DEVELOPMENT of ROTENONE and SIMILAR SUBSTANCES as INSECTICIDES ROLAND M. WHITTAKER Chemical Laboratories of Brooklyn College of the College of the City of New York
This article is a brief review of the history, dmelopment, and uses of plant fish poisons as insecticides. The phnt sources are giwen, the methods of preparation described, and s o w commercial aspects of the topic discussed. The active constituents of d ~ r i and s cubb,+.mmely rotenone, deguelin, and kphrosin are described. All references to the literature have been carefully given.
W
RITTEN records indicate the use of certain tropical plants as fish poisons and arrow poisons by the aborigines of South and Central America, Southeastern Asia, and the East Indies since the middle of the eighteenth century, although there is no doubt that the natives used the plants for these purposes long before that time ( I , 2,3). I n the case of the fish poisons the natives simply pounded certain portions of the plants, usually the roots, into a pulp and threw the pulp into fish-inhabited waters. In a relatively short time the fish were either dead or stunned and could be collected and eaten either raw or cooked. These facts were not much more than interesting topics for the curious until the recent concerted action on
the part of several governments to eliminate poisonous agricultural spray residues on agricultnral products. Then a search began for some substance toxic to insects but harmless to man. It was known that the root of the tuba, a low-climbing plant, had long been used by the Chinese as an insecticide -and that it was also one of the native fish poisons. This indicated that not only tuba root but all the plant substances used as fish poisons were worth investigating for their probable insecticidal value. In the past ten years we have learned many things about the use of these plants and their extracts as insecticides. Some of this information is summarized in the followingreview. PLANT SOURCES
Most of the plants from which the active constituents of fish poisons are derived belong to the Fabacee family ( 4 ) , also called Leguminosre or Papilionaceae. The genera which exhibit the insecticidal properties to the greatest extent are Derris Lour., or Deguelia, Lorachocurp2ds, and Cracca, although many others are known to contain the most active fish poison yet isolated in the pure state, namely rotenone. At the present time nearly all the commercial development has been
carried on either with roots of Derris ellipica or cube (L. nicou). According to Roark (4) derris is a vine-lie plant that climbs over adjacent timber and grows largely in eastern Asia. Cub6 root is obtained from a tree that reaches slightly taller than a man and grows extensively in Central and South America. Although in 1920 derris and cube were cultivated to some extent their use was restricted almost entirely to the neighborhood of their growth. In 1932 it was estimated (5) that 5,000,000 pounds of derris were cultivated annually in Johore, Federated Malay States, Java, and neighboring countries. From data based on the relative toxicity of the active constituents of derris and tobacco (6) it is estimated that this amount of dems was equivalent to 93,750,000 pounds of tobacco. As a cultivated product cub6 has not been developed to the same extent as derris, although some plantations have begun operation in Central and South America. Clark (7) isolated some of the active ingredients of derris from a plant native to North America, Crnccn uirginiana. This plant is described as being from 10 to 12 inches high, with an extended root system, occurring from New Hampshire to Florida, the Atlantic coast to the Mississippi valley. It is known by various names, such as goat's rue, wild sweet pea, turkey pea, devil's shoestrings, etc. (8). It should not be confused with vetch which it resembles to some extent. Recently Clark (7) reported obtaining a 4 6 % extract from. the roots of this plant which had a toxicity equal to that of pure rotenone on fish. The extract contained some rotenone, tephrosin, and other similar substances. This plant may be a possible source of an insecticide and anthelmintic that the farmers of the United States might well investigate.
fully purified, rotenone crystallizes from alcohol in transparent hexagonal plates and melts at 163°C. It is dimorphous, being converted into isorotenone upon treatment with sulfuric acid (46). Rotenone is subject to oxidation and reduction, giving rise to several substances in either case, depending upon the conditions and the reagents used. From the viewpoint of general use the oxidation of rotenone is considered quite important since the products of oxidation usually are less toxic to insects and fish (27). H. A. Jones (47) found that rotenone in various solvents was converted more or less rapidly into rotenolone and dehydrorotenone. As a result ef these experiments it was concluded that care must be taken in selecting a solvent for rotenone preparations, that air should be excluded from the solution container, and that rotenone should he stored in dry containers, as dry rotenone undergoes no decomposition on standing (16, 28, 30). Determination of the probable structure of rotenone has been one of the major steps in the recent development of organic chemistry. For a detailed discussion of this work and a more thorough outlime of the results of oxidation and reduction see the review of LaForge, Haller, and Smith (17). The accepted formula is:
THE ACTNE CONSTITUENTS
At the time of writing rotenone has not yet been synthesized. Rotenone was found to be fairly soluble in several organic solvents hut quite insoluble in water, although water emulsions can easily 'be prepared (18). Deguelin has the structure (12):
A detailed chemical examination of derris showed that the toxicity to fish and insects was due largely to the presence of four substances, rotenone (9),toxicarol (10, l l ) , deguelm (10, 12), and tephros+ (10, 13, 19). Rotenone, the most toxic of those named, was first isolated by Geoffroy (45) in 1895 from what was then called Robinia nicou but is now known as Lonchocarpus nicou. The.substance isolated by Geoffroywas called nicouline and was later found to be identical with a substance isolated by Nagai (9) from derris root and named by him after the Japanese name of the plant, "Rho-ten." These substances occur in widely varying amounts in the commercially available plant materials. An effort is made, however, to keep the rotenone content of the roots sold as good-grade root from 2.5% to 6% (14). Roots are usually sold on the basis of their rotenone content, which can be determined by several methods, but which is probably most easily estimated by extraction of the finely ground, airdried roots with carbon tetrachloride and crystallization of the rotenone from the extracting solvent (15). Rotenone can also be extracted from the plant material by many other organic solvents. When care-
OCH,
H
Deguelin
Tephrosin is a hydroxy deguelin with the hydroxyl group attached to carbon 7 or 8 in the formula given for deguelin (20). As late as July, 1934, the exact structure of toxicarol had not yet been determined (Zl),but Clark (11) gives part of the formula as represented. The nature of the CsH?O group and the exact nature of its attachment to the rest of the molecule are not known.
and their derivatives. Using goldfish as test animals, Gersdorff (25) found the relative toxicities to be: rotenone, 100; toxicarol, 65; deguelim, 56; tephrosin, 23. When used against the Aphis rumicis, Davidson (26) found aqueous suspensions of rotenone, deguelin, tephrosin, and toxicarol to have relative toxicities of 400, 40, 10, 1, respectively. A study of the toxicities of various derivatives of rotenone showed the following decreasing order of toxicity to goldfish: dihydrorotenone, rotenone, acetyldihydrorotenone, dihydrorotenoSome investigators are of the opinion that tephrosin lone, acetyldihydrorotenolone, and acetylrotenolone does not occur native in the plant but is formed during the isolation of rotenone, deguelin, and toxicarol from (27). From the above i t is obvious that until better the plant sources (22). These substances niay be criteria can be established, the relative toxicities of classified into three groups (21). The rotenone group is derris or cube preparations as insecticides should be characterized by an optically active dihydrobenzofuran indicated by their rotenone content. Rotenone compares very favorably with other system, with an isopropenyl side chain connected to the insecticides now in use. Darley (29) reports that dihydro-y-pyrone system. The degnelin group, inrotenone a t a concentration of 1 : 100,000 compared cluding deguelin itself and tephrosin, has an optically inactive dimethyl-dihydro-a-benzopyran system in favorably with nicotine a t 1:10,000 and with pyrethrins place of the dihydrobenzofuran of rotenone. The third a t 1:74,800, when used on two species of aphids. group includes toxicarol, the structure of which is not Shepard (30) claims that rotenone is more toxic to the yet definitely known, although it is known that it con- Aphis rumicis and to mosquito lam= than is nicotine. tains neither the dihydrobenzofuran nor the benzopyran Davidson (31) quotes experiments to show that on the Aphis rumicis rotenone is fifteen times more effective system. than nicotine. One pound of derris root (rotenone conThe structures of several other fish poisons from tent not mentioned) was found to be equivalent to plants other than cub6 or derris have been determined by Spath. None of these is of commercial importance 1.5 pounds to 2.5 pounds of calcium arsenate against the a t the present and none is closely related to rotenone in Colorado potato beetle (34). Against silkworm rotestructure, nevertheless it will be noted in the three none was thirty times more toxic than lead arsenate (35). formulas given below that they are also oxygen hetero- It must not be assumed from these statements that cyclics, containing the a-benzopyrone nucleus instead rotenone or its preparations are always effective. of the y-benzopyrone system of rotenone. Peucedanin Cases have been reported where rotenone was not as toxic as pyrethrins, nicotine, or other common insectiand oremelon from Peucedanum oiqicinale (23): cides (32). Gnadinger (33) 'x'eports that rotenone in an oil base is not as toxic as a similar pyrethrin preparation and that addition of rotenone to pyrethrin preparations does not increase the toxicity to flies. The grasshopper seems to be particularly resistant to rotenone (48). Rotenone and its various preparations have been more or less effective for the control of aphids, thrips, white fly larvzs, leaf hoppers, lanrg of beetles, tent caterpillars, chicken lice, roaches, cabbage worms, and mosquitoes (6), moths and moth l a m e (36), raspberry beetles (37),sheep tick (43),and numerous others (38). Rotenone is generally slower in action than other well-known insecticides now in use (49). The rotenone preparations show exceptional value Osthol from Imperatoria ostruthium (24): when their low toxicity to warmblooded animals is considered. When administered through the mouth pure rotenone produces no visible effects in dogs, cats, pigs, or sheep, in doses up to one grain per pound of body weight (39). Haag (40) reports that continued feeding of small doses of rotenone to dogs, cats, rabbits, pigeons, etc., caused death in 50% of theanimals without pronounced symptoms and no pronounced changes Osthol in the organs. Given intravenously, rotenone caused Some interesting facts regarding the relationship be- first stimulation of respiration, followed by periods of tween chemical structure and physiological behavior apniea and death due to respiratory depression. Derris have been brought out in the study of the comparative preparations and rotenone are thought to have little toxicities of rotenone, toxicarol, deguelii, tephrosin, permanent effect upon bacteria or fungi. They do.
however, destroy some protozoa (41). A most interesting use of rotenone as an anthelmintic has recently been made public. Crane (42) has found that rotenone fed to dogs in doses of 0.05 gram per kilogram of body weight is effective against the dog hookworm and round worm, is not effective against the dog coccidium, and is inefficient against canine tapeworms. Crane further states that doses as high as 0.2 gram per kilogram of body weight are not toxic to dogs, although doses of 0.1 to 0.2 gram caused transitory gastritis. The author of this paper has experimented to some extent with chickens along these lines and bas provided Dr. Glover of the Ontario Agricultural College with a supply of rotenone to continue the work. COMMERCIAL ASPECTS
Practically all the rotenone preparations now manufactured are made from materials imported to the United States either as dried roots or as concentrated extracts of the roots. Because of the relatively high cost, little pure rotenone is used. Commeroial preparations consist of ground dried roots with or without inert material and the extracts of the roots in various organic solvents. The roots as received in this country have usually been sufficiently dried and are immediately chopped and ground to a fine powder. Some industrial hazard is involved at this point, in that the roots frequently catch fire during the grinding unless special precautions are taken (28). Workmen not carefully protected from flying particles of derris dust have been known to have numb or irritated throats. This action is not permanent and R. W. Birdsall (28) reports that fresh air will eliminate the effects. Nevertheless, care should be taken in the chopping and grinding process. After grinding and mixing, the roots are usually analyzed. The analysis determines the next step in the process. If, for example, the roots were found to analyze 4% rotenone and a commercial dust of 1% rotenone content was desired, the roots would be carefully diluted, either with root from which the rotenone had previously been extracted or with some inert daterial such as kaolim. If an extract is required a definite amount of the root is extracted and the extract is diluted to obtain the final concentration desired. It will be noted that the assumption is made that all the rotenone is extracted from the root. This is probably true and most commercial houses sell their extracts upon the basis of the
amount of the rotenone originally in the root. Few companies analyze their finished extracts for rotenone content. Some do run Feet-Grady kill tests (50) on their extracts and standardize their products in this way. Derris and cube extracts are usually sold with alcohol, alcohol-acetone, acetone, kerosene, and other light fractions of petroleum as solvents. Many manufacturers combine the value of pyrethriis with rotenone by placing them both in their extract mixtures. Since rotenone is readily oxidized in aqueous solution the stock extracts usually contain only the organic solvent mixture, emulsifying agents, derris and pyrethrin extracts, and various essential oils. The extracts usually contain about 1% rotenone (although almost any concentration can be obtained if desired) and are much more concentrated than need be for common spray use. They are diluted with water just before use and sprayed in the form of a suspension. These dems extracts when used in sprays will eventually lose their toxic action. It is hard to estimate just how quickly this loss occurs. Jones (44) claims that derris root and derris root extracts lost more than half their toxicity during a ten-day exposure to sunlight. The prices for the raw materials and some of the finished products are quoted below. The cost of derris derivatives is gradually being reduced. Crude root (varier with rotenone content) Grovnd derrip dust (1% rotenone content) Ground d m i n dust (4% rotenone content) Ground derri. du3t (5% rotenone content)
Extract concentrate (25% rotenone) Extract (5% rotenone content) c . ~rotenone .
$0.25 per lb. 0.18 w lb. 0.34 per lb. 0.41 per lb. 5.00 per 10 lbr. 9.00 per galloo 25.00 per lb.
CONCLUSION .. I t will be seen from the foregoing review that from the commercial as well as the purely scientific angle rapid strides have been made in this relatively new field. From the commercial side there is the possibility of the development of other plant fish.poisons as insecticides and the intensive cultivation of t h e present known sources of these substances. From the scientific side the opportunities are almost limitless. There is the synthesis of rotenone to be completed, the study of the toxicities of the various parts of the rotenone molecule with a view to some cheaper synthetic substitute for this and similar substances, an?l a unique opportunity to study the relationship between chemical structure and physiological action.
LITERATURE CITED
G. E. RUMPHIUS, "Herbarium Amboinense," Amsterdam. 1747, Pt. 5, pp. 37-8. T. J. NEWBOLD. "Political and statistical account of the British Settlements in the Straits of Malacca." London, 1839, Vol. 2, pp. 398404. ANONYMOUS, "Poisonous plants of the Malay Peninsula." Malay Peninsula Agri: Bull.. 8,217 (1898). R. C. ROAR& "Chemical relationship between certain species of fabaceaus plants," J. Econ. Entomol., 26, 58794 (June, 1933). R. C. R o m , "Derris now produced on a large scale," ibid., 25, 1 2 W 5 (Dec.. 1932).
(6) W. M. DAVIDSON, "Rotenone as a contact insecticide," ibid., 23, 868-74 (Oct., 1930). (7) E. P. CLME. "The occurrence of rotenoneand related compounds in the roots of cracca uirginiane," Science (N. S.), 77, 311-2 (March, 1933). (8) A. E. GEORGIA, "A manual of weeds." Maemillan Company. New,York City. 1914, p. 238. (9) K. NAGAI,"Uber Rotenon, ein wirksamen Bestandteil der Derris Wurzel," J. Chem. Soc. Tokyo, 23, 740 (1902). (10) E. P. CLARK,"Some constituents of derris and cub6 roots other than rotenone," Science (N. 8.). 71, 396 (April 1930).
nicotine, and pyrethrins," J. Econ. Enlomol., 24, 111-5 (111 E. P. CL-. "Toxicarol I: A constituent of the South >--, (Feh., 1931). American fish poison cracco lozicara," J. A n . Chem. Soc., H. H. MPARD, "The relative toxicity of rotenone and nico52, 24614 (June, 1930); "Toxicarol 11: Some acetyl tine to Abhis rumicir L. and mosouito l a m . " ibid... 24. derivatives of toxicarol," ibid., 53, 2264-71 (June, 1931); 725-31 (june. 1931). "Toxicarol 111: A relation between toxicarol and the W. M. DAYIDSON, "Rotenone as a contact insecticide," rotenone a o u o of fish ~oisons." ibid., 54, 1600-2 (April, ibid., 23,868-74 (Oct., 1930). 1932); " ~ o x k a r o l IV: Concerning the structure of J. M. GINSBURG AND J. B. Sc~nam~r. "A comparison between toxicarol," ibid., 54, 2537-48 (June, 1932). 25. rotenone and wrethrins as contact insecticides." Qid..~. (12) E. P. CLARK,"Deguelm I: Preparation and purification of 918-22 (AU~.; i932). deeuelin." ibid.. 53. 313-7 (Jan.. 1931); "Deguelin 11: AND C. S. CORL,"Relative toxicity of C. B. GNADINGER ~ d a t i o n s h i pbitween degueh and rotenone,"~ibid.. 53, nvrethrins and rotenone as flv SDraV inmedients." 2369-73 (June, 1931); "Degueiin 111: The orientation of the methoxyl groups in deguelin, tephrosin, and A. KELSALL,J. P . SPITTALL,. R. P. GORHAM, AND G. P. rotenone." ibid.. 53. 3431-6 (Sept.. 1931); "2.4.5-TriWALKER, "Derris as an insecticide," Ent. Soc. Onferio methowbenzoi
