at 37 degrees C with 40 mM NO2- and 10 mM hexetidine. On the basis of extensive spectroscopic characterization and independent synthesis HEXNO has been assigned the structure of 1-(2-ethylhexyl)-3-nitroso-4-methyl-4-[[N-(2-ethylhexyl)-N- nitrosoamino]methyl]imidazolidine (7). The synthesis of HEXNO involves the novel interception by potassium nitrite in ether/18-crown-6 of an imminium ion produced from the reaction of hexedine with benzyl chloroformate. Collapse of the alpha-amino nitrous ester produced by this reaction yields the nitrosamine containing carbamate 8, which yields HEXNO after removal of the carbamate with trimethylsilyl iodide and subsequent nitrosation. The rapid formation of HEXNO from hexetidine and hexedine supports the hypothesis that tertiary geminal diamines will produce nitrosamines rapidly by a mechanism which involves the cleavage of a nitrosammonium ion with the assistance of the neighboring nitrogen atom. This process is deemed to be of possible importance in the endogenous production of potentially carcinogenic nitrosamines because of its low nitrite requirement and high nitrosation rate. The available data suggest the probable formation of HEXNO and other nitrosamines from hexetidine under conditions of its use.