A-Cyano pyrethroids

Metabolism of the 2,S -isomers proceeds sequentially hydroxylation at the phenoxy group, hydrolysis of the cyano group, and cleavage of the ester linkage (Coats et al. 1989). Fenvalerate and the IS-isomers yield two ester metabolites in feces from hydroxylation at the 4 - and 2 -phenoxy positions. Other significant metabolites were 3-phenoxybenzoic acid and its hydroxy derivatives from the alcohol moiety, 3-(4-chlorophenyl) isovaleric acid and its hydroxy derivatives from the acid moiety, and thiocyanate and carbon dioxide from the cyano moiety (Ohkawa et al. 1979). A slow elimination rate characterizes fenvalerate and other a-cyano pyrethroids when compared with... 

The effects of pyrethroids on acoustic startle response (ASR) were examined to detect the effects on sensorimotor function. Pyrethroids show various effects on ASR (Table 3). Crofton and Reiter reported that non-cyano pyrethroids showed no effect on the latency, while they increased the amplitude. a-Cyano pyrethroids showed increase or no change on the latency, while various effects on the amplitude were observed [30, 31]. Fenvalerate showed effects similar to non-cyano pyrethroids. In studies by Hijzen et al. [32, 33], the results of permethrin and deltamethrin on the amplitude were consistent with the findings by Crofton and Reiter, but cypermethrin induced contradictory effects. NAK 1901 showed similar effects to other non-cyano pyrethroids. The reason for the inconsistency of effects of pyrethroids on startle response remains unsolved. 

Hao XL, Kuang H, Li YL, Yuan Y, Peng CF, Chen W, Wang LB, Xu CL (2009) Development of an enzyme-linked immunosorbent assay for the a-cyano pyrethroids multiresidue in Tai lake water. J Agric Food Chem 57 3033-3039... 

Myelinated nerves of vertebrates are thought to sequester the pyrethroid molecules, known to be soluble in the myelin sheath, thereby preventing a portion of their chemical effect on the nerve axon. Fenvalerate, unlike other a-cyano pyrethroids, had little effect on the electro-physiological function of single myelinated nerve fibers in the frog Ram esculenta), suggesting that additional research is needed on mechanisms other than membrane sodium transport. 

Fenvalerate and other a-cyano pyrethroids, however, are consistently more resistant to oxidative attack than their noncyano analogs. Liver is the predominant site of fenvalerate metabolism via hydrolysis by one or more hepatic microsomal esterases inhibition of these enzymes results in enhanced toxicity. Hydrolysis has also been demonstrated in plasma, kidney, stomach, and brain tissues. Except for brain, however, these tissues were relatively unimportant in the detoxification process. 

Pyrethroid Esters of Benzene Acetate. These insecticides have more extensive stmctural optimization in both acid and alcohol moieties. Fenvalerate [51630-58-17, a-cyano-(3-phenoxyphenyl)methyl (+)-(2R,5)"Ct"isoprop5i-4-chlorophenylacetate (24) d 1.17, vp 1.4 p.Pa at 25°C), a mixture of four isomers, is soluble in water to 0.3 mg/L The rat oral LD q is 450 mg/kg. Esfenvalerate [66230-04-4] is the (+)-2-(i, 5)-isomer (mp 59°C). The rat LD qS are 75, 458 (oral), and the rabbit dermal LD q is 2000 mg/kg. These pyrethroids are widely used general-purpose insecticides for field, vegetable, and fmit crops. 

Synthetic pyrethroids with a-cyano ester group react with sodium hydroxide to yield hydrogen cyanide, which reacts with 4-nitrobenzaldehyde and 1,2-dinitrobenzene to yield a pink-colored derivative (o-quinonoid di-anion) according to the following scheme ... 

Figure 9 Structure of the immunogen hapten used to generate antibodies for a type I pyrethroid class-selective assay. Pyrethroids lacking an a-cyano group are generally termed type I. This hapten exposed the features most common to type I pyrethroids, the phenoxybenzyl group, the cyclopropyl group and the lack of a cyano group, resulting in antibodies that recognized permethrin, phenothrin, resmethrin and bioresmethrin, but not cypermethrin...

Synthetic pyrethroids now account for at least 30% of the world insecticide market and are rapidly replacing other agricultural chemicals for control of insect pests. Fenvalerate is one of the more widely used synthetic pyrethroid insecticides. It is derived from a combination of a-cyano-3-phenoxybenzyl alcohol and a-isopropyl phenylacetate ester. Technical fenvalerate is a mixture of four optical isomers, each occurring in equal amounts but with different efficacies against insect pests. Fenvalerate does not usually persist in the environment for >10 weeks, and it does not accumulate readily in the biosphere. Time for 50% loss (Tb 1/2) in fenvalerate-exposed amphibians, birds, and mammals was 6 to 14 h for reptiles, terrestrial insects, aquatic snails, and fish it was >14 h to <2 days and for various species of crop plants, it was 2 to 28 days. Fenvalerate degradation in water is due primarily to photoactivity, and in soils to microbial activity. Half-time persistence in nonbiological materials is variable, but may range up to 6 days in freshwater, 34 days in seawater, 6 weeks in estuarine sediments, and 9 weeks in soils. 

Type I those pyrethroids lacking the a-cyano group... 

In general, these authorities agree that pyrethroids containing both a halogenated acid esterified with the a-cyano-3-phenoxybenzyl alcohol — such as fenvalerate, deltamethrin, and cyper-... 

In 1958, Barthel et al. [25] reported dimethrin (15), which was the first substituted benzyl alcohol ester of chrysanthemic acid. This compound was not put into practical use due to its low insecticidal activities. Phenothrin (16), one of the m-phenoxybenzyl alcohol esters developed by Fujimoto et al. [26], was found to have superior chemical stability as well as safety, and has been the sole pyrethroid used as a lice control agent for humans. Further improvement was made by Matsuo et al. [27] who introduced a cyano function at the a position of the benzyl part of phenothrin, leading to a-cyano-m-phenoxybenzyl alcohol esters (17). Thereafter, this alcohol moiety has been used as a component for a number of photostable pyrethroids for agricultural purposes however, the development of cross-resistance can be seen in some pests. 

In an extension to the studies mentioned above, the actions of 11 commercial pyrethroids on calcium influx and glutamate release were assessed using a high-throughput approach with rat brain synaptosomes [75, 76]. Concentration-dependent response curves for each commercial pyrethroid were determined and the data used in a cluster analysis. Previously characterized Type II pyrethroids that induce the CS-syndrome symptoms (cypermethrin, deltamethrin, and esfenvalerate) increased calcium influx and glutamate release, and clustered with two other ot-cyano pyrethroids (p-cyfluthrin and A-cyhalothrin) that shared these same actions. Previously characterized Type I pyrethroids (bioallethrin, cismethrin, and fenpropathrin) did not share these actions and clustered with two other non-cyano pyrethroids (tefluthrin and bifenthrin) that likewise did not elicit these actions. 

Under the Food Quality Protection Act (FQPA), the U.S. EPA evaluates the potential for people to be exposed to more than one pesticide at a time from a group of chemicals with an identified common mechanism of toxicity. As part of the examinations, to clarify whether some or all of the pyrethroids share a common mechanism of toxicity, a comparative FOB (functional observational battery) studies with 12 pyrethroids were carried out under standardized conditions [15]. The FOB was evaluated at peak effect time following oral administration of non-lethal doses of pyrethroids to rats using com oil as vehicle. Four principal components were observed in the FOB data [22], Two of these components described behaviors associated with CS syndrome (lower body temperature, excessive salivation, impaired mobility) and the others described behaviors associated with the T syndrome (elevated body temperature, tremor myoclonus). From the analysis, pyrethroids can be divided into two main groups (Type I T syndrome and Type II CS syndrome) and a third group (Mixed Type) that did not induce a clear typical response. Five other pyrethroids were also classified by an FOB study conducted in the same manner [16]. The results of these classifications are shown in Table 1. The FOB results for all non-cyano pyrethroids were classified as T syndrome, and the results of four ot-cyano pyrethroids were classified as CS syndrome however, three of the ot-cyano pyrethroids, esfenvalerate, cyphenothrin, and fenpropathrin, were classified as Mixed Type. 

Although cumulative effects of cyano and non-cyano pyrethroids on motor activity were reported [23], it is difficult to demonstrate the common mechanism using such a non-specific endpoint, as motor activity is an apical measure of the disruption of nervous system function [24]. 

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