NITROSAMINE CHEMISTRY 595 2. Efj•ct of Phenols on Nitrosamine Formation In Table TTT are summarized literature reports of the •cc•. of phenols on the c __ .. of nitrosamines in amine--nitrite systems. In most cases phenols inhibited nitrosamine formation, but sometimes their presence intensified nitrosamine production. In systems containing nitrite, phenols and secondary amines several reactions compete: --formation ofquinones (eq 19) --formation ofC-nitrosophenols (eq 20) --direct formation of N-nitrosamines --phenol-catalysed formation of N-nitrosamines --aerobic oxidation of C-nitrosophenols to noncatalytic nitrophenols (105). Inhibition of nitrosamine formation by phenols occurs by reduction of nitrite to un- reactive nitric oxide (104) OH O + 2HNO2 + 2NO + 2H20 (19) or by removal of nitrite via C-nitrosation (98): OH OH • + HNO2 ) • NO + H20 (20) Under some conditions phenols can catalyse nitrosamine formation. In the presence of excess nitrite 4-methylcatechol catalyses the nitrosation of dimethylamine and piperidine (104) and both p-cresol and p-nitroso-0-cresol catalyse the nitrosation of pyrrolidine (105). Walker, Pignatelli and Castegnaro (100) investigated the effects of 0-65 mM_gallic acid on the formation of nitrosodiethylamine from 75 mM nitrite and 500 mM diethylamine. Figure 1 and Table IV are adapted from their data obtained at pH 4.2 where maximum nitrosamine formation occured. In the absence of gallic acid 0.39 mM nitrosamine was formed. At the lowest level of gallic acid added, 12.5 mM, nitrosamine formation increased nine-fold. However, further increases in gallic acid concentration decreased nitrosamine formation linearly. Extrapolation of the linear rela- tionship (Figure 1) indicates that addition of 144 mM gallic acid would result in com- plete inhibition of nitrosamine formation. This is equivalent to approximately 2 mol of gallic acid per mol of nitrite. This result is consistent with that obtained by Davies and coworkers (105) who found that the rate of nitrosation of pyrrolidine by nitrite increased linearly with the concentration of p-nitroso-0-cresol. They demonstrated that the nitrosating species responsible for catalysis is an adduct of nitrite and a tautomer of the nitrosophenol. A similar mechanism probably operates with gallic acid where a large excess of nitrite would lead to catalysis by C-nitrosogallic acid.

596 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS 20 qO 60 80 100 120 lqO 6ALLIC AClD• mM Figure 1. Effect of gallic acid on N-nitrosodiethylamine synthesis Thus, whether a phenol inhibits or catalyses nitrosamine formation largely depends on the relative concentration of nitrite and phenol. Excess nitrite C-nitrosates the phenol and subsequently forms the catalytic species. A large excess of phenol removes nitrite so that it is unavailable for reaction with amine, either directly or catalytically. No catalysis should occur with phenols such as c•-tocopherol, which are not C-nitrosated because the ring is fully substituted. Table IV Effect of Gallic Acid Concentration on Nitrosodiethylamine (NDEA) Synthesis from 75 mM Nitrite and 500 mM Diethylamine at pH 4.2 mM NDEA mM Gallic Acid (g) Found (N) Calc. (N a) 62.5 2.15 2.15 37.5 2.81 2.80 25.0 3.10 3.13 12.5 3.48 3.46 0.0 0.39 -- N •' = -0.0263 g + 3.79, the least squares line of best fit. 3. Inhibition by Sulfur Compounds Bisulfite reduces nitrite in two steps (106)--first to nitric oxide (eq 21) and then to ni- trous oxide (eq 22). Sulfamate reduces nitrite to molecular nitrogen (107) (eq 23). These substances inhibit nitrosamine formation (Table V). SO2 + 2HNO2 -- 2NO + SOz + 2NO + HzO -- N=O NaNO= + H2NSOaH -- NaHSO4 q- H=SO4 (21) q- HzSO4 (22) N= + H=O (23)