Responsibilities of the Chemist in the Development of Insecticides W. H. TISDALE and JONATHAN W. WILLIAMS
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Grasselli Chemicals Department, E. I. du Pont de Nemours & Company, Inc., Wilmington, Del.
The chemist must work with the entomologist, the toxicologist, and others concerned in the formulation of new and better insecticides, or in the improvement of old ones. All formulations must be tested to determine their insecticidal efficiency, as well as their toxicity to warm-blooded animals, before manufacture on a large scale is begun.
T h e successful development of insecticides requires a broad and thorough knowledge of the ever-changing and unfilled needs for better products, and of the fields of chemistry, physics, engineering, and biology that pertain to the development of better insecticides. The research chemist must understand and appreciate teamwork. The development of insecticides depends on close cooperation of the research, manufacturing, and analytical chemists with the entomologists, toxicologists, and others who m a y be directly or i n directly interested i n the program. I t is especially important that the research chemist have a thorough knowledge of organic chemistry and of the methods of organic synthesis. H e should also have a sufficient knowledge of biology to enable him to understand the biochemical structures and functions of insects and their plant and animal hosts on which the insecticides are to be used. Such information is helpful i n understanding the action of insecticides and may also point the way to the discovery of more effective and safer chemicals for insecticidal use. The chemist should have a general knowledge of chemical research i n other laboratories, from which products of insecticidal value may be obtained. Needs for Better Insecticides More effective and safer insecticides are needed, i n spite of the extensive progress made i n recent years. The chemist should familiarize himself with the needs i n the agricultural, storage, household, livestock, and industrial fields. The weak and strong points of the products i n use should be understood. Some of the commonly used products need better formulations, or better methods of application with the use of more effective supplements. Better products should replace some of those now i n use. Statistical evidence of ample potential should be available before work on a problem is begun. Several factors may govern the fitness of a product for a given use. Changes i n biological factors may render the insecticide unsuited for use. A new variety of the host, or crop plant, may be injured b y the insecticide, or a strain of the insect that is resistant to the chemical may evolve as a result of continued use. I n such cases a modification of the insecticide to render i t more effective, or a replacement, must be found. Certain insecticides, including the arsenicals and some of the newer chlorinated compounds, although they are safe when applied to foliage, accumulate i n the soil to the extent of eventually causing injury to crops. A new insecticide must be compatible with other insecticides, fungicides, and supple-
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merits with which it may be used. This involves the need for a knowledge of all such compounds that come into extensive use. For some important insect pests there are still no satisfactory chemical controls. Such problems should be given due consideration i n the development program. M a n y of these problems appeared to be solved with the discovery of D D T , benzene hexachloride (hexachlorocyclohexane), and some of the more recent insecticides. Further studies of the toxicity of some of these products to warm-blooded animals have raised the important question of the advisability of continuing their use where food and feed products are concerned. Considerable attention is being centered on rinding safer analogs, such as T D E and methoxychlor, and new and better insecticides.
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Synthetic Organics Synthetic organics dominate the field of new insecticides. M u c h time and money have been spent i n attempting to determine the chemical structures of rotenone, pyrethrum, and other natural insecticides, and to reconstruct them through synthesis. A great deal has been learned about the chemical structures of these compounds, but little success has been attained toward synthesis. Nicotine and, recently, a pyrethrumlike compound are exceptions, but the synthesis of nicotine is too expensive to be practical. The basic information obtained has possibly been helpful i n directing the thoughts of the chemist to the synthesis of entirely new compounds. A l l available information that offers possibilities must be used. However, what appears to be logical theory may not prove up i n the selecting of chemicals for insecticidal purposes. The chemical structure that, according to such theory as can be drawn from available knowledge, should be effective often proves ineffective, whereas structures considered ineffective under the same system of theorizing may prove to be effective. Much still depends on the " c u t and t r y " method. The chemist should explore the fields of chemicals with structures related to compounds known to be effective. H e should also study new classes of structures. Safety appears to lie i n numbers. The failure of several members of a new class of compounds does not prove that there are no effective members i n the group. Only certain of the analogs of D D T are good insecticides. E v e n D D T is not effective on some species of insects. Only the gamma isomer of benzene hexachloride is highly effective. The possibility of finding an insecticide that is safe to plants and warm-blooded a n i mals and universally effective appears remote. However, investigations have uncovered a few very promising products. A n outstanding example is methoxychlor, one of the analogs of D D T , which is far less toxic to warm-blooded animals than D D T . Poisonous insecticides are being used extensively. However, safety to plants and warm-blooded a n i mals, including man, should be one of the leading goals of the development program. The statement that " i t is hard to find a chemical that w i l l k i l l protoplasm and not k i l l protoplasm" overlooks the fact that some chemicals have properties that enable them to reach the living protoplasm of one organism and not that of another. M a n y factors may be involved. The chemist should be prepared to take full advantage of such differences. A thorough understanding of the chemical and biological actions involved is valuable.
Formulation The effective use of insecticides depends to a large extent on formulations prepared for or adjusted to specific uses. Seldom is an insecticide used i n its pure or technical form. I n order to do an efficient job of formulating insecticides, the chemist should know how they are to be used and b y what type of machine they are to be applied. Is the insecticide to be used as a spray, mist, fog, dust, aerosol, or dip? W i l l i t be applied to plants, v a l u able animals, or humans? W i l l i t come i n contact with humans or products that may be used for food b y humans or valuable animals? W i t h this information at hand, suitable carriers, solvents, and wetting, emulsifying, spreading, penetrating, stabilizing, and sticking agents may be selected for trial. A n extensive knowledge of possible supplements is desirable. The supplements must be compatible with the active chemical and with other AGRICULTURAL CONTROL CHEMICALS Advances in Chemistry; American Chemical Society: Washington, DC, 1950.
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supplements used. The use of synergists may be considered. T h e finished formulations must be stable i n storage and compatible with other chemicals, including other insecticides and fungicides with which they may be used. This involves a knowledge of the chemistry of fungicides and other chemicals that may be used i n conjunction with the insecticide. The preparation of formulations may involve the principles of physics and mechanics. T h e preparation of emulsions, fine particle materials, etc., constitutes an important part of insecticide development. A knowledge of the kinds of equipment used i n the preparation of formulations enables the chemist to handle the job with greater facility. Formulation is not confined to the preparation of suitable mixtures of new chemicals. M a n y old or established insecticides have been improved and i n some cases have been adapted to new uses through the development of new and suitable formulations. T o see and take advantage of these opportunities, the chemist must be familiar with the weak and strong points of the products i n use. Close cooperation with entomologists is necessary. A l l formulations should be thoroughly tested i n the laboratory and/or greenhouse to determine their insecticidal efficiency. Products that survive reasonably severe preliminary tests are ready for field trials. Extensive chemical work often is required to readjust the formulations as the laboratory and field trials are i n process. I t may take months or even years to arrive at a suitable formulation for some uses after the chemical is known to have outstanding merit. E v e n when a formulation has been proved satisfactory for a certain use, much remains to be done i n the development of suitable formulations for other uses and i n following through with the effective product. I t may be desirable to develop means of removing residues of the product from treated surfaces.
Toxicology Among the most important characteristics of an insecticide is its safety to humans. In recent years the United States Government, state authorities, and commercial organizations have given special and extensive attention to toxicity problems and to the safe use of toxic products. N e w insecticides are being thoroughly studied b y competent toxicologists. Unfortunately, some of the outstanding new chlorinated compounds are not as safe as they were once thought to be. I t has been necessary to modify or even withdraw claims concerning their safety to humans and specify methods of safe use, but advantage is still being taken of the original claims of safety i n some Latin-American countries, for instance, where poisonous products are recommended for use on stored grain and other food products. In order to avoid hazards to the chemist and his associates as well as to the user and consumer of treated products, a chemical showing sufficient promise should be subjected to acute toxicity tests b y a competent authority i n its early stages of development. Further experimental work should be governed b y the outcome of these tests. If toxic, i t should be handled with care. If symptoms of poisoning do not occur, the product should still be handled with reasonable care until chronic toxicity studies can be made. Such studies are expensive, and, as a rule, elaborate chronic studies are not considered necessary until it is reasonably certain that the product w i l l be put into use. A t this stage the question of public health becomes an important factor. Further toxicological studies, including those of chronic nature, may be required, so that effective directions for safe use may be issued. Attention should be given to the safety of any new formulations of the product once i t is i n use. New or modified formulations of old poisonous insecticides should be considered and the necessary directions for safe use be given. This may or may not involve the need for toxicological investigations.
Manufacture After a product has passed the critical tests as an insecticide and a preferred process of manufacture has been decided upon, full information concerning use, potential raw m a terials, and process is the basis for the preparation of firm cost estimates. These estimates may cover production on a small or pilot plant scale, or on a large scale. If estimates are favorable, the process information is passed along to the manufacturing unit which, as a AGRICULTURAL CONTROL CHEMICALS Advances in Chemistry; American Chemical Society: Washington, DC, 1950.
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rule, prepares for manufacture on a pilot plant basis. The research chemist should m a i n tain close cooperation with the manufacturing unit to ensure getting the process properly established for uniform production of a high-grade material. The analytical chemist should make regular checks on quality of production. When this pilot plant product goes into limited commercial use, the entomologists and chemists concerned should follow the results closely, to be sure that the product is up to standard i n a l l respects under different environmental conditions. Its stability under different storage conditions should be studied. Compatibility under conditions of use with other products with which it may be used is important. Everything possible should be done to assure its success at this point and to be sure that it merits large scale production. If the product survives the pilot plant stage of development and sufficient potential use is indicated, it passes to large scale production, where the responsibility shifts largely to the manufacturing and analytical chemists to produce a uniform, high-grade product. Interest of the research chemist should continue through cooperation with the manufacturing chemist, the entomologist, and the technical sales service men with the purpose of maintaining high efficiency and correcting any unforeseen weaknesses in the product.
AGRICULTURAL CONTROL CHEMICALS Advances in Chemistry; American Chemical Society: Washington, DC, 1950.
