A-Nitrosamine

Reduction of a nitrosamine to a secondary amine. Proceed as for a nitro compound. Determine the solubility of the residue after evaporation of the ether and also its behaviour towards benzenesulphonyl (or p-toluenesulphonyl) chloride. 

Table 2. Toxicological Properties of Some Representative A Nitrosamines in the BD Rat ...

Mutagenicity. The AJ-nitrosamines, in general, induce mutations in standard bacterial-tester strains (117). As with carcinogenicity, enzymatic activation, typically with Hver microsomal preparations, is required. Certain substituted A/-nitrosamine derivatives (12) induce mutations without microsomal activation (31,33,34). Because the a-acetoxy derivatives can hydroly2e to the corresponding a-hydroxy compounds, this is consistent with the hypothesis that enzymatic oxidation leads to the formation of such unstable a-hydroxy intermediates (13) (118). However, for simple /V-nitrosamines, no systematic relationship has been found between carcinogenicity and mutagenicity (117,119—123). 

V-Nitrosodiphenylamine can act as a nitrosating agent for other amines with all the consequences thereof (see A/-Nitrosamines). 

Although ultra accelerators or sulfur donors can be used together with primary accelerator (such as sulfenamide, TBBS) to improve cure rate as well as the heat resistance [16-18], their use is restricted because of the associated nitrosamine issue [19]. Accelerators derived from secondary amines, for example, MBS, TMTD, TETD, TMTM, and OTOS fall into this category. The combination of sulfenamide, such as CBS or TBBS, and a thiuram, such as TMTD or TETD, shows high-cure rates but suffers from the adverse effects on scorch resistance and vulcanizate dynamic property [20]. Additionally as previously mentioned, the use of TMTD or Tetraethylthiuram disulhde (TETD) or A-oxidiethylene dithiocarbamyl-A -oxidiethylene sulfenamide (OTOS) or 4,4 -Dithiodimorpholine (DTDM) is undesirable [21] due to concerns over carcinogenic nature of the A-nitrosamines formed from the parent amines. The solution to this originated by introduction of nitrosamine safe ultra accelerator such as TBzTD [22,23]. 

Today, more and more know how to design a cure system capable of meet these demanding requirements. Some new materials allow compounder to reformulate a cure system capable of providing improved performance. Antireversion chemicals constitute a class of such materials, once again emphasizing the need to meet the service conditions. Health and safety issues, as for example, that concerning A-nitrosamines, have also lead to the introduction of new mbber additives. 

Almost any class of reduced nitrogen compound can serve as the nitrosatable precursor of an N-nitroso compound. To make matters worse, every nitrogen coordination state from primary to quaternary has been converted to a nitrosamine. A glance at the list of some of the known nitrosatable substrates given in Table II illustrates what a wide variety of N-nitroso compounds analysts might expect to encounter in our complex environment. 

Table III shows that any of the higher oxidation states of nitrogen can serve as a nitrosating agent. To form a nitrosamine, all that need happen is for a nitrosating agent to encounter a nitrosatable substrate under favorable conditions, which might (but need not) involve acceleration of the reaction rate by one of the chemical or physical agents indicated in Table IV.

If the concepts and facts presented in this paper are correct, a major kind of human cancer in many regions of the world, cancer of the stomach, is due to a type of nitroso compound, a nitrosoureido derivative, even though not a nitrosamine It is quite certain that the formation of such compounds can be blocked by vitamin C and vitamin E, as well as by some other substances such as gallates Thus, the primary prevention of cancer caused by nitroso compounds is readily accomplished through an adequate Intake of such harmless inhibitors with every meal from infancy onwards ... 

It is clear that neither NMEA nor NDPA is appropriate for an internal standard in NDMA determination if criteria are interpreted strictly, but both compounds have been used for this purpose. Addition of a nitrosamine, not normally present in the sample, is helpful in detecting any gross errors in the procedure, but the addition should not be considered to be internal standardization. Utilization of NMEA or NDPA to indicate recovery of NDMA can lead to significant errors. In most reports of the application of these "internal standards", recovery of all nitrosamines was close to 100%. Under these conditions, any added compound would appear to be a good internal standard, but none is necessary. NDMA is a particularly difficult compound for use of internal standardization because of its anomalous distribution behavior. I mass j ectrometry is employed for quantitative determination, H- or N-labeled NDMA could be added as internal standard. Because the labeled material would coelute from GC columns with the unlabeled NDMA, this approach is unworkable when GC-TEA is employed or when high resolution MS selected ion monitoring is used with the equipment described above. 

The effort required to establish identity of a nitrosamine in an environmental sample depends on the nature of the problem and the specificity of the primary detection system. TEA response is much stronger evidence of identity than response from a flame ionization or nitrogen-specific detector. If TEA response is supported by chemical (9) or ultraviolet photolysis (8) supporting data, identification is adequate for many... 

This far into a nitrosamine symposium it should hardly be necessary to point out that nitrosamines are technically just one of a group of Ji-nitroso compounds that also includes nitros-amides, nitrosocarbamates, nitrosoureas, etc. Or that nitrosa-table pesticides encompass all the categories just mentioned and more. Or that many diverse pesticides, including herbicides, insecticides, and fungicides have been converted to Ji-nitroso derivatives in the laboratory (a recent review contained a 3-page, probably incomplete, compilation), or that some of the Ji-nitroso compounds thus synthesized were determined to be carcinogenic in test animals or mutagenic in various assays. 

Other environmental properties of interest are those that govern movement of chemicals, for these properties can influence not only the possibility of human exposure but also the lifetime and fate of the chemical. Clearly, if a nitrosamine is formed in, or introduced into, the soil and stays there, it presents little threat to man, and its lifetime will depend on the chemical or microbiological properties of the soil. If it should move to the surface and volatilize into the atmosphere, on the other hand, there will exist the possibility of human exposure via inhalation and also the possibility of vapor-phase photodecomposition. If a nitrosamine were to leach from soil into water, it could perhaps be consumed in drinking water alternatively, exposure of the aqueous solution to sunlight could provide another opportunity for photodecomposition. 

Mills AL, M Alexander (1976) A-nitrosamine formation by cultures of several microorganisms. Appl Environ Microbiol 31 892-895. 

The experimental details describe the use of a free secondary amine for the preparation of a nitrosamine. Identical results are, of course, obtained by employing solid diethylamine hydrochloride. 

The NO + 03 chemiluminescent reaction [Reactions (1-3)] is utilized in two commercially available GC detectors, the TEA detector, manufactured by Thermal Electric Corporation (Saddle Brook, NJ), and two nitrogen-selective detectors, manufactured by Thermal Electric Corporation and Antek Instruments, respectively. The TEA detector provides a highly sensitive and selective means of analyzing samples for A-nitrosamines, many of which are known carcinogens. These compounds can be found in such diverse matrices as foods, cosmetics, tobacco products, and environmental samples of soil and water. The TEA detector can also be used to quantify nitroaromatics. This class of compounds includes many explosives and various reactive intermediates used in the chemical industry [121]. Several nitroaromatics are known carcinogens, and are found as environmental contaminants. They have been repeatedly identified in organic aerosol particles, formed from the reaction of polycyclic aromatic hydrocarbons with atmospheric nitric acid at the particle surface [122-124], The TEA detector is extremely selective, which aids analyses in complex matrices, but also severely limits the number of potential applications for the detector [125-127],... 

Aminooxazole 11, readily obtained by reaction of N-Boc-L-Val-OH with aminomalononitrile p-toluenesulfonate and EDC in pyridine [5], was converted directly to bromooxazole 12 by in situ bromination via a nitrosamine intermediate. 

The various effects of the Toxic Substances Control Act (TSCA) on the metalworking fluids Industry is presented, with emphasis placed on nitrosamine contamination of the fluids. A review of the literature on the effects of various metalworking fluid additives on nitrosamine formation is also presented to aid the industry in dealing with the nuisance of nitrosamine contamination. It is concluded that with increased awareness of nitrosamine contamination as a result of the implementation of TSCA and careful consideration of the factors described in this paper, it may be possible to design and control a nitrosamine-free metalworking fluid. 

Section 8 of TSCA has made EPA and the industry aware of nitrosamine contamination in metalworking fluids. In one particular potentially significant notice of substantial risk (8E-1077-0 012), skin painting studies showed an increase above the expected normalincidence of tumors in the livers and lungs of mice with no unusual incidence of skin tumors. Due to the similarity between the observed effects and the mechanism of action of nitrosamines (i.e., the apparent systemic effect of the substance and organ specificity of the tumors), the company attributed the response to a nitrosamine contaminant in the fluid. 

Unfortunately, not all combinations of chemical additives in water-based fluids are completely compatible, and side reactions leading to various byproducts have been noted. The best known of these side reactions is the reaction between the corrosion inhibitor nitrite and the emulsifiers di- and triethanolamine (7) to form N-nitrosodiethanolamine (NDE1A), a nitrosamine reported to have carcinogenic activity (8, 9, 10). In fact, most nitrosamines are carcinogenic, and no animal species which has been tested is resistant to nitrosa mine-induced cancer. Although there is no direct evidence that firmly links human cancer to nitrosamines, it is unlikely that humans should be uniquely resistant. 

NDE1A is not the only nitrosamine reported to have been identified in metalworking fluids. A fluid in the Netherlands was found to be contaminated with 5-methyl-N-nitrosooxazolidine (17). The two most likely explanations by which nitrosooxazolidines may be formed in metalworking fluids are (1) simple nitrosation of oxazolidine antimicrobials and (2) nitrosation of primary beta-hydroxy amines (18). The latter reaction is an example of the conversion of a primary amine into a nitrosamine. 

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). 

Volatile nitroso compounds were determined in hams processed in elastic rubber nettings by SPE and GC-CLD577. By a similar method A-n i tro sodi ben zy lamine (278b), a semivolatile nitrosamine, was determined in these products by SPE followed by GC interfaced to a nitrosamine-specific TEA-CLD detector the coefficient of variation was 10.6% at the 2.1 ppb level578. The nitrosamines detected in ham most likely originate from the amine precursors in rubber and from the nitrite commonly used in the meat curing process. 

Many activations involve compounds which are used as pesticides. In the case of N-nitrosation, the precursors are secondary amines and nitrate. The former are common synthetic compounds and the latter is an anion found in nearly all solid and aqueous phases. The N-nitrosation of a secondary amine [R-NH-R ] occurs in the presence of nitrite formed microbiologically from nitrate. The product is an N-nitroso compound (i.e., a nitrosamine [RR -N-N=0]). The reason for concern with nitrosamines is their potency, at low concentrations, as carcinogens, teratogens, and mutagens. 

Fig. 1 Formation of tobacco-specific A -nitrosamines (Hoffmann et at. 1995). iso-NNAC, 4-(methylnitrosoamino)-4-(3-pyridyl)butyric acid iso-NNAL, 4-(methylnitrosoamino)-4-(3-pyridyl)- -butanol NAB, A -nitrosoanabasine NAT, A -nitrosoanatabine NNA, 4-(methylnitro-soamino)-4-(3-pyridyl)butanal NNAL, 4-(methylnitrosoamino)-l-(3-pyridyl)-l-butanol NNK, 4-(methylnitrosoamino)-l-(3-pyridyl)-l-butanone NNN, Af -nitrosonornicotine (Note NNA is a very reactive aldehydes and has therefore never been quantified in tobacco or tobacco smoke)...

Bhide SV, Nair J, Mara GB, Nair UJ, Kameshwar Rao BV, Chakraborty MK, Brunnemann KD (1987) Tobacco-specific A-nitrosamines (TNSA) in green mature and processed tobacco leaves from India. Beitr Tabakforsch 14 29-32... 

Synonyms AI3-00698 Benzenamine BRN 0909531 CCRIS 464 Curetard A Delac J Diphen-ylnitrosamine Diphenyl-A-nitrosamine A A-Diphenylnitrosamine A A-Diphenyl-A-nitrosamine EINECS 201-663-0 Naugard TJB NCI-C02880 NDPA NDPhA Nitrosodiphenylamine A-Nitroso-zj-phenylamine A-Nitroso-zj-phenylbenzenamine Nitrous diphenylamide NSC 585 Ortard Redax Retarder J Sconoc TJB Vulcalent A Vulcatard Vulcatard A Vultrol. 

The conversion of a nitrosamine to a nitramine can be affected by either nitrolysis or oxidation. While the results of these two reactions are identical, they are mechanistically very different. For this reason, the oxidation of nitrosamines is discussed separately in Section 5.9. 

The choice of reagent determines whether a nitrosamine undergoes conversion to a nitramine by either nitrolysis or oxidation. An example is given for the conversion of 1,3,5-trinitroso-1,3,5-triazacyclohexane (109) to l,3,5-trinitro-l,3,5-triazacyclohexane (3) (RDX) - the use of 30 % hydrogen peroxide in 99 % nitric acid at subambient temperature goes via oxidation of the nitrosamine functionality, whereas dinitrogen pentoxide in pure nitric acid makes use of a nitrolysis pathway via C-N bond cleavage. 

Because N-nitroso compounds can have such a wide variety of physical and chemical properties, and because they can be formed from a wide variety of precursors. analysis at the trace level is difficult. The most widely used technique is the use of a nitrosamine specific detector, called a TEA, which can be interfaced to either a gas chromatograph (GC) or a high pressure liquid chromatograph (HPLC) (31,32). General screening procedures which have been designed to detect all N-nitroso compounds have been developed (33,34). Structural confirmation of N-nitroso compounds is gen-... 

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