N-Nitroso Compounds - ACS Publications - American Chemical Society

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Downloaded by UNIV OF MICHIGAN ANN ARBOR on October 16, 2014 | http://pubs.acs.org Publication Date: December 9, 1981 | doi: 10.1021/bk-1981-0174.ch025

Reduction of Nitrosamine Impurities in Pesticide Formulations G. W. PROBST Lilly Research Laboratories, Elanco Products Company, Indianapolis, I N 46206

The d i s c o v e r y o f nitrosamine contaminants i n some p e s t i c i d e s has l e d t o a major t e c h n o l o g i c a l e f f o r t to prevent, reduce or e l i m i n a t e formation o f these inadvertent impurities in pesticide formulations. Although the nitrosamine contaminants occur a t low l e v e l s ( i n p a r t s per million), many have been found to cause cancer i n l a b o r a t o r y animals and may present a hazard t o p e s t i c i d e users. In p e s t i c i d e s , nitrosamines are formed i n several ways: by the a c t i o n of nitrosating agents on secondary amines in manufacturing processes, the use o f nitrite or nitrate as container c o r r o s i o n i n h i b i t o r s or as i m p u r i t i e s i n amine reagents used i n s y n t h e s i s . Reduction of nitrosamine formation can be accomplished by removal o f n i t r o s a t i n g agents, f o r example, n i t r o g e n oxides or t h e i r precursors, nitrite and n i t r a t e . A e r a t i o n and scrubbing o f the intermediate n i t r a t i o n products e f f e c t i v e l y removes potential nitrosating sources. Destruction of trace quantities o f nitrosamines i n technical materials, l i k e d i n i t r o a n i l i n e s , i s accomplished by treatment with hydrogen chloride gas, h y d r o c h l o r i c a c i d , and hydrobromic a c i d , or by the use o f a l i p h a t i c ketones and aldehydes i n the presence o f a strong a c i d . Agents which are l e s s efficient include halogens (e.g. molecular bromine and c h l o r i n e g a s ) , i n o r g a n i c a c i d h a l i d e s (e.g. phosphorus oxychloride and thionyl chloride), N-bromo-succinimide and o t h e r s . The mechanisms, as w e l l as scope and l i m i t a t i o n s o f removal, will be reviewed.

0097-6156/ 81 /0174-03 6 3 $ 0 5 . 0 0 / 0 © 1981 American Chemical Society In N-Nitroso Compounds; Scanlan, R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.


364

N-NITROSO COMPOUNDS

Formation of N-nitroso compounds has been observed from a l l types of amines, amides, quaternary ammonium compounds and many other nitrogen-containing compounds (Mirvish, 1975). Their carcinogenic potential (Magee and Barnes, 1967) has evoked much concern not only from preformed N-nitroso compounds in food (Lijinsky and Epstein, 1970), but as amine or amide precursors in the form of drugs (Lijinsky, 1974) ; Lijinsky et a l , 1975) and as pesticide residues consumed in food (Ceaborn, Radeleff and Bushland 1960? Maier-Bode 1968). The presence of v o l a t i l e nitrosamines i n pesticide formulations was f i r s t reported by Ross (1976) at the 172nd National Meeting of the American Chemical Society in San Francisco. The nitrosamines were detected with Thermal Energy Analyzer (TEA) coupled with an isothermal gas chromatograph. The TEA was developed by Fine et a l (1973) and Fine and Rufeh (1974). The instrument i s highly specific and sensitive for nitrosamines and i s adaptable for the direct testing of pesticide formulations. Of the pesticides tested by Ross et a l (1976), three formulations were dimethylamine salts of acidic herbicides and were found to contain 0.3-640 ppm of N-nitrosodime thy lamine (NDMA). One formulation of the dinitroaniline herbicide, t r i f l u r a l i n , was found to contain 154 ppm N-nitrosodipropylamine (NDPA) In conjunction with the observation, Ross et a l (1977) observed no detectable nitrosamines i n the a i r , water or crops as the result of application of TREFLAN (a registered trademark of Elanco Products Company, Division of E l i L i l l y and Company, for the herbicide t r i f l u r a l i n , α , α , α - t r i f l u o r o - 2 , 6 - d i n i t r o N,N-dipropyl-£-toluidine), containing NDPA. Nevertheless, confirmation of the observations, evaluation of the potential exposure to man and the environment and a reduction of the impurity were pursued immediately.

PESTICIDES CONTAINING NITROSAMINES Since the discovery of N-nitroso contaminants in certain pesticides, a wide variety of products has been analyzed i n response to a request from the United States Environmental Protection Agency (Environmental Protection Agency, 1977). The analysis and survey reports by Cohen et a l (1977), Bontoyan et al (1979) and Zweig et a l (1980) includes dinitroanilines, dimethylamine and ethanolamine salts of phenoxyalkanoic acids, quaternary salts, amides, carbamates, organophosphates, triazines, urea derivatives and some miscellaneous pesticides. Many pesticides have been nitrosated under laboratory conditions for various research purposes. A l i s t of 51 nitrosated pesticides reviewed by Kearney (1980) indicates the potential magnitude of the N-nitroso problem. However, the EPA analysis survey reveals that for positive detection, N-nitroso compounds in pesticide formulations is limited to

In N-Nitroso Compounds; Scanlan, R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.


25.

PROBST

Nitrosamine

Impurities

in

Pesticides

365

dinitroanilines, amines and ethanolamine salts of acidic herbicides and quaternary salts. As might be expected, there are exceptions; in the survey the pesticide thiram contained 1.2 ppm N-nitrosodimethylamine (DMNA). Eisenbrand et a l (1975) showed a rapid formation of N-nitrosamine from similar compounds ziram and fer bam, by both in v i t r o and in vivo studies. Thus, almost any compound belonging to the class of nitrogen-containing compound i s a candidate, either primarily or secondarily, for N-nitroso dérivatation. The scope of this review i s not to deal with every eventuality that leads to the formation of N-nitroso compounds, but to examine existing knowledge for the prevention or the removal of N-nitroso compounds from technically-produced pesticides and their accompanying use formulations. The chemistry and toxicology of nitrosamines have been adequately reviewed by Magee et a l (1976), Mirvish (1975), Douglas et a l (1978) and Fridman et a l (1971) · The problem of eliminating nitrosamines occurring as trace contaminants i n pesticide formulations is markedly different than that of dealing with neat reactions of a given nitrosamine.

SOURCE OF NITROSAMINE CONTAMINATION

Nitrosamines i n pesticides can occur as impurities or as inadvertant contaminants. They are formed in several ways: Formation of Nitrosamines i n Pesticides 1. 2. 3. 4. 5.

Side reactions i n the manufacturing synthesis Contaminated reagents used in manufacture Direct additives used as preservatives Nitrosating agents in the environment Intra-molecular rearrangements

Formation is dependent on the interaction of nitrogen-containing organic compounds with nitrosating agents, such as oxides of nitrogen. The levels of N-nitroso compounds i n pesticides have been reported to range up to 640 ppm. Considering the p o s s i b i l i t i e s from synthesis, higher values are easily conceivable. Factors Considered for Nitrosamine Elimination Reduction of Nitrosamine 1. 2.

Prevent the nitrosating reaction with amine precursors. Nitrosamine destruction by selective chemical action.


366

N-NITROSO COMPOUNDS

The literature has numerous citations on both the prevention and destruction of ηitrosamines. Techniques, such as the use of scavengers or selective reactions, may be applied to commercial pesticide products.


Some Factors to Consider i n Reduction of N-Nitroso Compounds i n Pesticides 1. Effectiveness of prevention vs destruction 2. Effect on the pesticide product 3· Introduction of other chemical by-products a. By reactions with the pesticide or other existing impurities b. Newly created by-products and impurities c. The effect on s t a b i l i t y of the formulation 4. Economics of production a. Special f a c i l i t i e s requirements b. Cost of stabilizers, scavengers, etc. c. Cost of agents and reactants 5. Regulatory requirements a. Allowable ηitrosamine levels (policy) b. Supplemental data requirements for product definition, chemistry, toxicology, environmental and use considerations PREVENTION OF NITROSAMINE FORMATION A.

Synthesis and Manufacturing

The discovery of nitrosamines i n pesticide formulations, Ross et a l (1976), led to remarkable public and regulatory reaction. The widely used herbicide, t r i f l u r a l i n , because of the inadvertent nitrosamine impurity, received the most attention. A l l dinitroaniline herbicides have s i m i l a r i t i e s ; therefore, t r i f l u r a l i n , with appropriate exceptions, w i l l serve as a suitable example. Most dinitroaniline s are synthesized from a precursor which is nitrated and subsequently aminated to yield the desired product. In the case of t r i f l u r a l i n , 4-chlorobenzotrifluoride (PCBT) i s dinitrated to y i e l d 4-chloro-3,5dinitro-a,ot,a-triflurotoluene (Dinitro PCBT), Preparative Route to Trifluralin


25.

PROBST

Nitrosamine

Impurities

in Pesticides

367

which i n turn i s aminated with n-dipropy lamine to yield the product, Probst et a l (1975). The formation of the impurity i n t r i f l u r a l i n occurs when the amine is added to the reactive mixture of 4-chloro-3,5-dinitro benzotrifluoride (Dinitro PCBT) containing residual nitrosating agents arising from the nitration reaction* CH,CH CH 4 CH CH CH . >H+lNO] — > - N 0 CH CH CH / CH CH CH 2

3

2

2

3

2

3

2

2

2

2

x

x


3

2

2

3

2

2

NDPA

Nitrosating reagents would include residual nitrate n i t r i t e or oxides of nitrogen. Laboratory studies with spiked samples of the Dinitro PCBT with low levels of nitrate and nitrite, then aminating to yield trifluralin, did not contribute significantly to nitrosamine formation. Therefore, the hypothesis was investigated that the active nitrosating agent present i n the Dinitro PCBT mixture was oxides of nitrogen, dissolved i n the reaction mixture. The active nitrosating agents, i n this case oxides of nitrogen, are indicated along with possible precursors, Ingold (1953)· Nitrosating Agents N 0

N2O4

+

H N0 + 2

2

N0 2

Precursors

N 0 2

3

NOBr N0C1

Many references suggest that the presence of any nitrogen oxides w i l l result, under equilibrum or under specific pH conditions, i n a nitrosating agent capable of converting amines or quaternary ammonium bases into nitrosamines, the rate and amount being a function of the existing conditions. Recognizing the conditions which result i n the formation of nitrosamines i n the manufacturing process, attention i s directed to the purification of Dinitro PCBT to remove the nitrogen oxides resulting from nitration prior to the amination step i n the synthetic sequence (Cannon and Eizember 1978)· Therefore, modification of the process was directed to the purification of Dinitro PCBT to remove nitrogen oxides. I f dinitro PCBT i s prepared without special purification procedures, nitrosamines i n the amount of 150-500 ppm are common. In the case of the synthesis of compounds, such as pendimethalin and butralin,


368

N-NITROSO COMPOUNDS

CH —ÇH—C H 3

NH—CH4

0 Ν>γΛ4Ν0 2

5

NH C

2

2

H

2 5

CH, C H /

C

3

P«ndimethalin

N-

N-Nitroso Compounds - ACS Publications - American Chemical Society

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