Nitrosating potential

The largest known htiman exposures to exogenous nltrosamines have been shown to occur in the work place, particularly in the rubber and leather tanning industries. Recent data for amines, nitrosating potential and nitrosamines will be presented in the framework of assessing the extent of the various exposures. 

Nitrosating Potential. The nitrosating potential of a sample is defined as its capacity to nitrosate amines to produce N-... 

Figure L Calibration plot for nitrosation potential showing amount of t -nitroso-thiomorpholine formed vs, the square of the nitrogen dioxide concentration. Standard conditions of 50%relative humidity, 25°C, and 1 L/min flow rate for 30 min...

Figure 20.2. Nitrosating potential as a function of filler surface area. [Adapted, by permission, from GorlU, De Kok J J, Bomal Y, Cochet P, Mueller H, Kaut. u. Gummi Kunst., 47, No.6, June 1994, 430-4.]...

As in the case of foods and other consumer products, nitrites have been found in cosmetic raw materials (3), Other potential nitrosating species have not been reported in these substances. 

Recently nitrosamines have attracted attention because of their marked carcinogenic activity in a wide variety of animal species Q, ). Nitrosamines are likely to be carcinogens in man as well human exposure to these compounds is by ingestion, inhalation, dermal contact and vivo formation from nitrite and amines Nitrite and amines react most rapidly at an acidic pH A variety of factors, however, make nitrosation a potentially important reaction above pH 7 these include the presence of microorganisms, and the possibilities of catalysis by thiocyanate, metals and phenols, and of transnitrosation by other nitroso compounds. 

N-Nitrosamine inhibitors Ascorbic acid and its derivatives, andDC-tocopherol have been widely studied as inhibitors of the N-nitrosation reactions in bacon (33,48-51). The effect of sodium ascorbate on NPYR formation is variable, complete inhibition is not achieved, and although results indicate lower levels of NPYR in ascorbate-containing bacon, there are examples of increases (52). Recently, it has been concluded (29) that the essential but probably not the only requirement for a potential anti-N-nitrosamine agent in bacon are its (a) ability to trap NO radicals, (b) lipophilicity, (c) non-steam volatility and (d) heat stability up to 174 C (maximum frying temperature). These appear important requirements since the precursors of NPYR have been associated with bacon adipose tissue (15). Consequently, ascorbyl paImitate has been found to be more effective than sodium ascorbate in reducing N-nitrosamine formation (33), while long chain acetals of ascorbic acid, when used at the 500 and lOOO mg/kg levels have been reported to be capable of reducing the formation of N-nitrosamines in the cooked-out fat by 92 and 97%, respectively (49). 

Interaction of lipid oxidation products and amino compounds. Amino acids and primary amines may be involved in other reactions which could lead to the formation of compounds having the potential to undergo N-nitrosation. Malonaldehyde, produced as a result of oxidation of lipids, particularly polyunsaturated fatty acids, has been shown to react with amino acids to produce... 

A group of amines which have the potential to produce NDMA upon nitrosation and an estimate of the relative amount of each amine in green malt is listed in Table III. 

Hard evidence for the first category seems to be nonexistent. An educated guess on the potential hazards would combine residue technology [how much of a secondary amine (or amide, urea, carbamate, etc.) might a person consume or otherwise be exposed to ], nitrosation chemistry (what would be the yield of in vivo nitrosation of the pesticide thus consumed ), and toxicology (what would be the toxicological effect and potency of the nitroso compound thus formed ). Frequently, these questions, which simplify to, "What dose—eg., in mg/kg—of a pesticide-derived nitroso compound might a person be exposed to and what would be the result if he were " are not carefully considered. 

Elimination or reduction of all potential nitrosating agents formed or added during the manufacturing process (e.g. nitrous acid resulting from nitration process during the process). 

Aromatic nitrosation with nitrosonium (NO + ) cation - unlike electrophilic nitration with nitronium (NO ) cation - is restricted to very reactive (electron-rich) substrates such as phenols and anilines.241 Electrophilic nitrosation with NO+ is estimated to be about 14 orders of magnitude less effective than nitration with N02+. 242 Such an unusually low reactivity of NO+ toward aromatic donors (as compared to that of NO ) is not a result of the different electron-acceptor strengths of these cationic acceptors since their (reversible) electrochemical reduction potentials are comparable. In order to pinpoint the origin of such a reactivity difference, let us examine the nitrosation reaction in the light of the donor-acceptor association and the electron-transfer paradigm as follows. 

Although a detailed kinetic analysis of the nitrosation reaction with NO+BFJ is not available, the time/conversions with various aromatic donors suggest that the reactivity does not follow the variation of the ionization potentials of the... 

The formation of the Wheland intermediate from the ion-radical pair as the critical reactive intermediate is common in both nitration and nitrosation processes. However, the contrasting reactivity trend in various nitrosation reactions with NO + (as well as the observation of substantial kinetic deuterium isotope effects) is ascribed to a rate-limiting deprotonation of the reversibly formed Wheland intermediate. In the case of aromatic nitration with NO, deprotonation is fast and occurs with no kinetic (deuterium) isotope effect. However, the nitrosoarenes (unlike their nitro counterparts) are excellent electron donors as judged by their low oxidation potentials as compared to parent arene.246 As a result, nitrosoarenes are also much better Bronsted bases249 than the corresponding nitro derivatives, and this marked distinction readily accounts for the large differentiation in the deprotonation rates of their respective conjugate acids (i.e., Wheland intermediates). 

S -nitrosothiols, several of which occur naturally, e.g., iS -nitrosocysteine and S-nitrosoglutathione, have an important role in NO transport and regulation in biological systems. Potential applications of RSNO compounds include their use as vasodilators in the treatment of angina and in the search for a cure for male impotence.11 The most convenient route to S-nitrosothiol formation is the nitrosation of thiols. 

Nitrosonium (NO+) is a strong oxidant and the reduction potential to NO has been measured in non-aqueous media (1.67 V vs. SCE in CH3CN), and estimated for water (Eq. (3)) (12,15). NO+ is subject to rapid hydrolysis to nitrite (2H+ + N02 ), and therefore if formed in biological media would be short-lived. However, other less water-sensitive chemical species can act as NO+ donors in reactions leading to the nitrosation of various substrates. For example, the reactions of certain metal nitrosyl complexes with nucleophiles such as R SH can lead to the transfer of NO+ as illustrated in Eq. (4). Such reactions will be discussed in greater detail below. 

The pH of a metalworking fluid must be kept above neutrality in order to prevent acid corrosion of the metal In vitro, acid catalyzed nitrosation is optimized at pH 3.5 (4 0) however, it has been shown that In the presence of other catalysts, aqueous solutions of amines and nitrite leads to significant yields of nitrosamines at room temperature over the pH range of 6.4 to 11.0 (41). Furthermore, C-nitro-containing, formaldehyde-releasing biocides, such as bronopol or tris nitro, exert their potential catalytic effect in alkaline solution. It would thus be desirable to determine the optimum pH for a metalworking fluid that would lead to the lowest concentration of nitrosamine possible. 

Although much of the biological literature focuses on nitrosating reactions of nitric oxide, chemically nitric oxide is a moderate one-electron oxidant, making formation of nitroxyl anion feasible under physiological conditions. The reduction potential to reduce nitric oxide to nitroxyl anion is +0.39 V, whereas it requires +1.2 V to oxidize nitric oxide to nitrosonium ion. Nitrosating reactions of nitric oxide are often mediated by conversion of nitric oxide to another nitrogen oxide species or by direct reaction with transition metals (Wade and Castro, 1990). 

---