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)

NITROSAMINE CHEMISTRY 597 Table V In Vitro Inhibition of Nitrosamine Synthesis by Sulfur Compounds Sunur Compound Amine System Effect of Sulfur Compound Reference Sodium Dimethylamine Model food systems Inhibits nitrosamine formation. 93 Bisulfite Ammonium 93 Sulfamate Sulfamic Acid 108 Cysteine Cysteine Glutathione Glutathione Dimethylamine, mor- Invitro pholine, piperazine Piperazine Aminophenazone Dimethylamine Piperazine Aminophenazone Dimethylamine Piperazine Methionine Dimethylamine Inhibits nitrosamine formation. Human gastric juice, Inhibits nitrosamine formation. in vitro In vitro Inhibits nitrosamine formation. 93 Human gastric juice, Inhibits nitrosamine formation. 108 in vitro In vitro Inhibits nitrosamine formation. 93 Human gastric juice, Inhibits nitrosamine formation. 91 in vivo In vitro Inhibits nitrosamine formation. 93 The thioIs cysteine and glutathione also inhibit nitrosamine formation. The thioether methionine is less effective. It is postulated that nitrite oxidizes methionine to the sulfoxide or sulfone and is in turn reduced to nitric oxide (93). ThioIs react with nitrite to form S-nitroso compounds (109). In the absence of nitrite preformed nitrosocysteine reacts with N-methylaniline, morpholine and pyrrolidine to form N-nitrosamines (105). In contrast catalysis of nitrosation by p-nitroso-0-cresol does not occur in the absence of nitrite. One would suggest transnitrosation of secon- dary amines by nitrosothiols, except that molecular oxygen appears to be necessary (105). 4. Miscellaneous Inhibitors The ammonium ion reacts with nitrite to form molecular nitrogen (107) by the follow- ing sequence: NH4 + • NHa + H + 2H + + NO2- • H2ONO + H2ONO + + NHa --- H20 + NHaNO + • N= + H + + H20 (24) Hydroxylamine reduces nitrite to nitrous oxide (107). NH2OH + HNO2 -- N20 + 2H20 (25) Vitamin A reacts with nitrite in acid solution but not under neutral conditions (108). Presumably oxidation of the vitamin involves its double bonds. Table VI summarizes literature indicating that urea, caffeine and ethanol are relatively ineffective inhibitors, but reduced nicotinamide adenine dinucleotide (NAD) is effec- tive. In alkaline solution even weak oxidants such as O2 convert nitrite to nitrate (110).