Dimethylnitrosamine

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. 

Examples of these improvements are the packaging of dimethylamine products in plastic-lined containers and the elimination of sodium nitrite in the final product. This change in packaging and formulating makes it hi ly probable that N-dimethylnitrosamine will not form during storage of the product. Another example of the improvement of products is that Treflan products today contain less than 1 ppm of N-dipropylnitrosamine (T.) whereas some of the older products contained levels as high as 115-150 ppm several years ago (i, ). 

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). 

Dimethylhydrazine Dimethylnitrosamine bis (Dimethylthiocarbamoyl) disulphide Dinitrohenzene (all isomers)... 

Bhattacharjee A et al. Molecular dissection of dimethylnitrosamine (DMN)-in-duced hepatotoxicity by mRNA differential display. Toxicol Appl Pharmacol 1998 150 186-195. 

Both isomers of dimethylhydrazine have been shown to be carcinogenic in rodents following chronic oral exposure and 6-mon inhalation exposure to 1,1-dimethylhydrazine. Increased tumor incidence was observed in mice, although these findings are compromised by the contaminant exposure to dimethylnitrosamine. An increased incidence of lung tumors and hepatocellular carcinomas was also seen in rats but not in similarly exposed hamsters. The U.S. Environmental Protection Agency (U.S. EPA) inhalation slope factors are currently unavailable for dimethylhydrazine. 

Inhalation studies at the U.S. Air Force Aerospace Medical Research Laboratory showed an increased tumor response (hemangiosarcomas and Kupffer cell sarcomas) in mice exposed at 5 ppm, 6 h/d, 5 d/w for 6 mon (MacEwen and Vernot 1977, and Flaun 1977, reviewed in Trochimowicz 1994). Rats similarly exposed at 5 ppm exhibited increased incidences of squamous cell carcinomas of the lung and hepatocellular carcinomas. Hamsters subjected to a similar experimental protocol failed to show an increased incidence of tumors (MacEwen and Vernot 1975). It must be noted that the 1,1-dimethylhydrazine used in these studies contained 0.12% dimethylnitrosamine, which could be a significant confounder. 

Two oral studies in rodents demonstrated the carcinogenic potential of dimethylhydrazines. Results of an inhalation study in mice showing an increased tumor response following exposure to 1,1-dimethylhydrazine may be compromised by the contamination of the test article with dimethylnitrosamine. Both inhalation and oral slope factors for the dimethylhydrazines have been withdrawn from IRIS. 

Haun, C.C. 1977. Canine hepatotoxic response to the inhalation of 1,1-dimethylhydrazine (UDMH) and 1,1-dimethylhydrazine with dimethylnitrosamine (DMNA). 

Chlordane interacts with other chemicals to produce additive or more-than-additive toxicity. For example, chlordane increased hepatotoxic effects of carbon tetrachloride in the rat (USEPA 1980 WHO 1984), and in combination with dimethylnitrosamine acts more than additively in producing liver neoplasms in mice (Williams and Numoto 1984). Chlordane in combination with either endrin, methoxychlor, or aldrin is additive or more-than-additive in toxicity to mice (Klaassen et al. 1986). Protein deficiency doubles the acute toxicity of chlordane to rats (WHO 1984). In contrast, chlordane exerts a protective effect against several organophosphorus and carbamate insecticides (WHO 1984), protects mouse embryos against influenza virus infection, and mouse newborns against oxazolone delayed hypersensitivity response (Barnett et al. 1985). More research seems warranted on interactions of chlordane with other agricultural chemicals. 

Reynolds ES. 1972. Comparison of early injury to liver endoplasmic reticulum by halomethanes, hexachloroethane, benzene, toluene, bromobenzene, ethionine, thioacetamide and dimethylnitrosamine. 

For instance, the chemotherapeutic drug cyclophosphamide is in most cases immunosuppressive however, it can also induce autoimmunity (Hutchings et al., 1985). Likewise, dimethylnitrosamine, a nitrosamine detected in some foods, has been shown to have both suppressing and enhancing effects on the immune system (Yoshida et al., 1989). 

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. 

Figure 1. Electrostatic potential on the molecular surface of dimethylnitrosamine, computed at the Hartree-Fock STO-5G //STO-3G level. Two views are presented the top shows the lone pair (purple color) on the amino nitrogen. Color ranges, in kcal/mole, are purple, more negative than -20 blue, between -20 and -10 green, between -10 and 0 yellow, between 0 and +13 red, more positive than +13.

Carlson J, Abraham R. 1985. Nuclear ploidy of neonatal rat livers Effects of two hepatic carcinogens (mirex and dimethylnitrosamine). J Toxicol Environ Health 15(5) 551-559. 

Timchalk C, Charles AK, Abraham R. 1985. Comparative changes in rat liver cytosolic proteins by mirex, diethylnitrosamine and dimethylnitrosamine exposure. Proc Soc Exp Biol Med 180 214-218. 

A H NMR spectrum of /V,/V-dimethylnitrosamine (38) was obtained as early as 1957, and the free energy of activation for rotation was determined to be ca. 23 kcal/mol at 215°C (74). This high a barrier in nitrosamines is reasonable because the canonical structure 39 is stabilized by the strongly electron-donating ability... 

Sato, S., Matsushima, T., Tanaka, N., Sugimura T. and Takashima, F. Hepatic tumors in the guppy (Lebistes retioulatus) induced by aflatoxin dimethylnitrosamine, and 2-acetylaminofluorene. J. Natl. Cancer Inst. (1973) 50, 765-778. 

Synonyms AI3-25308 BRN 1738979 CCRIS 261 Dimethylnitrosamine W-Dimethyl-nitrosamine A,A-Dimethylnitrosamine Dimethylnitrosomine DMN DMNA EINECS 200-549-8 A-Methyl-A/ nitrosomethanamine NDMA Nitrous dimethylamide NSC 23226 RCRA waste number P082. 

Soil In both soils and water, chemical and biological mediated reactions can transform thiram to compounds containing the mercaptan group (Alexander, 1981). Decomposes in soils to carbon disulfide and dimethylamine (Sisler and Cox, 1954 Kaars Sijpesteijn et al., 1977). When a spodosol (pH 3.8) pretreated with thiram was incubated for 24 d at 30 °C and relative humidity of 60 to 90%, dimethylamine formed as the major product. Minor degradative products included nitrite ions (nitration reduction) and dimethylnitrosamine (Ayanaba et al., 1973). 

Dimethyl monosulfate, see Dimethyl sulfate Dimethylnitromethane, see 2-Nitropropane Dimethylnitrosamine, see TV-Nitrosodimethylamine TV-Dimethylnitrosamine, see TV-Nitrosodimethylamine 7V,7V-Dimethylnitrosamine, see TV-Nitrosodimethylamine Dimethylnitrosomine, see TV-Nitrosodimethylamine 2-(2,2-Dimethyl-l-oxopropyl)-l//-indene-l,3(2Efl -dione, see Pindone... 

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