Metabolism of the cis- and trans-isomers of cypermethrin in mice

Metabolism in mice of the separated cis- and trans-isomers of the pyrethroid insecticide cypermethrin (NRDC 149), (RS)-α-cyano-3-phenoxybenzyl (1RS)-cis, trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate, was investigated in each case with preparations that were ¹⁴C-labelled in the benzyl and cyclopropyl moieties. Radioactivity from the trans-isomer was mainly excreted in the urine and that from the cis-isomer in the faeces. Elimination of both isomers was rapid except for a small portion (approximately 2%) of the cis-isomer which was released from the fat with a half-life of approximately 13 days. Metabolism of cypermethrin occurred mainly by ester cleavage and elimination of the cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethyl- cyclopropanecarboxylic acid moieties as glucuronide conjugates. The α-cyano-3-phenoxybenzyl alcohol released by ester cleavage was mainly converted to 3-phenoxy-benzoic acid which was partly eliminated unchanged, partly conjugated with aminoacids (mainly taurine) and glucuronic acid, and partly oxidised to 3-(4-hydroxyphenoxy) benzoic acid which was excreted as the sulphate conjugate. Metabolites retaining the ester linkage were formed by hydroxylation at various sites in the molecule with more hydroxylation of the cis- than of the trans-isomer occurring.     

Absorption and metabolism of permethrin and cypermethrin in the cockroach and the cotton-leafworm larvae

Permethrin was metabolised by attack at the ester bond, in vivo by adult cockroaches, Periplaneta americana and in vitro by esterase preparations. Metabolites retaining the ester linkage could not be detected. In all cases, the (1RS)-trans-isomer (transpermethrin) was more labile than the (1RS)-cis-isomer. Cypermethrin was metabolised at one-fifth the rate for permethrin. In-vitro and in-vivo studies with synergists indicated that cleavage of the ester bond in permethrin can be both oxidative for the (1RS)-cis-isomer and hydrolytic for the (1RS)-trans-isomer. The penetration of permethrin through the cuticle of the cockroach was significantly greater than that of cypermethrin. The penetration and metabolism of permethrin and cypermethrin in sixth-instar larvae of susceptible and resistant strains of the Egyptian cotton-leafworm, Spodoptera littoralis, were studied as possible factors in resistance. No significant differences were found. It is suggested that the major resistance factor to permethrin in S. littoralis is probably non-metabolic.     

The metabolism of the herbicide flamprop-methyl in rats and some comparative data for dogs,mice and rabbits

[¹⁴C]Flamprop-methyl administered orally to rats (3-4 mg kg^?1 body weight) was excreted mostly via the faeces (78.7 and 61.6% in males and females, respectively). Elimination was rapid and 90% of the dose of ¹⁴C was excreted in faeces and urine 0-48 h after dosing. The distribution of ¹⁴C between faeces and urine was different in males and females. No expired [¹⁴C]carbon dioxide was detected and less than 2% of the dose remained in the animals 4 days after dosing. The predominant metabolic pathway was hydrolysis of the ester bond to afford the carboxylic acid which was excreted unchanged and as its glucuronide conjugate. Aromatic hydroxylation occurred at the para- and meta-positions of the N-benzoyl ring. N-(3)-Chloro- 4-fluorophenyl-N-(3,4-dihydroxybenzoyl)-DL -alaninate was also formed. This hydroxylated form of flamprop-methyl was partially O-methylated at the 3-hydroxy group. Flamprop-methyl was also metabolised and eliminated rapidly by dogs, mice and rabbits. The last of these three species afforded very little aromatic hydroxylation and also differed from the others in that the metabolites were eliminated mostly in the urine. Aromatic hydroxylation lay in the order: male rat = female rat > dog= mouse>rabbit (female).     

Stability of cypermethrin and cyfluthrin on wheat in storage

Cypermethrin and cyfluthrin were applied to wheat, which was stored for 52 weeks at 25 or 35°C, and either 12 or 15% moisture content. Total residues and the proportions of the four pairs of enantiomers, cis I [(αR),(1R)-cis + (αS),(1S)-cis], cis II [(αR),(1S)-cis + (αS),(1R)-cis], trans III [(αR),(1R)-trans + (αS),(1S)-trans], and trans IV [(αR),(1S)-trans + (αS),(1R)-trans] for each pyrethroid were determined at five intervals during storage. For all storage conditions, the cis I isomers were the most stable, and the trans IV isomers were the least stable. Calculated half-lives (weeks) for the pairs of enantiomers at 25°C (12% moisture) and 35°C (15% moisture) were: cypermethrin, cis I, 252, 62 and trans IV 66, 27; cyfluthrin, cis I, 114, 52 and trans IV 42, 23. The results suggested that one of the enantiomers of the cypermethrin trans IV pair was degraded faster than the other.     

Green-odour compounds have antifungal activity against the rice blast fungus <Emphasis Type="Italic">Magnaporthe oryzae</Emphasis>

Four green-odour compounds—trans-2-hexenal, cis-3-hexenol, n-hexanal, and cis-3-hexenal—were applied (0.85 μg ml⁻¹ as vapour) to rice plants in laboratory conditions to observe their biological activity against the phytopathogenic fungus Maganporthe oryzae, which causes rice blast disease worldwide. Two compounds, trans-2-hexenal and cis-3-hexenal, showed remarkable disease suppression efficacy (99.7% and 100% suppression, respectively), while n-hexanal had moderate (86.5%) and cis-3-hexenol had weak (20.8%) disease-suppressing effects. Pre-application and post-application of trans-2-hexenal or cis-3-hexenal had slight effects on blast incidence, suggesting that these compounds had direct effects to suppress M. oryzae infection. In fact, trans-2-hexenal and cis-3-hexenal exhibited a growth suppression effect on M. oryzae. Interestingly, these two compounds inhibited appressorium formation at lower concentrations than the growth suppression. Studies on the hypersensitive response (HR)-like reaction and plant β-1,3-glucanase activity in rice plant confirmed that induced resistance was not the major factor involved in the disease suppression mechanism. Results of this study conclusively showed that trans-2-hexenal and cis-3-hexenal possess potent inhibitory activities against the growth and the appressorium formation of M. oryzae and could be used as antifungal agents to significantly reduce M. oryzae infections in rice.     

Metabolism of four resmethrin isomers by liver microsomes

Microsomal esterases of mouse and rat liver readily cleave the trans- but not the cis-isomers of resmethrin (5-benzyl-3-furylmethyl chrysanthemate). The ester linkage also appears to undergo oxidative cleavage when esterase attack is minimal, i.e., with (+)-cis- and particularly (?)-cis-resmethrin in microsome-NADPH systems and with any of the isomers when NADPH is added to microsomes pretreated with TEPP. Metabolites retaining the ester linkage are detected in significant amounts only with (+)-cis-resmethrin in which case they are formed by oxidation at either the trans(E)- or cis(Z)-methyl group of the isobutenyl moiety with or without oxidation of the benzylfurylmethyl group. Metabolites of each acid moiety include chrysanthemic acid and up to six derivatives of this acid formed by oxidation at the trans(E)- or cis(Z)-methyl group yielding the corresponding alcohol, aldehyde, or acid, with chrysanthemate isomer and enzyme source variations in the preferred site of oxidation. The major identified metabolite of the alcohol moiety is either benzylfurylmethanol or the corresponding carboxylic acid depending on the enzyme system used. In the course of microsomal oxidation, a fragment from the alcohol but not the acid moiety of (+)-trans- and (+)-cis-resmethrin is strongly bound to microsomal components. These findings confirm in vivo studies on the isomeric variations in metabolism of the resmethrin components.     

Metabolism of permethrin isomers in American cockroach adults,house fly adults,and cabbage looper larvae

Forty-two insect metabolites of [1RS,trans]-and [1RS,cis]-permethrin are tentatively identified in studies with Periplaneta americana adults, Musca domestica adults, and Trichoplusia ni larvae involving administration of ¹⁴C preparations labeled in either the alcohol or acid moieties. The less-insecticidal trans isomer is generally metabolized more rapidly than the more-insecticidal cis isomer, particularly in cabbage looper larvae, and metabolites retaining the ester linkage appear in larger amount with cis-permethrin. Although the dichlorovinyl group effectively blocks oxidation in the acid side chain, the permethrin isomers are metabolized by hydrolysis and hydroxylation at the geminal-dimethyl group (either trans- or cis-methyl substituent) and the phenoxybenzyl group (predominantly at the 4′-position in all species but also at the 6-position in house flies). The alcoholic and phenolic metabolites are excreted as glucosides, and the carboxylic acids are excreted as glucosides and amino conjugates (glycine, glutamic acid, glutamine, and serine) with considerable species variation in the preferred conjugating moiety.     

Distribution and depletion of [14C]resmethrin isomers administered orally to laying hens

The cis and trans isomers of the synthetic pyrethroid resmethrin, labelled with radiocarbon in either the alcohol or acid moiety, were individually administered orally to White Leghorn laying hens at a dosage of 10 mg kg^?1. With each isomer and label position, greater than 90% of the radiocarbon was eliminated in the excreta within 24 h after the treatment. Radiocarbon residues in the egg white and yolk fractions were low, with peak levels observed 1 and 4-5 days after treatment in white and yolk, respectively. In birds sacrificed 12 h after treatment, radiocarbon residues in tissues were low; the highest levels were found in the liver and kidney.     

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.     

Stereochemical and chiral aspects in the synthesis of 3-(2,2- dihalovinyl)-2,2-dimethylcyclopropanecarboxylic acids

The synthesis of (1RS)-cis,trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid by dehydrohalogenation of 4,6,6,6-tetrahalohexanoates has been modified to produce stereo-selectively the cis-isomer. A new stereospecific synthesis of cis-3-(2,2-dihalovinyl)-2,2-dimethylcyclopropanecarboxylic acids using a bicyclic lactone and its extension to the preparation of the optically active (1R)-cis acid are described.     

Characterization of residues in soybeans grown in soil treated with 1,3-dichloropropene soil fumigant

The metabolism of cis- and trans-1,3-dichloropropene (1,3-D) was studied in soybean plants grown in soil treated 24 days prior to planting with [U-¹⁴C]E- and Z-1,3-dichloropropene at 380 liters ha^?1. Isolation and identification of the ¹⁴C residue from soybean plants at 84 days (forage) and 176 days (mature) after application showed that no 1,3-dichloropropene or its putative metabolites, 3-chloroallyl alcohol and 3-chloroacrylic acid, could be detected in any of the tissues. The components of the ¹⁴C residue included major plant constituents (i.e. fatty acids, protein, pigments, organic acids, sucrose and other carbohydrates, and lignin).     

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.     

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.     

Synthetic pyrethroids containing a C–C triple bond

The three commercial synthetic pyrethroids containing a carbon–carbon triple bond, α-ethynyl-2-methylpent-2-enyl (1R)-trans-chrysanthemate, (S)-2-methyl-4-oxo-3-(2-propynyl)cyclopent-2-enyl (1R)-trans,cis-chrysanthemate and [2,5-dioxo-3-(2-propynyl)-1-imidazolidinyl]methyl (1R)-trans-chrysanthemate are reviewed with emphasis on their inventive histories. Their chemistry and efficacy are described briefly. The relationship between stereochemistry and the biological activity is also discussed. © 1998 SCI.     

The pyrethrins and related compounds. XIX Geometrical and optical isomers of 2,2-dimethyl-3-(2,2-dichlorovinyl)-cyclopropanecarboxylic acid and insecticidal esters with 5-benzyi-3-furylmethyi and 3-phenoxybenzyl alcohols

Esters of 2,2-dimethyl-3-(2,2-dichlorovinyl)-cyclopropanecarboxylic acid with appropriate alcohols are more active insecticides than the corresponding 3-isobutenyl compounds (chrysanthemates). (±)-Cis and (±)-trans forms of the dichloro acid are obtained by fractional crystallisation of the mixed acids or by hydrolysis of the ethyl esters separated by fractional distillation. The (±)-cis and (±)-trans acids are resolved into their (+)- and (-)-forms with α-methyl-benzylamine and threo-l-p-nitrophenyl-2-N,N-dimethyiamino-propane-1,3-diol respectively. As for the corresponding chrysanthemates, the (+)-cis and (+)-trans acids give esters more active as insecticides than their enantiomers.     

The metabolism in the rat of the herbicidally active isomer (R)- flamprop-methyl in comparison with the racemic form

A single dose (4 mg kg^?1) of ¹⁴ C-labelled (R)-flamprop-methyl to rat was rapidly metabolised and 90% of the dose was eliminated in urine and faeces within 48 h. Four days after dosing, tissue residues were 0–1 μg equivalents g^?1 tissue or much less, with the exception of kidney (0–22 μg g^?1). There was a statistically significant sex difference in the routes of elimination; this may be attributed to differences in the biliary elimination of the major metabolite, flamprop acid, or its glucuronide conjugate. The fate of racemic flamprop-methyl was very similar to that of the (R)-isomer. The major metabolic routes were hydrolysis of the esters to the corresponding acids, hydroxylation of the benzoyl aromatic rings and conjugation. The flamprop acid derived from the (R)-flamprop-methyl was found to be partially converted to the (S)-form (R:S ratio, 87:13). This reaction is discussed in the context of other such biological racemisations recently reported.     

Metabolism in rats of 3-phenoxybenzyl alcohol and 3-phenoxybenzoic acid glucoside conjugates formed in plants

Upon single oral administration to rats, the mono-, di- and tri-glucose conjugates of [¹⁴C]-3-phenoxybenzyl alcohol ( I ) or the mono-glucose conjugate of [¹⁴C]-3-phenoxybenzoic acid ( II ) were rapidly hydrolysed and extensively eliminated in the urine mostly as the sulphate conjugate of 3-(4-hydroxyphenoxy)benzoic acid ( X ). The faecal elimination was a minor route, whereas the biliary excretion was about 42% of the dose and the glucuronide conjugates of I , II and X were common major metabolites. The biliary glucuronides were cleaved in the small intestine to the respective aglycones, which were reabsorbed, metabolised further, and excreted in the urine as the sulphate conjugate of X . Although small amounts of the mono-, di-and tri-glucosides were found in the 0.5-h blood and liver samples following oral administration of the tri-glucoside of I , they were not detected in the urine, bile or faeces. Similarly the sulphate conjugate was one of the major urinary metabolites of germ-free rats, dosed with the ¹⁴C-glucosides via the oral or the intraperitoneal route, although they were excreted unchanged in certain amounts in the urine and faeces. The glucose conjugates were cleaved in vitro by gut microflora and in various rat tissues, including blood, liver, small intestine and small intestinal mucosa. The tissue enzymes showed a different substrate specificity in hydrolysis of the glucosides. However, they were not cleaved in gastric juice, bile, pancreatic juice or urine.     

Identification of products arising from the metabolism of cis- and trans-chlordane in rat liver microsomes in vitro: Outline of a possible metabolic pathway

The metabolism of pure cis- and trans-chlordane was studied in vitro. Microsomal preparations from the livers of male rats induced with cis- or trans-chlordane in feed for 10 days were used to metabolize the pure compound corresponding to the inducer. Subsequent extraction, column fractionation, and combined gas chromatography-mass spectroscopy resulted in the characterization of four compounds not previously reported from an in vitro system. In addition to the substrate, trans-chlordane extracts contained species with the following molecular weights and empirical formulas: $\text{m}\text{e}$ 370, C₁₀H₅Cl₇, heptachlor; $\text{m}\text{e}$ 352, C₁₀H₆OCl₆, a hydroxylated chlordene; and $\text{m}\text{e}$ 422, C₁₀H₆OCl₈, a hydroxylated chlordane. Dichlorochlordene, oxychlordane, and 1-chloro-2-hydroxy-dihydrochlordene were also present. With the exception of the hydroxychlordane, cis-chlordane extracts contained all of the metabolites found in the trans incubates. Additionally, a fully saturated compound, $\text{m}\text{e}$ 372, C₁₀H₇Cl₇, a dihydroheptachlor, was present. The 1,2-trans-dihydrodiol of heptachlor found in previous in vitro incubates of cis-chlordane was not present in this extract. This information has been incorporated into a proposed route for the biotransformation of the chlordanes that offers an explanation for the observed differences in the metabolism of cis and trans isomers. The pathway is based on the reductive dechlorination of the chlordanes through dihydroheptachlor to dihydrochlordene. Parallel pathways of hydroxylation, desaturation, and epoxide formation arise at each of these species and at chlordane itself.     

A new aqueous suspension concentrate formulation of cis‐permethrin and its insecticidal activity

Isomers of pyrethroids usually have different insecticidal activities. Permethrin, a non‐cyano pyrethroid, is not an exception and cis‐permethrin is much more active than the trans‐isomer against Triatoma infestans, vector of Chagas' Disease in Argentina. The large‐scale separation of cis‐ and trans‐permethrin was performed by successive recrystallizations from ethanol‐water mixtures. An aqueous suspension concentrate (flowable) formulation of pure crystalline cis‐permethrin was prepared and assayed for its insecticidal activity on wood and ceramic surfaces against nymph V of T infestans. This formulation was at least three times more effective than deltamethrin, with LC₅₀ values on ceramic of 0.11 µg cm⁻² and 0.33 µg cm⁻² respectively. On wood surfaces, the LC₅₀ value was 0.57 µg cm⁻² compared with 3.20 µg cm⁻² for deltamethrin. Against other insect species such as Periplaneta americana, Aedes aegypti and Culex quinquefasciatus, the suspension concentrate formulation of cis‐permethrin was, however, less effective than similar formulations of deltamethrin or β‐cypermethrin. © 2000 Society of Chemical Industry     

Toxicity of some pyrethroids to the adult desert locust,Schistocerca gregaria forsk

The toxicity of a number of topically applied pyrethroids has been tested against adult male desert locusts, Schistocerca gregaria: the most potent proved to be 5-benzyl-3-furylmethyl (+)-trans-chrysanthemate (bioresmethrin) with a weighted mean LD₅₀ of 4.0 μg/g. The remaining compounds may be ranked in order of toxicity as follows: 5-benzyl-3-furylmethyl (±)-cis-trans-chrysanthemate (resmethrin) > 4-allyl-2,6-dimethyl-benzyl(+)-trans-chrysanthemate > 4-allylbenzyl (+)-trans-chrysanthemate > 2,4,6-trimethylbenzyl (+)-cis-trans-chrysanthemate > 2,3,4-trimethylbenzyl (+)-cis-trans-chrysanthemate > 2,4-dimethylbenzyl (±)-cis-trans-chrysanthemate; 2-methylbenzyl (±)-cis-trans-chrysanthemate. A small factor of synergism (4.2) was obtained with bioresmethrin following pre-treatment with sesamex, but with resmethrin the synergistic ratio (1.6) was of little practical significance.