The metabolism of fenvalerate in plants: The conjugation of the acid moiety

The metabolism of the pyrethroid insecticide fenvalerate [(RS)-α-cyano-3-phenoxybenzyl (RS)-2-(4-chlorophenyl)-3-methylbutyrate] ( I ), and of its most insecticidal (αS,2S) isomer ( II ), has been examined in cabbage plants grown and treated under laboratory conditions with [¹⁴C]chlorophenyl- and [ring-¹⁴C]benzyllabelled preparations of the two compounds. Both insecticides disappeared from the treated leaves with similar half-lives of approximately 12–14 days; they underwent ester cleavage to a significant extent, together with some hydroxylation at the 2- or 4-position of the phenoxy ring, and hydrolysis of the nitrile group to amide and carboxyl groups. Most of the carboxylic acids and phenols thus produced occurred as glycoside conjugates. In separate experiments, the uptake and metabolism of 2-(4-chlorophenyl)-3-methylbutyric acid ( X ), the acidic half of the molecule, were examined in the laboratory, using abscised leaves of kidney bean, cabbage, cotton, cucumber and tomato plants. The acid X was found to be readily converted, mainly into glucose and 6-O-malonylglucose esters in kidney bean, cabbage and cucumber plants, into glucosylxylose, sophorose and gentiobiose esters in cotton, and into two types of triglucose esters with differing isomerism in tomato. One of the acetyl derivatives of the trisaccharide conjugates was identical with the synthetic deca-acetyl derivative of the [1 → 6]-triglucose ester.     

Pyrethroid insecticides derived from substituted biphenyl-3-ylmethanols

The synthesis of a series of mono- and disubstituted biphenyl-3-ylmethyl esters of 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid is described. The bioactivity of these compounds against Spodoptera eridania, Epilachna varivestis, Oncopeltus fasciatus, Acrythosiphon pisum and Tetranychus urticae is presented and discussed. Substitution of fluorine, chlorine and methyl groups in the 2-position of the biphenyl ring generally led to an increase in activity over the unsubstituted parent biphenyl ester. In addition, pyrethroid esters derived from these 2-substituted biphenyl-3-ylmethanols appeared to have a broader spectrum of activity than ‘classical’ pyrethroids. For example, the (1RS)-cis-3-(2,2-dichlorovinyl)-2, 2-dimethylcyclopro-panecarboxylic acid ester of 2-methylbiphenyl-3-ylmethanol was acaricidal, while maintaining a level of activity against other insects that was equal to or greater than cis-permethiin. Biological data on other esters of this novel alcohol are also presented.     

The pyrethrins and related compounds. Part XXII. Preparation of isomeric cyano-substituted 3-phenoxybenzyl esters

Preparation of 3-phenoxybenzyl chrysanthemates and their dihalovinyl analogues substituted with a cyano group at the 2-, 6-, (R)-α-, or (S)-α- positions is described. The (R)- and (S)- isomers of α-cyano-3-phenoxybenzyl esters of 2,2-difluoro-, -dichloro-, and -dibromo-vinyl analogues of cis- and trans- chrysanthemic acid are separated chromatographically, as are the separate pairs of enantiomers of fenvalerate, (RS)-α- cyano-3-phenoxybenzyl (RS)-2-(4-chlorophenyl)-3-methylbutyrate. An optically active ester of α-cyano-3-phenoxybenzyl alcohol (obtained using D -oxynitrilase) with 2,2,3,3-tetramethylcyclopropanecarboxylic acid is synthesised.     

Disposition kinetics,cytotoxicity and residues of fenvalerate in tissues following oral administration to goats

Disposition kinetics in goats of fenvalerate [(RS)-α-cyano-3-phenoxybenzyl (RS)-2-(4-chlorophenyl)-3-methylbutyrate] were studied after oral administration at 5 mg kg^?1. The insecticide persisted in blood for up to 48 h. The V_d(area), t_1/2(β), and t_1/2(Ka), of fenvalerate were 12.14 (±0.39) litre kg^?1, 12.25 (±0.25) h and 0.63 (±0.11)h, while the AUC and Cl_B values were respectively 7.35 (±0.39) μg h ml^?1 and 0.68 (±0.04) litre kg^?1 h^?1. The residues in tissues reached a peak four days after insecticide administration and then started to decline. Maximum residue was found in the adrenal gland, followed by liver, kidney and intestine. Both GOT and GPT activities in kidney tissue, but only GPT activities in liver tissue had decreased significantly 4, 8 and 22 days post-administration. The fenvalerate did not produce any significant effects on serum acetylcholinesterase, cholesterol or protein levels in goats. Histopathological examination showed fatty changes in the periphery of lobule, congestion in sinusoid, haemolysis in central vein, necrosis and periportal fibrosis around the central vein of liver, and necrosis in kidney of fenvalerate-treated goats.     

Separation and identification of short-lived free radicals formed by photolysis of the pyrethroid insecticide fenvalerate

Using a spin-trap reagent 3-nitrosodurene (1,2,4,5-tetramethyl-3-nitrosobenzene), the short-lived free radicals generated by ultraviolet irradiation of fenvalerate [(RS)-α-cyano-3-phenoxybenzyl (RS)-2-(4-chlorophenyl)-3-methylbutyrate] in degassed benzene or dichloromethane, were scavenged as the more stable nitroxide radicals. These radicals were separated by high-performance liquid chromatography and identified individually by electron-spin resonance spectroscopy, as well as by gas chromatography/mass spectrometry. As a result, they were found to be the spin adduct mixtures of the 4-chloro-α-isopropylbenzyl and α-cyano-3-phenoxybenzyl radicals, which are involved in the photo-induced decarboxylation process of fenvalerate. Discrimination of the radicals was also performed by the isotope-labelling method whereby the benzylic proton in the acid moiety was deuteriated. The spin numbers of the nitroxides decreased by about five-fold when photolysis was carried out in oxygenated benzene solution. N-Benzylidene-tert-butylamine N-oxide trapped both radicals but much less efficiently. The nitroxide of the 4-chloro-α-isopropylbenzyl radical was predominant at 25°C or –40°C, but the proportion of the α-cyano-3-phenoxybenzyl nitroxide radical increased at the lower temperature.     

Insecticidal activity of the pyrethrins and related compounds. Part XI. Relative potencies of isomeric cyano-substituted 3-phenoxybenzyl esters

The insecticidal activities to Musca domestica L. and Phaedon cochleariae Fab. of a series of 3-phenoxybenzyl pyrethroid esters with a cyano substituent at the 2-, 6-. (R)-α-, or (S)-α-position are compared with those of the unsubstituted analogues. Only an (S)-α-substituent enhances activity; others diminish or almost eliminate it. (RS)-α-mixtures are generally less active than would be predicted from the potencies of their separate constituents.     

Synthetic pyrethroids: Toxicity and synergism on dietary exposure of Tribolium castaneum (Herbst) larvae

The potency of six dietary pyrethroids, as toxicants and inhibitors of weight gain in first- and fourth-instar Tribolium castaneum (Herbst) larvae, decreased in the order of cis-cypermethrin and deltamethrin > trans-cypermethrin and cis-permethrin > fenvalerate and trans-permethrin. Dosages that reduced larval weight also delayed pupation and emergence, probably due to their antifeeding activity. Three oxidase inhibitors (piperonyl butoxide, O, O-diethyl O-phenyl phosphorothioate, and O-isobutyl O-prop-2-ynyl phenylphosphonate), at a dietary concentration of 100 mg kg^?1, had little or no effect on the toxicity of trans-permethrin, but strongly synergised the toxicity of cis-cypermethrin by about 3-, 3- and 10-fold, respectively. Piperonyl butoxide also synergised the toxicity of cis-permethrin, trans-cypermethrin and deltamethrin, but not that of fenvalerate. On the other hand, an esterase inhibitor, profenofos, did not enhance the potency of any of the α-cyano-3-phenoxybenzyl pyrethroids. Oxidases appear to be more important than esterases in pyrethroid detoxification by T. castaneum larvae.     

Structure—activity relationships in pyrethroid esters derived from substituted 2-phenoxy-3-methylbutanoic acids

Non-cyclopropane pyrethroid esters of different substituted 2-phenoxy-3-methylbutanoic acids have been synthesised using the three alcohols—3-phenoxybenzyl alcohol, α-cyano-3-phenoxybenzyl alcohol and 3, 4-methylene-dioxybenzyl alcohol. Among the 35 esters synthesised and tested against Culex quinquefasciatus Say, the Bancroftian filariasis vector, for both larvicidal and adulticidal activities, α-cyano-3-phenoxybenzyl 2-(4-fluorophenoxy)-3-methylbu-tanoate, with an LC₅₀ value of 2.5 × 10^?3 mg litre^?1 for larvicidal activity, and α-cyano-3-phenoxybenzyl-2-(4-chlorophenoxy)-3-methylbutanoate, with an LD₅₀ value of 30 times; 10^?4 ug insect^?1 for adulticidal activity, were found to be as effective as fenvalerate, a well-known non-cyclopropane pyrethroid ester. Structure-activity studies showed that the insecticidal activity is dependent on the nature and position of the substituent in the phenyl ring of the acid moiety and also on the type of alcohol moiety.     

Pyrethroid toxicology in the frog

Adult Rana pipiens pipiens (Shreber) are highly sensitive to insecticidal α-cyano-3-phenoxybenzyl esters administered subcutaneously, i.e., LD₅₀ 0.13–0.35 mg/kg for deltamethrin and the most potent isomer of each of cis-cypermethrin, fenpropathrin, and fenvalerate and 0.65 mg/kg for (1R,αS)-trans-cypermethrin. Pyrethroids lacking the α-cyano substituent [pyrethrins, S-bioallethrin, kadethrin, and the Cis- and trans-isomers of (1R)-tetramethrin, (1RS)-resmethrin, (1R)-phenothrin, and (1R)-permethrin] vary greatly in their toxicity (LD₅₀ 0.14 to > 60 mg/kg) and the trans isomers are much less toxic than the corresponding cis isomers. The trans/cis specificity is due in large part to relative detoxification rates based on synergism studies with the resmethrin and permèthrin isomers and liver pyrethroid esterase assays with the permethrin and cypermethrin isomers. Poisoning by the noncyano compounds involves hyperactivity and tremors whereas by the cyanophenoxybenzyl esters involves tonic seizures and choreoathetosis, i.e., types I and II syndromes, respectively. Picrotoxinin, t-butylbicyclophosphate, and five other small cage compounds give a third type of syndrome with clonic seizures. Diazepam and its 2′-fluoro-4-methyl-4,5-dihydro analog (RO 5-3636) are more effective than 23 other compounds tested in protecting against deltamethrin toxicity. Diazepam is most effective in alleviating the Type II syndrome, intermediate with the type I syndrome, and is not active with picrotoxinin.     

The effect of host plant on colorado potato beetle (coleoptera: Chrysomelidae) susceptibility to pyrethroid insecticides

In laboratory studies, Colorado potato beetle (CPB) (Leptinotarsa decemlineata Say) reared on eggplant were significantly more susceptible to permethrin than CPB reared on tomato. Field studies conducted in 1984 and 1985 showed that the percentage reduction of CPB larvae reared on eggplant due to foliar applications of fenvalerate was significantly greater than the percentage reduction of CPB larvae reared on either potato or tomato. Plant defoliation was greater on eggplant and potato than on tomato. Eggplant and potato yields increased as the dose of fenvalerate increased and the potato beetle population decreased, but tomato yields were unaffected by fenvalerate treatments. The effects and biological activity of individual plant chemical compounds (i.e., glvcoalkaloids) in various Solanum species need to be examined in detail before the full significance of the role of these compounds in host-plant resistance and their interaction with CPB insecticide resistance are understood.     

The pyrethrins and related compounds; Part XXIII:Kinetic control in the formation of pyrethroidal estersb

The unequal amounts of the two diastereomers of (RS)-1-(3-phenoxyphenyl)ethyl (RS)-2-(4-chlorophenyl)-3-methylbutyrate, obtained from equimolar proportions of the alcohol and acyl chloride under normal conditions, imply stereoselectivity in the reaction. The extent to which this depends on the nature of the α-substituent for arange of 3-phenoxybenzyl esters, on the nature of the acid, and on the method of esterification is investigated. Selectivity arises from kinetic, rather than thermodynamic control.     

Insecticidal activity of the pyrethrins and related compounds. IX. 5-benzyl-3-furylmethyl 2,2-dimethylcyciopropanecarboxylates with non-ethylenic substituents at position 3 on the cyclopropane ring

The insecticidal activities against houseflies (Musca domestica L.) and mustard beetles (Phaedon cochleariae Fab.) of 29 new 5-benzyl-3-furylmethyl 2,2-dimethyl-cyclopropane-carboxylates are compared with those of the corresponding chrysanthe-mate (bioresmethrin) to assess the influence of non-ethylenic and isobutenyl substituents at position 3 of the cyclopropane ring. Of the new groups investigated, only 3-methoxyiminomethyl gives equal or enhanced activity; 3-(2-furyl) esters are moderately effective, but 3-phenyl and 3-alkoxycarbonyl compounds show weak activity. A 3-(2,2,2-trihaloethyl) compound was more active than compounds with other saturated groups, such as isobutyl.     

The uptake of metabolites of permethrin by plants grown in soil treated with [14C]permethrin

Sugar beet, wheat, lettuce and cotton were grown in soil treated with [¹⁴C]permethrin, the crops being sown at intervals of 30, 60 and 120 days after treatment of the soil. The uptake of radioactive residues into these crops was measured. Low radioactive residues (up to 0.86 μg g^?1) were detected in the mature plants sown 30 days after soil treatment, and this uptake declined significantly as the interval between soil treatment and sowing increased. Metabolites derived from the acid moiety of the permethrin molecule were shown to constitute the greater part of the residue transferring from the soil to the crops. (1RS)-cis- and (1RS)-trans-3-(2,2-dichlorovinyl)- 2,2-dimethylcyclopropanecarboxylic acid and 3-(2,2-dichlorovinyl)-1-methylcyclopropane-1,2-dicarboxylic acid were identified as the major acidic metabolites. The latter compound is a metabolite of permethrin which has not previously been identified in soil or plants.     

Alkyl aryl ketone oxime O-ethers: A novel group of pyrethroids

The alkyl phenyl ketone oxime O-benzyl ethers are a new group of insecticidal compounds. Although they lack the ester linkage, they resemble the pyrethroids in general, and the esters of 2-phenylalkanoic acids, in particular fenvalerate, because they show similar physiological effects on isolated nerve preparations and on whole insects; they also show a similar pattern of change of biological activity in response to structural change. The compounds may exist as two geometric isomers, of which only the (E) series shows significant biological activity; this observation appears to have some bearing on the relationship between conformation and activity in the pyrethroid series as a whole.     

Quantitative structure-activity relationships of pyrethroid insecticides

The structure-activity relationships of two congeneric series of pyrethroid insecticides, the methylbenzyl (1RS)-cis,trans-chrysanthemates tested against Musca domestica (houseflies) and Phaedon cochleariae (mustard beetles), and the (E)-4-aryl-3-chlorobut-2-enyl chrysanthemates and their corresponding 2,2,3,3-tetramethylcyclo-propanecarboxylates tested against M. domestica only, have been examined using multiple regression analyses and substituent constants. With M. domestica, different optimum partition values (π) were indicated for knockdown and toxicity; with P. cochleariae, an optimum π value for toxicity, similar to that for M. domestica, was obtained 24 h after application, but at later times the more lipophilic compounds were more effective. For the methylbenzyl chrysanthemates, a steric constraint associated with 3,5-dimethyl substitution reduced toxicity approximately five-fold. The influence on toxicity of geometrical isomerism and electronic effects are briefly discussed. Differences between the required polarities for knockdown and toxicity are attributed to variations in the binding affinities of pyrethroid molecules at the sites of action.     

2-anilino-3-methylbutyrates and 2-(isoindolin-2-yl)-3-methylbutyrates,two novel groups of synthetic pyrethroid esters not containing a cyclopropane ring

A new series of substituted 2-anilino-3-methylbutyrates has been prepared; bioassay data for these compounds on Heliothis virescens, Musca domestica, Aphis fabae and Tetranychus urticae are presented and discussed. Some unexpected relationships were observed between the nature of the substituents and the biological activity. Increases in foliar stability were noted with certain substitution patterns. Both α-cyano-3-phenoxybenzyl 3-methyl-2-(α, α, α,2-tetrafluoro-p-toluidino)butyrate and the corresponding 2-(2-chloro-α, α, α-trifluoro-p-toluidino)-3-methylbutyrate showed good stability in air and light, and exhibited biological activities of a similar nature and potency to those of previously known synthetic pyrethroids. Esters of the (R)-2- anilino-3-methylbutyric acids are far more active than those prepared from the (S)-enantiomers. The (R)-configuration at C-2 in these acids is sterically equivalent to the active absolute configuration at the chiral carbon α to the carboxylate group in both the permethrin and the fenvalerate types of pyrethroids. A new class of insecticidal 2-(isoindolin-2-yl)alkanoates is also reported. In this series the most biologically active analogue was α-cyano-3-phenoxybenzyl 3-methyl-2-(4,5,6,7-tetrafluoroisoindolin-2-yl)butyrate. These esters were considerably less stable than the anilino analogues on exposure to air and light.     

Pharmacokinetics of fenvalerate after intravenous administration to sheep

The pharmacokinetics of total radioactivity and of intact fenvalerate were determined in sheep treated intravenously with radiolabelled or non-radiolabelled fenvalerate. Mean residence times (MRT) of total radioactivity and intact fenvalerate in plasma were 910 (±75) and 39 (±3) min, while harmonic mean elimination-phase half-lives (TM_β) were 990 and 82 min, each respectively. Systemic clearance values (Cl_S) of total radioactivity and intact fenvalerate were 2·8 (±0·3) ml min⁻¹ kg⁻¹ and 51·3 (±5·9) ml min⁻¹ kg⁻¹, respectively. Volumes of distribution at steady state (V_SS) were each near 2500 ml kg⁻¹. Elimination of radioactivity occurred, in part (33·3 (±3·3)% of dose), by renal excretion, at a rate (0·9 (±0·1) ml min⁻¹ kg⁻¹), similar to that of glomerular filtration. These data are consistent with a disposition model according to which intact fenvalerate was rapidly distributed into a peripheral compartment, where metabolism occurred. In addition, since the elimination half-life of fenvalerate from plasma was less than 90 min after intravenous injection, ‘flip-flop’ kinetics should be considered when longer elimination half-lives are observed after oral or dermal exposures.     

The pyrethrins and related compounds. Part XXVIII: Alkenyl- and alkynyl-substituted benzyl esters

Over 100 benzyl esters of pyrethroidal acids were synthesised and tested for insecticidal activity to establish detailed structure–activity relationships in compounds with side-chains similar to those in the natural pyrethrins. Alkenyl, and corresponding alkynyl, side-chains were effective, both at the 3- and 4-positions, as were side-chains with extended substitution in either E or Z forms. A cyano group at the α-position increases activity if the side-chain is at C-3, but lowers it drastically if the substituent is at C-4. Similarly, methyl groups at C-2 and/or C-6 may increase activity whether the unsaturated side-chain is at C-3 or C-4, but only in the absence of an α-cyano group.     

Interception and persistence of parathion and fenvalerate on cotton plants as a function of application method

Parathion (O,O-diethyl O-4-nitrophenyl phosphorothioate) and fenvalerate [(RS)-α-cyano-3-phenoxybenzyl (RS)-2-(4-chlorophenyl)-3-methylbutyrate] were applied by controlled droplet applicators (CDAs) and conventional hydraulic nozzles in refined soybean oil, soybean oil + water, or water, to mature cotton plants (Gossypium hirsutum L.) as ULV (ultra-low volume, < 5 litre ha^?1), VLV(very low volume, 5-50 litre ha^?1), or LV(low volume, 50–200 litre ha^?1) carrier rates. The use of CDA or soybean oil applied as ULV and VLV sprays did not produce greater deposition or persistence for either insecticide during the 49-h test period following application. In general, insecticide persistence was greatest when applied with water or soybean oil + water as LV sprays using the conventional TX8 hydraulic nozzle.     

Analysis of soils for diclofop-methyl and diclofop

A method is described for the analysis of soils for residues of the herbicide diclofop-methyl, methyl (RS)-2-[4-(2,4-dichlorophenoxy)phenoxy]propionate, and its breakdown product diclofop, (RS)-2-[4-(2,4-dichlorophenoxy)phenoxy]propionic acid. Diclofop-methyl undergoes hydrolysis in the soil to diclofop, which also has herbicidal activity. A procedure, using a 1% phosphoric acid solution for extraction purposes, has been developed and gives good recoveries of both diclofop-methyl and diclofop at the 0.5 and 0.05 mg kg^?1 levels. After methylation, gas-liquid chromatography with electron-capture detection is used to determine total residue concentrations.