Cypermethrin trans isomers

Different isomers may have different rates of degradation in the environment which would change the overall risk. For example, in the case of cypermethrin, the trans-isomers were preferentially degraded over the cis-isomers. Of the two active isomers of this insecticide, the (lR)-ds-(aS)-isomer was degraded more slowly than (1 R)-tmns-(u. S)-i sorn er by bacteria and in whole sediments [150]. By selecting for the isomer (or process that produces a majority of that isomer) with the more rapid degradation profile, the ecological risk should be reduced. 

Synthetic pyrethroids are geometric isomers with cis, trans configurations. Commercially available preparations of cypermethrin contain a mixture of cis and trans isomers in various proportions, for example, 60 40 and 80 20. Cypermethrin (cis trans 60 40) 2.5% solution is equivalent to cypermethrin (ids trans 80 20) 1.25% solution for pour-on application to sheep. Permethrin, which is the active ingredient incorporated in ear tags for cattle and insecticidal collars for dogs and cats, contains a mixture of cis and trans isomers in the proportion 40 60. 

The inactive racemate III of cypermethrin (containing isomers C + D) is in hexane the less soluble one [820], while the active racemate IV of cyfluthrin cristallizes from this solvent [842]. After seeding with pure I and III the inactive part, containing I (isomers C + D) and III (isomers H + G) crystallizes from a solution of cis/trans cypermethrin in methanol. They can be reepimerized after filtering off. The active racemates II (isomer A + F) and IV (isomer B 4- E) enriched in the mother hquor can now also be crystallized, but only after seeding with the right crystalls [843]. 

An effective TLC separation and a simple but sensitive detection of the halogenated synthetic pyrethroids was developed (121). By this method permethrin, cypermethrin, decamethrin, and fenvalerate were detected and distinguished from DDT, DDT metabolites, and HCH isomers. Twenty different solvents and solvent mixtures were checked for the chromatographic separation of the above insecticides. The best resolutions were achieved by /i-hexane benzene (45 55) and n-hexane-chloio-form (60 40), which gave distinct separation of cis and trans isomers of permethrin and cypermethrin (121) (Table 9) as well. 

Crawford et al. (1981a) orally administered separate cis and trans isomer mixtures or cis-trans mixtures of radiolabeled cypermethrin (cyclopropyl- " C,... 

A total of 98.9% of the label from the cis-isomers was recovered in 8 days and 103.2% for the trans- isomers was recovered in 3 days. No respiratory " C02 was eliminated. The radioactivity from (cyclopropyl- " C)-c/s, trans-cypermethrin (mixture) was eliminated in the urine of both male (55.8%) and female (66.5%) rats. Fecal elimination amounted to 28.7% by male and 27.0% by female rats. Less than 0.1% of the dose was eliminated as respiratory carbon dioxide. The radioactivity from the (cyano- " C)-c/s, trans-cypermethrin (mixture) was different from the other two labels as the a-cyano group was released and converted to thiocyanate ion, which was slowly eliminated from the body. The majority of the administered radiocarbon was recovered in the feces (42.0-57.2%) with lesser amounts in urine (8.3-9.6%). Respiratory carbon dioxide contained 1-2% of the administered radioactivity. Tissue residues from (benzyl-C " ) c/s-cypermethrin were highest in fat (0.83-1.46 pg/g) of male and female rats, 8 days after administration. 

Ross et al. (2006) studied the hydrolytic metabolism of Type 1 pyrethroids (bioresmethrin, IRS fraws-permethrin, and IRS c/s-permethrin) and several Type II pyrethroids (alpha-cypermethrin and deltamethrin) by pure human CEs (hCE-1 and hCE-2), a rabbit CE (rCE), and two rat CEs (Hydrolases A and B). Hydrolysis rates were based on the formation of 3-phenoxybenzyl alcohol (PBAlc) (CAS no. 13826-36-2) for the cis and trans isomers of permethrin. For bioresmethrin, hydrolysis was based on the production of the trans-chrysanthemic acid (CPCA) (CAS no. 10453-89-1). For alpha-cypermethrin and deltamethrin, hydrolysis was based on the formation of c/s-permethrinic acid (DCCA) (CAS no. 57112-16-0) and 3-phenoxybenzyl aldehyde (PBAld CAS no. 39515-51-0), respectively. Human CE-1 and hCE-2 hydrolyzed trans-permethrin 8- and 28-fold more efficiently (based on kcat/Km values) than did c/s-permethrin, respectively. The kinetic parameters (Fmax> for the hydrolysis of trans- and c/s-permethrin, bioresmethrin and alpha-cypermethrin by rat, mouse, and human hepatic microsomes are given in Table 7. The trans- isomer of permethrin is more readily hydrolyzed by rat, mouse and human hepatic microsomal carboxylesterase than c/s-permethrin (13.4, 85.5 and 56.0 times, respectively). However, the lower for hydrolysis of cis-permethrin in human microsomes suggests that there are both stereoisomer and species-specific differences in metabolism kinetics. 

Hydrolysis of the pyrethroids may occur prior to hydroxylation. For dichloro groups (i.e., cyfluthrin, cypermethrin and permethrin) on the isobutenyl group, hydrolysis of the trans-isomers is the major route, and is followed by hydroxylation of one of the gem-dimethyls, the aromatic rings, and hydrolysis of the hydroxylated esters. The cis-isomers are not as readily hydrolyzed as the tran -isomers and are metabolized mainly by hydroxylation. Metabolism of the dibromo derivative of cypermethrin, deltamethrin, is similar to other pyrethroids (i.e., cyfluthrin, cypermethrin, and permethrin) that possess the dichloro group. Type 11 pyrethroid compounds containing cyano groups (i.e., cyfluthrin, cypermethrin, deltamethrin, fenvalerate, fenpropathrin, and fluvalinate) yield cyanohydrins (benzeneacetonitrile, a-hydroxy-3-phenoxy-) upon hydrolysis, which decompose to an aldehyde, SCN ion, and 2-iminothia-zolidine-4-carboxylic acid (TTCA). Chrysanthemic acid or derivatives were not used in the synthesis of fenvalerate and fluvalinate. The acids (i.e., benzeneacetic acid, 4-chloro-a-(l-methylethyl) and DL-valine, Af-[2-chloro-4-(trifluoromethyl) phenyl]-) were liberated from their esters and further oxidized/conjugated prior to elimination. Fenpropathrin is the oifly pyrethroid that contains 2,2,3,3-tetramethyl cyclopropane-carboxylic acid. The gem-dimethyl is hydroxylated prior to or after hydrolysis of the ester and is oxidized further to a carboxylic acid prior to elimination. 

Synthetic pyrethroids (cypermethrin, permethrin) and natural pyrethrins (pyrethrum extract) combined with piperonyl butoxide constitute the most important class of insecticide applied topically to horses (Table 5.7). The liquid concentrate containing cypermethrin which, after dilution, is applied to horses by spray contains a mixture of the isomers in equal proportion (cis trans 50 50). 

Rat toxicity values were obtained from EPA publication-600/2-81-011, "Analytic Reference Standards and Supplemental Data for Pesticides and Other Organic Compounds". The rat oral LDso for the racemic mixture of cypermethrin is 251 mg/kg. The mouse intracerebral LDso values are 0.6 jug/g brain weight for the 1 ff,cis,(XS and 1.6 for the 1 ff> trans, -S isomers (15). 

Diastereomeric racemates of a-cyanobenzyl esters or allethronyl esters not only have different tendencies of formation or energy contents, but also different solubilities in the case of the crystallizable isomers. This can be utilized to separate one isomer by its crystallization out of a solution or melt of the mixture [816]. The other one can subsequently be epimerized by basic treatment [817], thus forcing the overall reaction by a second order asymmetric transformation [818] to yield only one racemate, containing the insecticidal isomer, if this is the less soluble one. Unfortunately however, the opposite is true for allethrin [818a], cycloprothrin [819], trans-cypermethrin [820], other analogues of fenvalerate (Table 105) [821] and fluvalinate. 

The overall situation for the cis/trans-mixture of cypermethrin 376 is even more complex. Eight diastereomerically and enantiomerically related isomers A to H have different physical properties. The stereochemical relations are depicted in the following Fig. 1 ... 

Permethrinic acid has two enantiomer pairs and four isomers (2" = 4) (Table B33, Appendix B). The acid leaving group for permethrin, cypermethrin, and cyfluthrin is permethrinic acid. The structure of this acid is given in Table 3. Angerer and Ritter (1997) separated the methyl esters of cis- and trans-permethrinic acid on a polysiloxane capillary column by GC (Table C18, Appendix C). The carboxylic acids of several of these pyrethroids were also listed as trans- or cw-3-(2, 2-dichlorovinyl)-2, 2-dimethyl cyclopropane carboxylic acid. The acids may be separated on a CHIREX phase 3005 column (Phenomenex, 2320 W 205th Street, Torrance, CA 90501) by HPLC. 

Crow et al. (2007) examined the catalytic activity of carboxylesterase (rCE proteins hCE-1 and hCE-2) on Type 1 pyrethroids (i.e., IRS frans-permethrin (98% pure, 93% trans and 5% cis), IRS cA-permethrin (99% pure), IR trans-resmethrin (bioresmethrin, 99% pure, 97% trans and 2% cis)). Type 11 pyrethroids (i.e., alpha-cypermethrin (99% pure, mixture of isomers), lambda-cyhalothrin (99% pure, mixture of isomers), and deltamethrin (99% pure)). 

The 3D QSAR pharmacophore model selected very fast and very slow metabolizers, leaving the catalytic hydrolysis rates in the middle group as being questionable. Catalytic rates ( cat) for the pyrethroids that were outside of the training set (8-25 h ) were obtained by extrapolation. Less confidence should be placed on these predicted values. The hydrolysis rate for deltamethrin (IR, cis, aS) fell into the middle group and was not included in Table 19. However, catalytic rates (rat serum carboxylesterases) for two trans deltamethrin (1R,3S, aR lS,3R,oR) isomers were included in the table and compared favorably with the rat hydrolase A and B values in Table 11. Cypermethrin (IR, trans, aR), cyfluthrin (IR, trans, oR IR, trans, oR), and permethrin (IR, trans IS, trans) were fast metabolizers. Among the slow metabolizers were permethrin (IS, cis), cyfluthrin (IS, cis, aS) and cypermethrin (IR, trans, aS). 

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