Permethrin isomers

Content see Annex 1, section 1.2 the m-isomer must be in the range 25-40% of the total permethrin isomer content. 

Glickman, A.H., A.A.R. Hamid, D.E. Rickert and J.J. Lech. Elimination and metabolism of permethrin isomers in rainbow trout. Toxicol. Appl. Pharmacol. 57 88-98, 1981. 

Glickman, A.H., T. Shono, J.E. Casida and J.J. Lech. In vitro metabolism of permethrin isomers by carp and rainbow trout liver microsomes. J. Agric. Food Chem. 27 1038-1048, 1979. 

Although the concentrations of permethrine were quite low (10-30 ng/m ) identification by retention time and quantification was possible with GC-FID because the chamber air was very clean and the PUF blank did not interfere with the peaks of the two permethrine isomers. A cold injection system (Gerstel, Miihlheim) did improve the detection limit by better transfer and allowing the injection of 2-10 pi of the extract. 

Permethrin (isomer Spray Cattle, pigs. Ectoparasites 4 mg/kg bw for cattle... 

Lactonization occurred during treatment with strong acids or as artifacts of TLC separations. The glucuronides were partially converted to lactone derivatives when dilute methanolic HCL solutions were evaporated to dryness. Ninety-seven to hundred percent of the two mixed cfr-permethrin isomers and the two mixed trans isomers ( C-acid and alcohol labeled) were recovered in urine and feces. The hydrolysis products of ( C-acid-lR, trans) and ( " C-alcohol-lR, trans) permethrin were largely eliminated in urine (81-90%), while only 45-54% from aT-permethrin appeared in urine. The glucuronide of CI2CA was the principal metabolite found in the urines of (IR, trans 56.1%) and (IRS, trans 41.9%) permethrin-treated rats, while a lesser amount were found in the urines of (IR, cis 18.5%) and (IRS, cis 13.8%) permethrin-administered rats. For rats administered the C-alcohol-labeled permethrin, the principal metabolite was 4-OH PB acid sulfate in urine of rats administered (IR, trans 30.7%) and (IRS, trans 42.8%) permethrin. Less of this metabolite was found in urine of rats administered the (IR, cis 19.5%) and (IRS, cis 29.3%) permethrin. 

In lake water, permethrin degraded more rapidly than in flooded sediments to trans- and a 5-(dichlorovinyl)dimethylcyclopropanecarboxylic acid. The cis- isomer was more stable toward biological and chemical degradation than the trans isomer (Sharom and Solomon, 1981). 

Some pyrethroids have as many as eight different isomers, and there are several different types. Acute toxicity of a mixture of two isomers depends on the ratio of the amounts of isomers in the formulation. For example, the female rat s acute oral LD50 of permethrin increases from 224 mg/kg to 6,000 mg/kg as the proportion of transisomer increases from 20% to 80%. The route of exposure also is critical in assessing the acute toxicity of a synthetic pyrethroid. Like DDT and many other registered insecticides, naturally occurring pyrethrins and the synthetic pyrethroids are nerve poisons. 

Both cis and trans isomers are biologically active, though usually not equally so, one form being more toxic in some compounds and the other form being more toxic in others. For example, the technical grade of permethrin contains 40% cis isomer and 60% trans isomer. Studies show that the cis isomer is five times more toxic than the trans isomer against tobacco budworms (Bigley and Plapp, 1978). 

Pyrethroid insecticides can exist as enantiomers because they have two chiral centers, i.e., asymmetric carbons at C-l and C-3. An enantiomer exhibits optical activity and R/S configuration. Thus, a pyrethroid can show as either dextrorotatory (+) or levorotatory (-) isomer. A pyrethoid also can exist as either R or S form. However, only C-l is important to the biological activity of these compounds, and, for activity, it must be in the R position. As shown next, to be the 1R form, the -COOR group must be below the page. The IS form, which has -COOR group above the page, is nontoxic. Therefore, the active isomer of deltamethrin is expressed as (+)-ris-(lR) deltamethrin. The active isomer of permethrin is (lR)-ds-permethrin. 

Pyrethrins and synthetic pyrethroids are among the safest of the topically applied ectoparasiticides, because of their selective toxicity for insects (mam-malian-to-insect toxic dose ratio is greater than 1000, compared with 33 for organophosphates and 16 for carbamate insecticides). In contrast to the very wide margin of safety for mammalian species, pyrethroids are toxic to fish. The synergistic action of pyrethrins and piperonyl butoxide (in combination preparations) is due to the inhibition by piperonyl butoxide of the microsomal enzyme system of some arthropods. Preparations of synthetic pyrethroids (permethrin, cypermethrin) often contain a mixture of drug isomers in varying proportions. 

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. 

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). 

Bridges (1957) has reported that PBO slows the penetration of [ "Cjallethrin into adult susceptible house flies, and in a recent study Kcnnaugh et al (1993) showed that PBO could also influence Ihe penetration of isomers of permethrin into the larvae of H. amuse ra ... 

Permethrinic acid,3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxyl-ic acid, is another kind of cyclopropanecarboxylic acid producing insecticides of higher performance and stability [5]. The structure of permethrin, a totally synthetic pyrethroid, is shown in Fig. 2. The most effective isomer of permethrinic acid is shown to be the d-cis isomer rather than the d-trans isomer [6]. 

For the analysis of isomers of the synthetic pyrethroid insecticde permethrin, enantiomeric amides were prepared using carbon-yldiiminazole and a range of chiral amines of which R(-) - or S(+)-amphetamine gave baseline separation of the four isomers (Taylor et al. 1993). 

The most remarkable compound listed is probably permethrin, a rebuilt chemical with much higher stability and insecticidal activity than the natural pyrethroid. Not much later the difference in activity between the various stereoisomers was taken into account. Permethrin is a racemic mixture, but in the products called bio-, as in bioallethrin and bioresmethrin, as well as in deltamethrin and several other newer pyrethroids, the inactive stereoisomers have been removed. Deltamethrin has a cyano group, making mirror-image isomerism possible. The one shown is the most potent. Substances without the cyclopropane moiety were also found. Fenvalerate was developed by Sumitomo Chemical Co. Ltd. and described in 1974, whereas its most active isomer was found and described in 1979. 

Stereo specific Aspects. It has been well established that the ensuing receptor interaction of the pyrethrums with the sodium channel complex is absolutely stereospecific and, therefore, solely dependent on the stereochemistry of the carboxylic acid in question. Interestingly, in the case of permethrin the most active isomers are the IR, 3-cis- and IR, 3-tr /is-cyclopropane-carboxylates. However, the IS cis- and IR ra 5-isomers are inactive and are found to serve as antagonists to the therapeutic action of the corresponding IR-isomers. 

Some veterans were exposed to these pesticides by intentional application, but because many exposures were accidental, it has been difficult to assess pesticide exposure accurately and therefore a topical dose in exposed veterans. Permethrin was intentionally impregnated into the soldier s uniform fabric at a concentration of 0.125 mg/cm to help control insect infestation while in the dessert. This pyrethroid insecticide consists of four different isomers (Figure 9.1), with the cis isomer more toxic than the trans isomer. Permethrin is a large moleeule (MW = 391.3) and has a log octanol-water partition coefficient of 6.5, which suggests that it could readily partition from the uniform into the lipophilic stratum comeum layer of the soldier s skin. With a transfer rate of 0.49% per day of permethrin from the fabric to skin, the daily dose was estimated to be 6.8 x 10" mg/kg/day (National Research Council... 

The dramatic influence of the pH of the medium was first encountered at the separation of optical isomers of a s-permethrinic add carried out with half an equivalent amount of (S)-2-benzylaminobutanol ((S)-BAB). The resolution started in the presence of a 25 mol % excess of sodium hydroxide. In such a medium the diastereoisomeric salt containing the almost pure (S)-CPA crystallized ee %%) with a yield of 27% counted to the amount of racemic acid. After removal of the precipitate by filtration, the excess alkali was neutralized with a counted amount of hydrochloric add. That time the resolving agent remained in the filtrate crystallized with (R)-CPA enantiomer as diastereoisomeric salt and in the second mother liquor an almost racemic CPA-Na salt was found (it can be recycled into the resolution). 

The Zn-reagent approach was also applied to the single optical isomers [419]. Replacement of both chlorine atoms in permethrin by CFj-groups still gives a quite active pyrethroid [422], however not so easy and cheap to synthesize (Reaction scheme 146) [423]. The diene 220 based on hexafluoroacetone, is even less reactive towards diazoester. 

---