Deltamethrin isomers

The deltamethrin / -isomer content, determined by the method described in section 2.2, shall not be higher than 2% of the deltamethrin content found under section 1.2.1. 

Table C6 Separation of deltamethrin isomers on chiral HPLC column ...

Although the methodology does not apply to others, one of the members of this family, deltamethrin (31), is made at scale by a selective crystallization. In the presence of a catalytic amount of base, only one of the isomers crystallizes from isopropanol (Scheme 31.27).253... 

Note The method used to determine the deltamethrin i -isomer content differs slightly from the method described in the current WHO specification for deltamethrin technical and deltamethrin formulations (WP, EC, DP, UL, SC) in order to accommodate the extraction of deltamethrin active ingredient from the water-dispersible tablet. 

Deltamethrin R-isomer standard. Analytical grade, of known purity. 

Weigh (to the nearest 0.1 mg) about 20mg of deltamethrin i -isomer into a 50-ml volumetric flask. Dissolve and make up to volume with the mobile phase mixture. Pipette 10.0ml of this solution into a 100-ml volumetric flask, make up to volume with the mobile phase mixture and mix thoroughly. 

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. 

We explored the potency of pyrethroid action in this system using deltamethrin, NRDC 157 (3-phenoxybenzyl [lR,cis]-3-( 2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate the non-cyano analog of deltamethrin), and their nontoxic enantiomers as test compounds ( Table II). Deltamethrin produced half-maximal enhancement of veratridine-dependent activation at 25 nM, whereas NRDC 157 was approximately tenfold less potent and the nontoxic enantiomers were inactive. These findings demonstrate that the effect of pyrethroids on mouse brain sodium channels is both potent and stereospecific for toxic isomers. The relative potencies of deltamethrin and NRDC 157 in this assay also agree well with their... 

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. 

Examples of single isomer agrochemicals are / -mecoprop, an important herbicide, and i, i ,5-deltamethrin, a neuroactive insecticide. 

Deltamethrin (90% ci s-isomer) Topically (dip, spray, pour-on) Cattle, sheep, chickens Ectoparasites (flies, including tsetse flies) Cattle 0.25-1.5 mg/kg bw as a single application or as repeated application (every 3-6 weeks)... 

In the case of deltamethrin the highly active 1-R-cis-aS-isomer is the less soluble one and thus the complete base catalyzed transformation of IR-cis-aR-isomer to IR-cis-aS... 

Deltamethrin (XX, Fig. 7) has been developed for control of insect pests of crops, livestock, and humans. Deltamethrin and its trans isomer have been reported to be highly active against insects, but only deltamethrin is of high acute toxicity to mammals (111). Some isomerization takes place when deltamethrin is exposed to light. The eight possible isomers of deltamethrin were isolated from environmental samples and separated by TLC (112). The cis and trans isomer pairs were resolved in a benzene-carbontetrachloride (1 1) mixture (Table 9) after three developments in the same direction. 

In the natural pyrethrin esters, the presence of two asymmetric cyclopropane carbons implies the possible existence of four stereoisomers (Deltamethrin Monograph 1982). However, in the natural pyrethrins, only the (IR, 3R) configuration exists. This fact limits the number of acids (isomers) that need to be considered in developing analytical methods for detecting pyrethrin residues in food products, or animal tissues and fluids (i.e., blood, urine, and feces). For the alcohol component, three alcohols exist pyrethrolone, cinerolone and jasmolone, and all three possess an asymmetric center that has an (S) configuration. 

In Table 3, we present the structures and names of the chrysanthemic acids that are used in the synthesis of allethrin, cyfluthrin, deltamethrin, permethrin, fenvalerate, phenothrin, resmethrin, and tetramethrin. These acids (isomers), depicted in Tables B31-B35, Appendix B, are released during metabolism and are excreted in the urine of exposed animals. A short discussion of each acid and their isomers is presented in the following paragraphs. 

Decamethrinic acid Table B35, Appendix B, gives the four isomers arising from the hydrolysis of deltamethrin. 

Figure 5, obtained from Wolansky and Harrill (2008), shows the acute toxicity (LD50) values in rats for the parent pyrethroids and one or more of their eruiched isomers. Stmctural information on the compounds tested and their purity was limited to a few of the more commonly used pyrethroids (i.e., allethrin, resmethrin, bifenthrin permethrin, deltamethrin, cypermethrin). The authors recognized the need to standardize test materials, the pyrethroid isomers used in the tests, and their purity for improving the value of information obtained from toxicological studies. 

In the past, industry sold most pyrethroids as isomer mixtures however, in recent years the active isomer or isomers are being made and sold under different, but similar product names (e.g., biopermethim, cismethrin, bioresmethrin, and deltamethrin). This reflects the fact that the manufactures were able to economically produce one, or primarily one isomer. It is, therefore, reasonable to now develop PBPK models for these active isomers, rather than to try to construct them to only reflect the metabolism of mixtures. As a result of our having reviewed the metabolism of the 15 pyrethroids of interest in this paper, we have attempted to point out the isomers of each product that were studied (e.g., labeled with " C), and to provide their relative insecticidal activities. In Appendix D, Tables D1-D15, we... 

In a rat study involving the two isomers of bifenthrin, the major metabolites found in rat plasma (Smith et al. 2002 TuUman 1987) were the parent compound, the hydrolysis product, 2-MBP alcohol, [l l-biphenyl]-3-methanol, 2-methyl (CAS no. 76350-90-8), and the oxidized product of the alcohol, 2-MBP acid, [1,1 -biphenyl]-3-carboxylic acid (CAS no. 115363-11-6). The 2-MBP acid compound is analogous to 3-phenoxybenzoic acid (CAS no. 3739-38-6), the hydrolysis product of cypermethrin, deltamethrin, permethrin, and fenvalerate (Huckle et al. 1981a, b, 1984 lARC 1991 Woollen et al. 1992). In addition to these ester-cleaved products, 4 -OH, 2-MBP alcohol (CAS no. 115340-46-0) and 4 -OH, 2-MBP acid (CAS no. NA) were found. According to Kaneko (2010), these metaboUtes are metaboUcaUy converted to dimethoxy 2-MBP alcohol and dimethoxy 2-MBP acid. 

Table D6, Appendix D, gives the metabolites of deltamethrin as presented in Figs. 58.8 and 76.8, respectively, by Kaneko and Miyamoto (2001) and Kaneko (2010). Deltamethrin (CAS no. 52918-63-5) is sold as a single chiral isomer [(IR, aS)-cis deltamethrin].

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. 

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