N-Nitroso contamination

When EPA became aware almost five years ago that N-nitroso contaminants occurred in a number of pesticide products, the Agency immediately acted on the authority of Section 3 of FIFRA to place a moratorium on new registrations of pesticides suspected to contain N-nitroso contaminants at detectable levels (this term is defined and explained later in the text). As has been discussed in other papers of the Symposium, many N-nitroso compounds are animal carcinogens and, consequently, suspected human carcinogens. 

N-Nitroso contamination in pesticide products was first reported by D. Fine and co-workers (] ) who had developed a novel and specific analytical method for N-nitroso compounds, called thermal energy analysis. 

During the next two years (1976 and 19TT)> registrants of pesticides and EPA laboratories analyzed several hundred samples of N- containing pesticides for N-nitroso contaminant occurrence and concentration. Results of these analyses have been reported elsewhere. What these analyses revealed was what was... 

The basic tenets of the proposed policy is to encourage the manufacturer to reduce or eliminate the N-nitroso contaminant level in his product, or failing this to establish that the level does not exceed an "acceptable risk to the user of the pesticide or the general public. This latter process of evaluation also requires that the Agency consider the benefits of this pesticide together with the risk in order to reach a final decision. Since there might be hundreds of products falling under this policy, the... 

That all or some of these steps are practical has been demonstrated by the observation that many N-nitroso contaminants have been removed from commercial products since they were first discovered in 1977 or that the nitroso levels have been reduced in these products below 1 ppm. 

If, on the other hand, it can be demonstrated that the particular N-nitroso contaminant is not an oncogen, the product will be cleared for registration without having to perform an exposure analysis. 

Based on the experience gained during the past U to 5 years, it was demonstrated that no pesticides were canceled on the basis of unacceptably high levels of N-nitroso contaminants. It is anticipated that the EPA Nitroso Policy will improve pesticide products even further by a reduction or elimination of N-nitroso contaminants from potential sources. In this way, the human risk from these potentially hazardous chemicals will be minimized. 

N-nitroso contaminants in pesticides can be avoided by simple process changes and the elimination of nitrite salts in the formulation" (46). 

It Is now a relatively straightforward matter to analyze commercial pesticide mixtures for nitrosamlne contamination as part of the normal quality control process (2.18). and, as Illustrated above, some of the major contamination problems have begun to be solved by means of technological Improvements. If further research brings about the circumstance In which there Is no detectable N-nItroso compound In any pesticide sold an here, will that mean that pesticide use Is safe from nitrosamlne-formatlon problems I believe that considerably more research must be done before a responsible answer to this question can be given. To elaborate on this position, let me focus on the herbicides for a moment. 

For the above reasons, EPA s Office of Pesticide Programs has proposed a policy on the procedures for regulating pesticides contaminated with N-nitroso compound 0. Comments from the public and involved parties were invited and will be considered when EPA is preparing its final policy on N-nitroso compounds in pesticides, later in 1981 or early 1982. It is the intent of this paper to discuss l) the proposed policy by EPA 0 the important issues raised during the public comment period and (3) suggest what the final policy might look like. 

EPA "Pesticides Contaminated with N-Nitroso Compounds, Proposed Policy", Fed. Reg., June 25, 1980, U285U. 

N-Nitroso compounds occur in many operations in the rubber industry. Some nitrosamines (nitrosodiphenylamine, N-N-dinitrosopentamethylenetetramine, polymerized N-nitroso 2,2,4-trimethyl-l,2-dihydroquinoline and N-methyl-N-4-dinitroso aniline) are used as organic accelerators and antioxidants in the production of rubber and often the products are found to be contaminated with such compounds [19]. 

Miscellaneous. Volatile nitrosamines can escape into the atmosphere from a variety of other sources. Automobile and diesel engine exhausts may contain N-nitroso compounds, including NDMA at trace levels (5). Nitrosodiethanolamine (NDEIA) is a likely air contaminant in machine shops which use cutting and grinding fluids contaminated with high concentrations of NDElA (10). Several herbicides, known to contain appreciable levels of volatile nitrosamines (9), are applied as aqueous sprays it is likely that worker exposure via inhalation may be appreciable. 

Table 1 indicates our survey of prescription and non-prescription drugs. We have investigated only a single manufacturer s product for each item. Contaminants in three presciption and two over-the-counter formulations were shown to give a positive TEA response. Subsequent chemical tests showed that for the prescription drugs, the impurities were probably N-nitroso compounds, although this has not been confirmed by mass spectrometry. Several other drugs which contained TEA positive materials were demonstrated not to contain N-nitroso compounds by a series of chemical tests used in conjunction with HPLC-TEA. 

The results imply that for the majority of drug products tested, there does not appear to be a serious problem with regard to the presence of N-nitroso compound contaminants. 

In a preliminary study we have recently reported (1) that the air in three rubber and tire industry plants was contaminated with several N-nitroso compounds. The compounds included N-nitrosomorpholine (NMOR), N-nitrosodimethylaminne (NDMA), and N-nitrosodiphenylamine (NDPhA). The latter compound is used as a vulcanization retarder, so its presence near processes employing it was not surprising. Bismorpholine-carbamylsulfonamide, a cross-linking accelerator used in rubber tires was found in tire factories and may be contaminated with NMOR. The source of the NDMA was not identified, but it could arise from nitrosation of amines which may be decomposition products of diamine based accelerators, as pointed out by Yeager, et al (2). 

Further discoveries of consumer and industrial products contaminated with N-nitroso compounds (11) led to the speculation that industrial workers that either use or manufacture these products may be exposed to significant amounts of these carcinogenic agents. These discoveries of environmentally occurring N-nitroso compounds plus increased understanding of the mechanism by which they can be formed from their widely available precursor amines (12) and oxides of nitrogen (13), has resulted in this study of worker... 

To illustrate the use of the recommended method, consider the reduction of N, N-nitroso-dimethylamine (NDMA), a mutagenic and carcinogenic contaminant that has been subject to considerable study (11). Reduction can occur at the N-N bond (Equation 1), or at the N-O bond (not shown). 

Certain naturally-occurring contaminants in food (e.g., afla-toxin and N-nitroso compounds), and nonnutritive constituents (e.g., hydrazines in mushrooms) are carcinogenic in animals and pose a potential risk of cancer to humans. These and other compounds thus far shown to be carcinogenic in animals have been reported to occur in the average U.S. diet in small amounts however, there is no evidence that any of these substances individually makes a major contribution to the total risk of cancer in the United States. This lack of sufficient data should not be interpreted as an indication that these or other compounds subsequently found to be carcinogenic do not present a hazard. 

Spiegelhalder B, Preussmann R. 1984. Contamination of toiletries and cosmetic products with volatile and nonvolatile N-nitroso carcinogens. J Cancer Res Clin Oncol 108 160-163. 

While laboratory studies indicate that low molecular weight nitrosamines including NDPA can volatilize rather rapidly after application to the surface of warm soil, incorporation into the soil of the nitrosamine co-applied with a dinitroaniline herbicide, decreases both the rate and extent of volatilization (49,59). However, in either case volatilization obser d occurred within 3 or 4 days after application. No uptake of C into the stems, leaves and beans was found xj en soybeans were grown in soil treated with 100 ppb of NDPA- C, or N-nitrosopendimetha-lin- C [N-(1-ethyl propyl)-N-nitroso-3,4-dimethy1-2,6-dinitro-benzenamine (60). It should be noted that N-nitrosopendimethalin (a contaminant of the pesticide pendimethalin) (61) was relatively stable in soil and significant quantities could be recovered unchanged after several months. 

Mitch WA, Sharp JO, Trussell RR, et al. (2003) N-nitroso-dimethylamine (NDMA) as a drinking water contaminant a review. Environmental Engineering Science 20 389-404. 

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