Dimethylnitrosamine formation

Mills, A.L. and Alexander, M. Factors affecting dimethylnitrosamine formation in samples of soil and water, J. Environ. Qual., 5(4) 437-440, 1976. 

Hashimoto S, Yokokura T, Kawai Y, et al. 1976. Dimethylnitrosamine formation in the gastro-intestinal tract of rats. Fd Cosmet Toxicol 14 553-556. 

H. V. Mailing, Dimethylnitrosamine Formation of mutagenic compounds by interaction with mouse liver microsomes, Mutat. Res. 13, 425-429 (1971). 

A,V-Dimethylnitrosamine formation has been observed in simulated polluted atmospheres (Hanst et al., 1977 Pitts et al., 1978 Tuazon et al., 1978). It can be formed following OH attack on dimethylamine by the following mechanism ... 

The above scheme satisfies much of the metabolic data however, some of it is speculative, and it is certainly incomplete. The evidence for the formation of the a-hydroxylated intermediate is circumstantial. The acetate ester of a-hydroxylated dimethylnitrosamine has been prepared (12.13) and has been found to be a potent, directly acting carcinogen (14). Other esters of a variety of a-hydroxylated nitros-amines have also been prepared (15). While it has been shown that DMN acetate is hydrolyzed to hydroxymethylmethyl-nitrosamine by an esterase enzyme, it has been pointed out that these derivatives of the a-hydroxylated nitrosamines also dissociate to N-nitrosoimmonium ions (15 16). 

Only a few studies have been undertaken on the role of bacteria in nitrosation at neutral pH in the Intestinal tract itself. Hashimoto al. (9 ) demonstrated that by changing the equilibrium between different species of microorganisms in the gut, (by administration of antibiotics and inoculation with nitrate-reducing strains) dimethylnitrosamine (NDMA) accumulated in the stomach and cecum of rats fed dlmethylamine (DMA) and nitrate. The authors describe only one experimental group, however, and the mechanism of NDMA formation is not clear. 

A strain of Escherichia coli produces a naphthotriazole from 2,3-diaminonaphthalene and nitrite that is formed from nitrate by the action of nitrate reductase. The initial product is NO, which is converted by reactions with oxygen into the active nitrosylating agent that reacts chemically with the amine (Ji and Hollocher 1988). A comparable reaction may plausibly account for the formation of dimethylnitrosamine by Pseudomonas stutzeri during growth with dimethylamine in the presence of nitrite (Mills and Alexander 1976) (Figure 2.2f). 

Mills and Alexander [4] have discussed the factors affecting the formation of dimethylnitrosamine in samples of soil. Dimethylnitrosamine was formed as readily in sterilized samples as in non-sterile samples, indicating that, although micro organisms can carry out an enzymatic nitrosation in some soils, dimethylnitrosamine can be formed by a non-enzymatic reaction, even at near neutral conditions. The presence of organic matter appears to be important in promoting nitrosation in the presence of the requisite precursors. 

Ayanaba, A., Verstraete, W., and Alexander, M. Formation of dimethylnitrosamine, a carcinogen and mutagen, in soils treated with nitrogen compounds. Soil Sci Soc. Am. Proc., 37 565-568, 1973. 

By comparison with other areas of consumer products, relatively little is known about the possible presence of N-nitroso derivatives in pharmaceuticals. Eisenbrand et, have reported on the presence of dimethylnitrosamine in all 68 samples of aminopyrine analyzed in Germany (23). They suggested that DMN could have been formed in various drug formulations by two main routes. One was by the in situ reaction of aminopyrine with nitric oxides in the air, and the other involved the synthetic process used in the manufacturing process itself (23). The levels of DMN found ranged from less than 10 ppb to just under 400 ppb. It has been found for several years that animals fed aminopyrine and sodium nitrite in their diets show the formation of malignant tumors (24, 25). In view of the presence of substantial amounts of DMN in the... 

Mills and Alexander [78] have discussed the factors affecting the formation of dimethylnitrosamine in samples of water and soil. 

Jadhav and Magar (463) applied an ascorbic acid glaze, which delayed the yellow discoloration and allied organoleptic changes, to frozen white pomfret, surmai, and mackerel fish. Use of phosphates in combination with ascorbate esters has been declared to improve the color and flavor of fish products (464). Shellfish (465,466,467) including prawns and breaded shrimp, have been ascorbic acid treated, the latter in combination with citric acid. Formation of dimethylnitrosamine in Alaskan pollack roe (468) was inhibited when ascorbic acid was in-... 

The carcinogenicity of dimethylnitrosamine and 4-nitrosomorpholine was reduced by deuterium substitution for hydrogen on carbon atoms alpha to the amino nitrogen.81 82 Consistent with the hypothesis that alpha-carbon oxidation is required for reactive metabolite formation from nitrosamines, there is a substantial primary deuterium isotope effect (ku/kg = 3.8) on the rate of dimethylnitrosamine N-demethylation. 3 Specific deuteration of 3-methylcholanthrene, a potent polycyclic hydrocarbon carcinogen, showed that oxidation of the 1-carbon atom is critical in the tumor-initiating process in mouse skin. ... 

Ayanaba A, Alexander M. 1974. Transformation of methylamines and formation of a hazardous product, dimethylnitrosamine, in sanples of treated sewage and lake water. J Environ Qual 3 83-89. 

Kobayashi M, Tchan YT. 1978. Formation of dimethylnitrosamine in polluted environment and the role of photosynthetic bacteria. Water Res 12 199-201. 

Stumpf R, Margison GP, Montesano R, Pegg AE. 1979. Formation and loss of alkylated purines from DNA of hamster liver after administration of dimethylnitrosamine. Cancer Res 39 50-54. 

Baneijee S, Pack EJ, Sikka H, et al. 1984. Kinetics of oxidation of methylhydrazines in water, factors controlling the formation of 1,1-dimethylnitrosamine. Chemosphere 4 549-559. 

The adduct obtained with diethylnitrosamine is the same as that obtained with ethylene.50 Ethylene formation from diethylnitrosamine has not been reported but alkyl alcohols, which derive from the cationic Intermediates required for olefin formation, are known as metabolites of dialkyInitro-samines.51 Heme alkylation by dimethylnitrosamine must, in any case, involve a species other than an olefin metabolite. 9... 

Exhibits acute, delayed, and chronic toxicity moderately toxic by intraperitoneal route low to moderately toxic by ingestion—LD50 values showing wide variation with species the data reported appear to be questionable highly toxic in dog but low oral toxicity in rat toxic effects in humans unknown but expected to be similar to other urea derivatives susceptible to formation of dimethylnitrosamine under certain conditions, which is carcinogenic EPA-listed extremely toxic substance (U.S. EPA 1989). 

Similarly, Schwarz et al. (1982) found no significant difference in the formation of DNA adducts with [ C]-dimethylnitrosamine in the livers of rats pretreated for 2 wk with ethanol (20% w/v in the drinking water). In addition, the ratio of 0 -methylguanine, a product which has been implicated in mutagenesis, to N -methylguanine in DNA did not change following ethanol pretreatment. Belinsky et al. (1982) confirmed a lack of effect of ethanol (at 35% of caloric intake for 3 wk) on in vivo activation of dimethylnitrosamine in rat hepatocytes. 

Emissions of nitrosamines (specifically, iV-nitrosamines) arouse particular concern owing to associated cancer risks." All secondary amines are potential precursors to N-nitrosamines and it will be apparent from considerations of the reactions both prior to cure and accompanying cure (e.g. eqns (24), (27)) that amines may be commonly encountered in vulcanized mixes and the vapours from them. Some of the amines already encountered in emissions from rubber are listed in Table 8. It should be made clear from the outset that not all the amines listed are secondary, and that primary amines are not direct precursors to AT-nitrosamines. Considerable attention has been focused on iV-nitrosamine formation within the rubber industry, and various monitoring exercises have detected such nitrosamines in both vapours and solvent extracts.In one study airborne concentrations in excess of 1 mg/m were found for dimethylnitrosamine (A/ -nitrosodimethylamine), and as high as 4-6mg/m for N-nitrosomorpholine." However, the amine is only one-half of the equation and effort has also been directed to establishing the identity... 

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