Analysis of Pesticide Formulations - ACS ... - ACS Publications

15 Analysis of Pesticide Formulations Establishment of Methods and Collaborative Testing

Downloaded by UNIV OF CALIFORNIA SAN DIEGO on December 4, 2015 | http://pubs.acs.org Publication Date: June 5, 1984 | doi: 10.1021/bk-1984-0254.ch015

J. R. PLIMMER Agrochemicals and Residues Section, Joint FAO/IAEA Division, International Atomic Energy Agency, Vienna, Austria

The analysis of pesticide formulations is linked to specifications based on the requirements of the user. Methods of analysis for many pesticides purchased by international organizations are developed through collaborative studies initiated by the Collaborative International Pesticides Analytical Council and the Association of Official Analytical Chemists. The producer is not only concerned with analytical techniques needed for quality control but also with regulatory requirements that have imposed greater demands for analytical information in recent years. Improved analytical capabilities for detection of contaminants of potential toxicological significance, such as chlorodioxins and nitrosamines, have generated continued demands for data by regulatory agencies. Novel formulations, such as controlled-release formulations, require special analytical techniques to ensure satisfactory performance.

The majority of p u b l i c a t i o n s on p e s t i c i d e a n a l y s i s deal with terminal residues and t h e i r determination. From a p r a c t i c a l standpoint, the determination of the a c t i v e ingredient in a t e c h n i c a l p e s t i c i d e or a formulation i s e q u a l l y important, i f not always apparently so s c i e n t i f i c a l l y c h a l l e n g i n g . In recent years, new dimensions have been added to the problem by r e g u l a tory requirements, and i t has been recognized that c e r t a i n contaminants, present i n manufactured products, might present p o t e n t i a l r i s k s to man and the environment. From a p r a c t i c a l standpoint, the manufacture and sale of p e s t i c i d e products must be l i n k e d at a l l times to an a n a l y t i c a l c o n t r o l system capable of adequately measuring a c t i v e i n g r e d i e n t s , since f l u c t u a t i o n s

0097-6156/ 84/ 0254-0193S06.00/ 0 © 1984 American Chemical Society

In Advances in Pesticide Formulation Technology; Scher, H.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.


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ADVANCES IN PESTICIDE FORMULATION TECHNOLOGY

in t h e i r content or q u a l i t y w i l l i n f l u e n c e the economics of production and the performance of the formulated product. The f i r s t c o n s i d e r a t i o n i s the content of a c t i v e i n g r e d i e n t , because the b i o l o g i c a l a c t i v i t y and a p p l i c a t i o n rates must be based on t h i s f i g u r e . S p e c i f i c a t i o n s r e q u i r e a statement as to the content of the a c t i v e i n g r e d i e n t . I t i s a l s o important that the content of i m p u r i t i e s be defined i f these i n t e r f e r e with the a c t i v e i n g r e d i e n t , or are phytotoxic, such as j>-nitrophenol i n parat h i o n ; or are c o r r o s i v e to packages or machinery; or induce chemical degradation; or are unduly hazardous t o man or the environment, such as c h l o r i n a t e d d i o x i n s or nitrosamines. The s p e c i f i c a t i o n must guarantee the i d e n t i t y and quantity of a c t i v e ingredient and s e t l i m i t s f o r undesirable i m p u r i t i e s . The s p e c i f i c a t i o n serves to guide buyers; i t serves f o r comparison o f batches; to recommend a n a l y t i c a l procedures f o r a c t i v e ingredient or i m p u r i t i e s ; to provide methods and c r i t e r i a f o r i d e n t i t y of the a c t i v e i n g r e d i e n t ; and to provide chemical and p h y s i c a l parameters as a d d i t i o n a l t e s t s f o r judging the s u i t a b i l i t y of formulations. I t ensures that the product i s s a t i s f a c t o r y f o r the use f o r which i t was intended by r e q u i r i n g that the product possess defined chemical and p h y s i c a l c h a r a c t e r i s t i c s that can be v e r i f i e d by t e s t methods. The producer i s concerned to ensure that h i s product performs c o n s i s t e n t l y and meets the requirements of the user and u s u a l l y provides s p e c i f i c a t i o n s , but i n many cases, n a t i o n a l and i n t e r n a t i o n a l bodies have developed s p e c i f i c a t i o n s , part i c u l a r l y f o r those products f o r which patents no longer e x i s t , to meet t h e i r own needs f o r purchase of p e s t i c i d e s . S p e c i f i c a t i o n s may r e f e r to t e c h n i c a l or formulated p e s t i cides . TABLE I . a) b) c) d) e) f) K>

FAO S p e c i f i c a t i o n s

origin d e t a i l s of methods r e f e r r e d to statement of scope information on the method of a n a l y s i s l a b o r a t o r y work to e s t a b l i s h s p e c i f i c a t i o n comparative l a b o r a t o r y work other r e l e v a n t information

The development of s p e c i f i c a t i o n s cannot be e f f e c t i v e l y accomplished without proper a n a l y t i c a l methodology. This a l s o includes p h y s i c a l t e s t s to ensure s u i t a b i l i t y as w e l l as chemical analyses. Recognition of t h i s need has l e d to i n t e r n a t i o n a l cooperation and c o o r d i n a t i o n of e f f o r t . In t h i s respect the C o l l a b o r a t i v e I n t e r n a t i o n a l P e s t i c i d e s A n a l y t i c a l


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Council (CIPAC) and the A s s o c i a t i o n Chemists (AOAC) have provided a lead of c o l l a b o r a t i v e methods.


FAQ

of O f f i c i a l through the

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Analytical preparation

Specifications

Following a s e r i e s of meetings that began i n 1965, a manual on the use of FAO s p e c i f i c a t i o n s f o r plant p r o t e c t i o n products was published i n 1971 (1). The FAO development of p e s t i c i d e s was on s i m i l a r l i n e s to those p r e v i o u s l y e s t a b l i s h e d by WHO and published i n the handbook " S p e c i f i c a t i o n s f o r P e s t i c i d e s Used i n P u b l i c Health" (1967) (2). The preparation of separate FAO s p e c i f i c a t i o n s was deemed necessary because the p e s t i c i d e s used f o r c o n t r o l of vectors of human health are not n e c e s s a r i l y s u i t a b l e f o r plant p r o t e c t i o n . The s p e c i f i c a t i o n s are prepared by a Working Party cons i s t i n g of o f f i c i a l governmental s c i e n t i s t s a s s i s t e d by a technical representative from the World Health Organization and by t e c h n i c a l observers from the s e c r e t a r i a t s of i n t e r n a t i o n a l p e s t i c i d e organizations which have l i a i s o n status with FAO. I n d u s t r i a l s c i e n t i s t s may be consulted or i n v i t e d as advisers to deal with p a r t i c u l a r items. D r a f t s p e c i f i c a t i o n s are prepared and submitted f o r review by the Working Party. Table I. shows the type of information to be submitted as a d r a f t s p e c i f i c a t i o n . I f s u i t a b l e , d r a f t s are c i r c u l a t e d and sent out f o r comment by industry and coope r a t i n g government agencies. A f t e r comment they are r e c i r c u l a t e d , and, subject to recommendations of the group, are adopted as: TENTATIVE: based on minimum requirements, manufacturers method of a n a l y s i s , not c o l l a b o r a t i v e l y studied; PROVISIONAL: some c o l l a b o r a t i v e study of a n a l y t i c a l method or FULL FAO s p e c i f i c a t i o n s : a l l necessary requirements and CIPAC method of a n a l y s i s . These s p e c i f i c a t i o n s are subsequently published. The Working Party discusses patented products d i r e c t l y with the manufacturer and any experts the Working Party may wish to consult. In the case of commodity products, where patents have expired, worldwide c o n s u l t a t i o n i s necessary to ensure that a l l i n t e r e s t e d p a r t i e s may comment. World industry conveniently i n t e r a c t s with the working Party through the Groupement I n t e r n a t i o n a l de Fabricants de P e s t i c i d e s (GIFAP). However, non-members of GIFAP may a l s o by involved i n c o n s u l t a t i o n . The Working Party agreed that collaboratively tested methods of a n a l y s i s would be used and both CIPAC and the AOAC have made a v a i l a b l e methods which they adopted a f t e r c o l l a b orative testing. CIPAC i s i n t e r n a t i o n a l i n composition, but



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many of i t s reports have o r i g i n a t e d from the P e s t i c i d e s Analyt i c a l Advisory Committee (PAC) of the M i n i s t r y of A g r i c u l t u r e of the United Kingdom, which undertakes preparation of CIPAC methods of a n a l y s i s f o r t e c h n i c a l and formulated p e s t i c i d e s and prepares s p e c i f i c a t i o n s where r e q u i r e d . The U.K. e f f o r t to c o n t r o l p e s t i c i d e s through proposed s p e c i f i c a t i o n s and methods of a n a l y s i s began s h o r t l y a f t e r World War I. Subsequently, there were continued e f f o r t s by the M i n i s t r y of A g r i c u l t u r e and the A s s o c i a t i o n of B r i t i s h Insecticide Manufacturers to produce specifications and methods of a n a l y s i s , but the flow of new p e s t i c i d e s made t h i s task almost insurmountable. Since other countries were engaged i n wasteful d u p l i c a t i o n of these e f f o r t s , i t was proposed i n 1957 by Dr. R. deB. Ashworth (3) that a n a t i o n a l committee should be appointed by each country to be responsible f o r methods of a n a l y s i s of t e c h n i c a l and formulated p e s t i cides. C o l l a b o r a t i v e methods would be t e s t e d and coordinated by an i n t e r n a t i o n a l committee, the C o l l a b o r a t i v e I n t e r n a t i o n a l P e s t i c i d e s A n a l y t i c a l C o u n c i l (CIPAC). The U.K. n a t i o n a l committee, PAC, has i t s counterparts i n other European c o u n t r i e s . At the f i r s t meeting of CIPAC i n 1957, in addition to the U.K., representatives from the Netherlands, Federal Republic of Germany, and France p a r t i c i pated. European representation subsequently increased and agreement was reached with FAO that the a n a l y t i c a l methods would be published i n the "FAO Plant P r o t e c t i o n B u l l e t i n " . At about the same time WHO and CIPAC a l s o agreed to c o l l a b o r a t e i n the preparation of methods. Representation increased at subsequent meetings, and there are now Members from 21 count r i e s ; correspondents (Associate Members) from the O f f i c i a l A s s o c i a t i o n of A n a l y t i c a l Chemists (AOAC), the Food and A g r i c u l t u r a l Organization of the United Nations (FAO), the World Health Organization (WHO), and from s i x more countries. Observers from other c o u n t r i e s and the European Economic Community a l s o attend. There i s c l o s e cooperation with GIFAP and with official and industrial laboratories concerned with development of a n a l y t i c a l methods (4). The aims of CIPAC include the f o l l o w i n g : "a) to promote i n t e r n a t i o n a l agreement on: (i) methods f o r the a n a l y s i s of p e s t i c i d e products and of such other substances as the C o u n c i l may, from time to time, determine; ( i i ) methods f o r the physio-chemical e v a l u a t i o n of t e c h n i c a l p e s t i c i d e s and formulations; (iii) methods f o r c o r r e l a t i n g b i o l o g i c a l e f f i c a c y with p h y s i c a l and chemical p r o p e r t i e s of pesticide. b) to f o s t e r i n t e r - l a b o r a t o r y c o l l a b o r a t i v e a n a l y s i s among i n t e r e s t e d l a b o r a t o r i e s . "



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A d d i t i o n a l aims include sponsoring symposia on methods of a n a l y s i s , p u b l i s h i n g agreed methods, proceedings of symposia, etc. and c o l l a b o r a t i n g with other organizations ( 3 ) . Although the e v o l u t i o n of a n a l y t i c a l methodology i n the United States has d i f f e r e d from that i n Europe, there has been c l o s e cooperation between the AOAC and CIPAC. Collaboration was proposed at the 7th meeting of CIPAC i n 1963, and i n 1971 CIPAC met i n Washington, and i t was agreed that to avoid d u p l i c a t i o n of e f f o r t CIPAC and AOAC would work c l o s e l y t o gether, and a document "Guidelines f o r C o l l a b o r a t i o n Between AOAC and CIPAC" was prepared ( 5 ) . This l i a i s o n had l e d to j o i n t work on the development of methods, so that AOAC, CIPAC, and WHO, where appropriate, adopt each other's methods. This i s i n d i c a t e d by the designat i o n of a method as CIPAC-AOAC or AOAC-CIPAC to i n d i c a t e the o r g a n i z a t i o n r e s p o n s i b l e f o r development of the method. In the CIPAC Handbook, methods designated CIPAC methods have been collaboratively investigated; those classified as " p r o v i s i o n a l " have been l e s s thoroughly studied or may be l e s s s a t isfactory. Need f o r C o l l a b o r a t i v e Study In the United States, the A s s o c i a t i o n of O f f i c i a l A n a l y t i c a l Chemists has been recognized as an o r g a n i z a t i o n that p r i m a r i l y serves the needs of government r e g u l a t o r y and research agenc i e s f o r a n a l y t i c a l methods and i t i s now attempting to extend that r o l e to the i n t e r n a t i o n a l scene. Through i t s e f f o r t s , the c o l l a b o r a t i v e study has become a most important t o o l f o r v a l i d a t i o n of a n a l y t i c a l methods and f o r determining t h e i r reliability. In the c o l l a b o r a t i v e study, a number of l a b o r a t o r i e s are provided with i d e n t i c a l sets of samples that l i e w i t h i n the range of the s e l e c t e d method. The o b j e c t i v e of the c o l l a b o r a t i v e study i s to examine the accuracy, p r e c i s i o n , s e n s i t i v i t y , range, l i m i t of d e t e c t i o n and other c h a r a c t e r i s t i c s of the method. This i s accomplished under the d i r e c t i o n of an A s s o c i a t e Referee, who, as a s p e c i a l i s t , i s i n turn operating under the guidance and a d m i n i s t r a t i v e s u p e r v i s i o n of a General Referee. The procedural d e t a i l s have been described (6-7). A minimum of s i x samples are sent to not fewer than f i v e l a b o r a t o r i e s to be studied by the s e l e c t e d method. The agreed d e f i n i t i o n of C o l l a b o r a t i v e Study (AOAC - CIPAC) i s "An a n a l y t i c a l study i n v o l v i n g a number of l a b o r a t o r i e s analyzing the same sample(s) by the same method(s) f o r the purpose of v a l i d a t i n g the performance of the method(s) ( 5 ) .


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The


Need f o r Harmonization

This paper has been concerned p r i m a r i l y with the r o l e of CIPAC and AOAC i n the preparation of a n a l y t i c a l methods f o r p e s t i cide formulations. The l e g a l enforcement of standards makes i t important to use v a l i d a t e d procedures f o r determination of pesticides. To avoid d u p l i c a t i o n of e f f o r t and a l s o to f a c i l i t a t e i n t e r n a t i o n a l commerce, the acceptance and v a l i d a t i o n of methods should be an i n t e r n a t i o n a l a c t i v i t y and the r o l e of CIPAC i n t e r n a t i o n a l l y has corresponded to that of national committees or o r g a n i z a t i o n s . As the r o l e of international bodies becomes i n c r e a s i n g l y more important, i t i s appropriate to focus on t h e i r a c t i v i t i e s i n r e l a t i o n to a n a l y t i c a l chemistry. Although there i s a common basis f o r a n a l y t i c a l operat i o n s , i t has been recognized that some agreement i s now e s s e n t i a l among i n t e r n a t i o n a l o r g a n i z a t i o n s as to the development of standard methods on a c o l l a b o r a t i v e b a s i s . In a paper presented i n 1981 at the Symposium on Harmoniz a t i o n of C o l l a b o r a t i v e A n a l y t i c a l Studies i n H e l s i n k i , F i n land, Dr. H. Egan c a l l e d f o r d i s c u s s i o n of the various p h i l o sophies adopted f o r establishment of standard methods of a n a l y s i s and emphasized the need to examine c r i t e r i a used f o r v a l i d a t i o n of methods, with p a r t i c u l a r reference to the i n t e r n a t i o n a l p o s i t i o n (8). Problems a r i s e through the absence of systematic coordination among the various bodies involved. Even though a method may have been c o l l a b o r a t i v e l y studied, p o s s i b l y on an i n t e r n a t i o n a l b a s i s , other o r g a n i z a t i o n s not involved i n the study may have no means of determining whether the method meets t h e i r needs. There i s need f o r r e c o g n i t i o n of and agreement as to the d e f i n i t i o n of a number of common a n a l y t i c a l parameters such as accuracy, p r e c i s i o n , repeata b i l i t y , r e p r o d u c i b i l i t y and l i m i t of detection and a common understanding as to where the values of the various parameters should l i e f o r the acceptance of a method or f o r the agreement as to the equivalence of methods. The f o l l o w i n g d e f i n i t i o n s were suggested f o r important a n a l y t i c a l terms (8): " L i m i t of Detection: The smallest concentration of (or amount) of substances which can be reported with a s p e c i f i e d degree of c e r t a i n t y by a d e f i n i t e , complete a n a l y t i c a l procedure . S e n s i t i v i t y : The change i n measured value r e s u l t i n g from a concentration change of one u n i t . Precision ( R e p r o d u c i b i l i t y ) : The closeness of agreement between the r e s u l t s obtained by applying the experimental procedure several times under p r e s c r i b e d c o n d i t i o n s i n an i n t e r l a b o r a t o r y study. Accuracy: The closeness of agreement between the true value and the mean r e s u l t s obtained by applying the experi-



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mental procedure a very l a r g e number of times. In p r a c t i c e t h i s should involve as many r e s u l t s as p o s s i b l e , the t o t a l number being s t a t e d . " A f u r t h e r p h i l o s o p h i c a l problem that must be r a i s e d i s that of the d e s c r i p t i o n of a n a l y t i c a l methods. The c o l l a b o r a t i v e studies used by the AOAC to support methods of a n a l y s i s have been based g e n e r a l l y on methods prepared i n standardized format i n which apparatus, reagents and procedures are r i g i d l y prescribed. During the past two decades, l a b o r a t o r i e s have acquired i n c r e a s i n g l y complex and expensive instrumentation obtained with regard to the tasks to be performed and resources a v a i l a b l e . This d i v e r s i t y has made i t more d i f f i c u l t to conduct c o l l a b o r a t i v e sudies based on r i g i d p r e s c r i p t i o n s of equipment and components, such as chromatographic columns, etc. Within recent years there have been e f f o r t s w i t h i n AOAC to write a n a l y t i c a l methods i n generic terms and conduct c o l l a b o r a t i v e studies of such methods. The methods are d e t a i l e d in terms of performance parameters rather than i n terms of specific instruments or components, thus the analyst may choose p a r t i c u l a r instrumental configurations or operating conditions as long as performance c r i t e r i a are satisfied. Several methods of t h i s type have been described, and the r a p i d adoption of automated or semi-automated a n a l y t i c a l procedures, which d i f f e r from l a b o r a t o r y to l a b o r a t o r y , makes i t important to examine method v a l i d a t i o n by c o l l a b o r a t i v e study i n the broader context of the generic d e s c r i p t i o n of methods (9-10). Methods of A n a l y s i s

and

Tolerances

Non-specific methods that employ simple methods and reagents have been f r e q u e n t l y employed f o r determination of a c t i v e ingredients. Total chlorine and acid content may, for example, be used to measure phenoxyalkanoic a c i d s . These methods have been l a r g e l y d i s p l a c e d by more s p e c i f i c methods, such as gas chromatography, but where s p e c i f i c methods are una v a i l a b l e , as i n the case of maneb, zineb, and other complex organometallic ethylene dithiocarbamate d e r i v a t i v e s , i n d i r e c t methods are used. The importance of s p e c i f i c methods can be r e a l i z e d by cons i d e r a t i o n of b i o l o g i c a l a c t i v i t y . Analysis of malathion content by t o t a l phosphorus or a c o l o r i m e t r i c method may give a s i g n i f i c a n t l y higher f i g u r e than a n a l y s i s by gas chromatography. This i s p a r t i c u l a r l y important i n terms of b i o l o g i c a l a c t i v i t y and i n d i c a t e s the n e c e s s i t y of i n d i c a t i n g the method of a n a l y s i s when the content of a c t i v e ingredient i s s p e c i f i e d by the purchaser.


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Allowance must be made f o r v a r i a t i o n from the true content of a c t i v e i n g r e d i e n t because a n a l y t i c a l methods are subject to e r r o r and v a r i a t i o n s i n c o n d i t i o n s during manufacture may a l s o cause h e t e r o g e n i t i e s of product composition. The allowance i s known as a t o l e r a n c e and represents the p e r m i s s i b l e departure from the d e c l a r e d f i g u r e . I t i s i n f l u e n c e d by: a) the r e p r o d u c i b i l i t y of the a n a l y s i s ; b) sampling e r r o r o f the product; c) demands of the buyer.

TABLE I I .

Trace Contaminants i n T e c h n i c a l P e s t i c i d e s and Formulations CHLORINATED DIOXINS AND DIBENZOFURANS ISOMALATHION NITROSAMINES CHLORINATED AZOBENZENES AND AZOXYBENZENES ETHYLENE THIOUREA

Contaminants

and Environmental Problems

The question of p e s t i c i d e residues and t h e i r environmental imp l i c a t i o n s must be considered i n the context of the a c t i v e i n g r e d i e n t and i t s accompanying t r a c e m a t e r i a l s . The IUPAC d e f i n i t i o n of a p e s t i c i d e residue i s "any substance or mixture of substances i n or on any substrate r e s u l t i n g from the use of a p e s t i c i d e and includes any d e r i v a t i v e s , such as degradation and conversion products, m e t a b o l i t e s , r e a c t i o n products and i m p u r i t i e s " (11). The s i g n i f i c a n c e of that residue depends on the t o x i c o l o g i c a l p r o p e r t i e s of the substance and the degree of exposure. Thus, by d e f i n i t i o n , m a t e r i a l s a s s o c i a t e d with the p e s t i c i d e i n the formulation must n e c e s s a r i l y be cons i d e r e d as " p e s t i c i d e r e s i d u e s " . I t i s t h e r e f o r e important that s u f f i c i e n t information be a v a i l a b l e to determine whether use of a p e s t i c i d e might r e s u l t in the occurence of residues i n a crop or a commodity, not only i n the case of the a c t i v e i n g r e d i e n t and i t s a l t e r a t i o n products, but a l s o f o r by-products of manufacture and contaminants . In recent years, there have been a number of examples of such problems (Table I I . ) . The proposed data requirements f o r p e s t i c i d e r e g i s t r a t i o n prepared by the U.S. Environmental Prot e c t i o n Agency address t h i s t o p i c . T h i s has been an extremely c o n t r o v e r s i a l r e g u l a t o r y problem. I t i s c l e a r l y important to know the composition of a p p l i e d p e s t i c i d e s i n c l u d i n g the major a s s o c i a t e d contaminants i n order to assess t h e i r p o t e n t i a l f o r environmental impact, but as the q u a n t i t a t i v e s i g n i f i c a n c e of



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contaminants decreases, a corresponding increase i n toxicol o g i c a l s i g n i f i c a n c e would seem to be a p r e - r e q u i s i t e i f quant i t a t i v e a n a l y s i s i s to be r e q u i r e d f o r l o w - l e v e l components. The r e g u l a t i o n s state that the "Agency i s proposing that a l l i m p u r i t i e s occuring i n manufacturing use products end-use products i n q u a n t i t i e s greather than 0.1 percent of the product (by weight) be i d e n t i f i e d . In a d d i t i o n , the Agency w i l l r e q u i r e f u r t h e r chemical a n a l y s i s on a case-by-case b a s i s when the manufacturing process or other product chemistry data suggests the presence of l o w - l e v e l , yet h i g h l y - t o x i c i m p u r i t i e s " (12). This approach was adopted because i n v i t r o microbial assays to screen p e s t i c i d e products f o r p o t e n t i a l l y genotoxic l o w - l e v e l components appeared to give a s u b s t a n t i a l proportion of f a l s e p o s i t i v e or f a l s e negative r e s u l t s . A number of p r a c t i c a l problems l e d to the development of these recommendations. Adverse e f f e c t s , such as unpredicted p h y t o t o x i c i t y , l e d to the r e c o g n i t i o n that some products were likely to contain manufacturing i m p u r i t i e s or contaminants that a f f e c t e d t h e i r margin of s e l e c t i v i t y when a p p l i e d to crops or t h e i r p o t e n t i a l f o r damage to neighbouring crops, as i n the case of phenoxy h e r b i c i d e s i n which e s t e r i f i c a t i o n with a l c o h o l s of low molecular weights gave v o l a t i l e e s t e r s . The r e c o g n i t i o n of the adverse consequences of contaminants has been accompanied by s i g n i f i c a n t advances i n analyt i c a l methodology. In f a c t , r e c o g n i t i o n of the problems and the development of techniques f o r t h e i r s o l u t i o n s have proceeded hand-in-hand, as i s exemplified by the chlorinated d i o x i n s and the nitrosamines. Chlorinated d i o x i n s are c h l o r i n e s u b s t i t u t e d dibenzo-j>dioxins. The most t o x i c of the l a r g e number of p o s s i b l e i s o mers i s 2,3.7,8-tetrachlorodibenzo-p-dioxin (TCDD). Chlorinated d i o x i n s , c h l o r i n a t e d dibenzofurans, and t h e i r precursors have been found i n many c h l o r i n a t e d phenols, depending on t h e i r o r i g i n and c o n d i t i o n s of s y n t h e s i s . Extensive literature now deals with the problem of the d i o x i n s and the lower l i m i t s of t h e i r d e t e c t i o n are c o n t i n u a l l y extended. The major pesticides of concern are pentachlorophenol and 2.4,5-T [(2,4,5-trichlorophenoxy)acetic acid]. Pentachlorophenol (PCP), an important wood p r e s e r v a t i v e , has been the focus of a great deal of a t t e n t i o n as a source of t o x i c contaminants. Long and painstaking i n v e s t i g a t i o n s i n t o the composition of " t o x i c f a t s " i n chicken feed revealed l i n k s between the use of pentachlorophenol f o r hide p r e s e r v a t i o n and the deaths of l a r g e numbers of chickens when the h i g h l y t o x i c halogenated d i o x i n , 1,2,3,6,7,8-hexa-chlorodi-benzo-p-dioxin, was i s o l a t e d from t o x i c f a t s (13).



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Some formation o f TCDD may occur during the a l k a l i n e h y d r o l y s i s of 1,2,4,5-tetrachlorobenzene to 2 , 4 , 5 - t r i c h l o r o phenol, (the precursor of 2,4,5-T) because the r e a c t i o n i s conducted at e l e v a t e d temperatures under pressure. In 1972, a n a l y s i s of 2,4,5-T samples by gas chromatography i n d i c a t e d that 23 of the 42 samples t e s t e d contained up t o 10 ppm TCDD (14). A r e p o r t that 2,4,5-T caused b i r t h defects i n mammals had drawn a t t e n t i o n to the problem o f 2,4,5-T and the samples used i n the t e s t s were found to contain 27+8 ppm o f TCDD as a contaminant (15>). The p o s s i b i l i t y that TCDD might enter the environment l e d the r e g u l a t o r y agencies i n 1971 t o enforce a maximum content o f 0.1 ppm TCDD i n manufacturing specificat i o n s f o r 2,4,5-T. However, improved manufacturing p r a c t i c e s had reduced the TCDD content i n most commercial grades o f 2,4,5-T g e n e r a l l y to 0.01 ppm or lower by 1980. Malathion (0,0-dimethylphosphorodithioate o f d i e t h y l mercaptosuccinate) i s used e x t e n s i v e l y throughout the world as an insecticide. I t i s p a r t i c u l a r l y useful f o r control of insect vectors r e s p o n s i b l e f o r the spread o f m a l a r i a and has replaced DDT [ l , l , l - t r i c h l o r o - 2 , 2 - b i s (£>-chlorophenyl)ethane] and benzene hexachloride as r e s i s t a n c e to these i n s e c t i c i d e s has increased. I t i s g e n e r a l l y regarded as one o f the s a f e s t organophosphate i n s e c t i c i d e s , but i n 1976 there was an outbreak o f poisoning among 7500 workers i n the m a l a r i a c o n t r o l programme i n Pakistan (16). The symptoms were t y p i c a l l y those of organophosphate poisoning and were observed with 3 formulations. However, incidence o f poisoning was g r e a t e s t with the products that contained the g r e a t e s t amount of isomalathion, a t o x i c degradation product. Poor work p r a c t i c e s r e s u l t e d i n excessive skin contact and absorption o f p e s t i c i d e , but the u n a n t i c i p a t e d t o x i c i t y provoked d e t a i l e d i n v e s t i g a t i o n of the p r o p e r t i e s o f the formulations and t h e i r s t a b i l i t y i n storage under t r o p i c a l c o n d i t i o n s . A n a l y s i s showed that these 2 f o r mulations had an isomalathion content greater than 2 percent and showed high mammalian t o x i c i t y (16). The s t a b i l i t y o f malathion and f e n i t r o t h i o n (0,0-dimethyl 0-(4-nitro-m-tolyl) phosphorothioate formulations has been i n v e s t i g a t e d (17.). A number o f products are formed when malat h i o n formulations are s t o r e d a t e l e v a t e d temperatures. However, the q u a n t i t y of S-methyl isomer (isomalathion) formed appeared to c o r r e l a t e best with increased mammalian t o x i c i t y and the r a t e o f i s o m e r i z a t i o n was dependent on " i n e r t " i n g r e d i e n t s i n the formulation. Although there was some formation of the S-methyl isomer o f f e n i t r o t h i o n , an increase i n t o x i c i t y was not observed a f t e r storage at elevated temperatures. Isomalathion may be q u a n t i t a t i v e l y determined by gas chromatography and the World Health Organization has s p e c i f i e d that the isomalathion content o f a 50 percent powder be no greater than 0.9 percent a f t e r 6 days a t 55°C.



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Several nitrosamines are known to act as mutagens or c a r cinogens i n l a b o r a t o r y animals; t h e r e f o r e , there has been a considerable effort to identify environmental sources of nitrosamines. Nitrosamines may be formed by the a c t i o n of n i t r o u s a c i d on secondary amines. Thus, there are a wide v a r i e t y of p o t e n t i a l s u b s t r a t e s , because n i t r o u s a c i d , as n i t r i t e , and secondary amines, are almost u b i q u i t o u s . The presence of nitrosamines i n p e s t i c i d e formulations u s u a l l y r e s u l t s from the byproducts of a n i t r o s a t i o n step or a r e a c t i o n between amine s a l t s of c e r t a i n p e s t i c i d e s and n i t r i t e used as a c o r r o s i o n i n h i b i t o r i n the formulated product. F l u o r i n a t e d t r i f l u r a l i n ( a , a ,a - t r i f l u o r o 2,6-dinitro-N,N-dipropyl-j>-toluidine) was found to c o n t a i n nitrosamines, and i t seems l i k e l y that these arose by the n i t r o s a t i o n of the amine used i n the condensation with the n i t r a t e d chlorobenzene intermediate i n the synthesis or by n i t r a t i o n of the product, t r i f l u r a l i n i t s e l f . Nitrosamines have a l s o been found i n other p e s t i c i d e s prepared by s i m i l a r n i t r a t i o n processes. The nitrosamines a s s o c i a t e d with phenoxy or benzoic acids formulated as amine s a l t s probably a r i s e by n i t r o s a t i o n of the amine when n i t r i t e i s used as a c o r r o s i o n i n h i b i t o r . However, the f i n d i n g of nitrosodimethylamine i n batches of dimethylamine used f o r formulations i n d i c a t e s that the question of sources may be complex. Although N-nitroso compounds may be analyzed by gas-chromatography using a number of types of detector types, a s p e c i f i c and s e n s i t i v e method i s a v a i l a b l e . The thermal energy analyser (TEA) depends on the measurement of i n f r a r e d emission generated by the decay of e x c i t e d N O 2 molecules to the ground s t a t e . The p y r o l y t i c rupture of N-NO bonds generates n i t r o s y l r a d i c a l s (ΝΟ·) which are reacted with ozone, prepared by an e l e c t r i c discharge, to give the e x c i t e d N O 2 molecules (18). The azo compound, 3,3 ,4,4 -tetrachloroazobenzene, bears a s t e r i c resemblance to TCDD. I t induces a r y l hydro carbon hydrolase a c t i v i t y i n mice and c h i c k embryos. I t may be acnegenic and i t i s a p o t e n t i a l carcinogen (19). I t has been detected as a contaminant in formulations of the h e r b i cide, propanil (3,4-dichloropropionanilide). Azobenzenes have also been detected i n commercial samples of the urea herbicides, diuron [3-(3,4-dichlorophenyl)-l,1-dimethylurea] and 1i nuron [3-(3,4-di chlorophenyl)-1-methoxy-l-methylurea 3 (20), but the amounts detected i n p r o p a n i l were hundreds of times greater than those found i n the d i c h l o r o p h e n y l u r e a herbicides. T h i s problem probably a r i s e s i n manufacture and, as i n the case of the c h l o r o d i o x i n s , i s a s s o c i a t e d with the t e c h n i c a l product. /

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Ethylene bisdithiocarbamate f u n g i c i d e s (mancozeb, maneb, nabam, zineb, etc.) may break down i n aqueous s o l u t i o n to pro duce ethylene t h i o u r e a and other degradation products. Ethy lene t h i o u r e a (ETU) produces t h y r o i d tumours i n experimental animals and i t i s a l s o t e r a t o g e n i c and mutagenic (21). Anal yses of f u n g i c i d e formulations f o r ETU content revealed that i t was present as a manufacturing impurity and i t a l s o arose as a degradation product i n some formulations during storage and handling (22-23). Thus, contaminants present i n t e c h n i c a l products may be produced by r e a c t i o n s with formulation i n g r e d i e n t s or by changes that occur under c o n d i t i o n s of storage. Specifica t i o n s , t h e r e f o r e , must take i n t o account such e v e n t u a l i t i e s and include s u i t a b l e procedures f o r a n a l y s i s or performance tests. Conclusion S p e c i f i c a t i o n s f o r formulated or t e c h n i c a l p e s t i c i d e s must be based on s a t i s f a c t o r y a n a l y t i c a l methods. C o l l a b o r a t i v e study methods that are acceptable to a number of international o r g a n i z a t i o n s are a v a i l a b l e through CIPAC-AOAC cooperation. I n t e r n a t i o n a l l y , more e f f e c t i v e use of current analytical methodology could r e s u l t from increased e f f o r t s towards har monization of methods and terminology. Although r e l a t i v e l y simple a n a l y t i c a l methods are some times u s e f u l f o r formulation a n a l y s i s , i t i s important to recognize the problems inherent i n n o n - s p e c i f i c methods and a l s o the need to detect and measure p o t e n t i a l l y harmful con taminants i n t e c h n i c a l p e s t i c i d e s or formulations.

Literature Cited 1. FAO Working Party of Experts on the Official Control of Pesticides: Section Β (Specifications), FAO Agricultural Development Paper, No. 93, "Manual on the Use of FAO Spe cifications for Plant Protection Products", Food and Agri cultural Organization of the United Nations, Rome, 1971. 2. "Specifications for Pesticides Used in Public Health", World Health Organization, Geneva, 1967. 3. Ashworth, R. deB., Henriet, J., Lovett, J.F., CIPAC Hand book Vol. 1, Raw G.R., Ed., Collaborative International Pesticides Analytical Council, Ltd., Harpenden, Hertford shire, England, 1970. 4. Lovett, J.F. in "Collaborative Interlaboratory Studies in Chemical Analysis" (IUPAC Symposium Series), Egan H. and West T.S., Eds., Pergamon Press, Oxford, 1982, P. 139.



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5. "Guidelines for Collaboration between the Association of Official Analytical Chemists (AOAC) and the Collaborative International Pesticide Analytical Council (CIPAC)", J. Assoc. Off. Anal. Chem. 1974, 57, 447-9. 6. Association of Official Analytical Chemists, Handbook for AOAC Members (5th Edition), Association of Official Analy tical Chemists, Arlington, VA, 1982, P. 28. 7. Analytical Chemistry 1978, 50, 337A-340A. 8. Egan, H. in "Collaborative Interlaboratory Studies in Chemical Analysis" (IUPAC Symposium Series), Egan, H., and West, T.S., Eds. Pergamon Press, Oxford, 1982, P. 3. 9. Kane, P.F., Stringham, R.W., Assoc. Off. Anal. Chem. 1983, 66, 513. 10. Kane, P.F., "Instrument Specification in Official Methods: A Discussion", The Referee (A.O.A.C.), 1983, 6, (9) 4. 11. Bates, J.A.R., Pure and Appl. Chem. 1982. 54, 1361. 12. U.S. Environmental Protection Agency Pesticides Registra tion; Proposed Data Requirements, 24, Nov. 1982, 40 CFR Part 158, Federal Register 1982, 41 (227) 53182. 13. Metcalfe, L.D., J. Assoc. Off. Anal. Chem. 1972, 55, 542. 14. Woolson, E.A., Thomas, R.F., Ensor, P.D.J., J. Agric. Food Chem. 1972, 20, 351. 15. Courtney, K.D., Gaylor, D.W., Hogan, M.D., Falk, H.J., Bates, R.R., Mitchell, I., Science 1970, 168, 864. 16. Baker, E.L., Jr., Warren, Μ., Zack, Μ., Dobbin, R.D., Miles, J.W., Miller, S., Teeters, W.R., The Lancet 1978, 31-34. 17. Miles, J.W., Mount, D.L., Starger, M.A., Teeters, W.R., J. Agric. Food Chem. 1979, 27, 421. 18. Kearney, P.C., Pure and Appl. Chem.. 1980, 52, 499-526. 19. Bunce, N.J., Corke, C.T., Merrick, R.L., Bright, J.H., Chemosphere 1979, 8, 283. 20. Sundström, G., Jansson, B., Renberg, L., Chemosphere, 1978, 7, 973. 21. Vettorazzi, G., Residue Reviews, 1977, 66, 137. 22. Bontoyan, W.R., Looker, J.B., Kaiser, T.E., Giang, P., Olive, M.B., J. Assoc. Off. Anal. Chem., 1972, 55, 923. 23. Bontoyan, W.R., Looker, J.B., J. Agric. Food Chem., 1973, 21, 338. RECEIVED

March 30, 1984


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