Neurotoxicity is observed at 15 mg/kg/day of esfenvalerate (0.1, 1, 7.5, or 15 mg/kg/day; gavage; from GD 13 to 19) [1].

Absorption, Distribution and Excretion
On a single oral dose or five consecutive oral doses of (14)C esfenvalerate or (14)C-fenvalerate labeled in the acid moiety to 13-day pregnant rats at rates of 2.5 and 10 mg/kg/day, respectively, the maternal blood and placenta generally showed higher (14)C levels as compared with the fetus and amniotic fluid. Both compounds and their metabolites did not transfer readily from the maternal blood to the fetus, the amount of (14)C transferred being less than 0.07% of the dose. There were no substantia differences in the fetal (14)C level and the transfer ratio ((14)C tissue level/(14)C maternal blood level) between both labeled preparations. Major (14)C-compounds in the fetus, maternal blood and placenta were the parent compounds, CPIA(2-(4-chlorophenyl)isovaleric acid) and CPIA-hydroxylated derivatives and there was no qualitative difference in metabolic fates between the two compounds, except that a trace amount of CPIA-cholesterol ester (cholesteryl (2R)-2-(4-chlorophenyl)isovalerate) was detected in the maternal blood and placenta only with fenvalerate. CPIA-cholesterol ester did not seem to transfer from the maternal blood to the fetus. Overall, esfenvalerate and fenvalerate seem to behave in the same manner as far as placental transfer was concerned.
Pydrin insecticide (Y-rich) is an isomerically enriched form of fenvalerate containing an excess ratio of the active diastereomers SS and RR (designated Y) over the less active diastereomers RS and SR (designated X) at a ratio of approximately 85:15. Fenvalerate contains Y:X in a ratio of 45:55. Following a single oral dose of the Y-rich insecticide (8.4 mg/kg) to male and female Sprague-Dawley rats, more than 90% of the administered radioactivity from the acid moiety (chlorophenyl-(14)C) and the alcohol moiety (phenoxyphenyl-(14)C) was eliminated within the first 24 hr. There was no major difference between the two different fenvalerate preparations in either the elimination rate or the metabolites distribution profile. Cleavage of the ester linkage was the primary metabolic pathway. The acid and alcohol portions of the parent molecule underwent hydroxylation, oxidation, and conjugation. These metabolic reactions were not dependent on the isomeric composition of the test material. Tissue residue data showed that (14)C residues were not retained in the various organs ... . /Pydrin insecticide (Y-rich)/
Following a single oral administration of the four chiral isomers of (14)C-chlorophenyl-fenvalerate to Sprague-Dawley rats and ddY mice (2.5 mg/kg body weight), the (2R, alphaS) isomer showed, in both rats and mice, relatively greater residues in the analyzed tissues (except fat), particularly in adrenal glands, compared with the other three isomers. Similarly, this isomer showed higher tissue concentrations than the other isomers when mice were fed a diet containing 500 mg/kg of the (2S, alphaS), (2R, alphaS), or (2R, alphaR) isomers for two weeks. The greater amount of radioactive residues from the administration of (2R, alphaS) isomer, as compared with those of other isomers, was explained by the preferential formation of a lipophilic metabolite from the (2R, alphaS) isomer found in all examined tissues, which was not easily excreted. The amounts of the lipophilic metabolite differed among tissues, being higher in adrenal, liver, and mesenteric lymph nodes. This metabolite was identified as cholesteryl (2R)-2-(4-chlorophenyl)isovalerate. The presence of the same metabolite was also indicated in rat tissues ... . /Fenvalerate isomers/
Two 3-month-old lambs were fed a diet containing 45 mg/kg fenvalerate for 10 days and then killed to determine the concentrations of fenvalerate in the kidney, liver, leg muscle, and renal fat ... . Among the analyzed tissues, fat showed the highest fenvalerate level (3.6-4.4 mg/kg dry weight) while other tissues contained less than 0.3 mg/kg. Fenvalerate gave two gas chromatographic peaks and each peak contained a pair of its enantiomers. In all cases, the ratio of the areas of these peaks (peak 1 (RS,SR)/peak 2 (SS,RR)) was 1.08 both for fenvalerate in the diet and for fenvalerate recovered from the fortified control fat. In contrast, the fenvalerate isolated from lamb fat had a peak area ratio of 0.76-0.78. Thus,one or both of the first eluting enantiomers appeared to be metabolized more rapidly than the other enantiomers. /Fenvalerate isomers/
For more Absorption, Distribution and Excretion (Complete) data for ESFENVALERATE (9 total), please visit the HSDB record page.

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Metabolism / Metabolites
The metabolism of racemic fenvalerate and of its (2S, alphaS) isomer was examined in cabbage plants grown under laboratory conditions and treated (20 ug per leaf) with (14)C-chlorophenyl- and phenyl-(14)C-benzyl-labelled preparations of the two compounds. Both compounds disappeared from the treated leaves with similar half-lives of approximately 12-14 days. They underwent ester cleavage to a significant extent, together with some hydroxylation at the 2- or 4-position of the phenoxy ring and hydrolysis of the nitrile group to amide and carboxyl groups. Most of the carboxylic acids and phenols thus produced occurred as glycoside conjugates. ... The uptake and metabolism of 2-(4-chlorophenyl)isovelaric acid (CPIA) ... was examined in the laboratory using abscised leaves of kidney bean, cabbage, cotton, cucumber, and tomato plants. The acid ... was found to be readily converted, mainly into glucose or 6-O-malonylglucose esters in kidney bean, cabbage, and cucumber, into glucosylxylose, sophorose, and gentiobiose esters in cotton, and into two types of triglucose esters with differing isomerism in tomato. One of the acetyl-derived glucoside conjugates was identical with the authentic decaacetyl derivative of the (1-6)-triglucose ester ... .
Pydrin insecticide (Y-rich) is an isomerically enriched form of fenvalerate containing an excess ratio of the active diastereomers SS and RR (designated Y) over the less active diastereomers RS and SR (designated X) at a ratio of approximately 85:15. Fenvalerate contains Y:X in a ratio of 45:55. Following a single oral dose of the Y-rich insecticide (8.4 mg/kg) to male and female Sprague-Dawley rats ... there was no major difference between /chlorophenyl-(14)C- and phenoxyphenyl-(14)C-/ fenvalerate preparations in ... the metabolites distribution profile. Cleavage of the ester linkage was the primary metabolic pathway. The acid and alcohol portions of the parent molecule underwent hydroxylation, oxidation, and conjugation. These metabolic reactions were not dependent on the isomeric composition of the test material. Tissue residue data showed that (14)C residues were not retained in the various organs ... . /Pydrin insecticide (Y-rich)/
In mice, fenvalerate is metabolized in a similar way to that in rats, but the following significant species differences were found ... (a) the taurine conjugate of phenoxybenzoic acid (PBacid) was found in mice but not in rats; (b) 4'-OH-PBacid sulfate occurred to a greater extent in rats than in mice; and (c) a greater amount of thiocyanate was excreted in mice than in rats. No significant sex differences were observed in rats and mice. The metabolism of the stereoisomers of fenvalerate, ((2S, alphaRS) and (2S, alphaS)) was apparently similar to that of racemic fenvalerate.
In an in vitro study on the metabolism of the four chiral isomers of fenvalerate using homogenates from various tissues of mice, rats, dogs, and monkeys, only the (2R, alphaS) isomer yielded cholesteryl-(2R)-2-(4-chloro-phenyl)isovalerate (CPIA-cholesterol ester) as a major metabolite. Mouse tissues exhibited a higher rate of CPIA-cholesterol ester formation than those of other animals. Of the mouse tissues tested, the kidney, brain, and spleen showed the greatest ability to form this ester, the relevant enzyme activity being mainly localized in the microsomal fractions. Carboxyesterases for mouse kidney microsomes hydrolyzed the (2R, alphaS) isomer only of fenvalerate to give CPIA and yielded the corresponding cholesterol ester in the presence of artificial liposomes containing cholesterol. It appears that the CPIA-cholesterol ester resulted from the stereoselective ((2R, alphaS) only) formation of the CPIA-carboxyesterase complex, which subsequently reacted with cholesterol to yield the CPIA-cholesterol ester ... The /mouse/ kidney, spleen and brain hydrolyzed only the (2R, alphaS) isomer. Liver hydrolyzed the (2R, alphaS) and (2R, alphaR) isomers to a greater extent than the (2S, alphaR) and (2S, alphaS) isomers, while plasma hydrolysed the (2S, alphaR) and (2R, alphaR) isomers more rapidly than the (2S, alphaS) and (2R, alphaS) isomers. The stereoselectivity of hydrolysis of the four isomers by mouse liver microsomes was found to be same as that in vivo. Of the four isomers, the (2R, alphaS) isomer alone was transformed to cholesteryl-(2R)-2-(4-chlorophenyl) isovalerate (CPIA-cholesterol ester) by microsomes of the brain, kidney, spleen, or liver but not by plasma. The rate of CPIA-cholesterol ester formation was lower in the liver than in other tissues. The optimum pH (7.4-9.0) for the formation of this ester was nearly the same as that for hydrolysis of the (2R, alphaS) isomer to form CPIA in mouse kidney microsomes. /Fenvalerate isomers/
For more Metabolism/Metabolites (Complete) data for ESFENVALERATE (8 total), please visit the HSDB record page.

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Biological Half-Life
One male and one female Sprague-Dawley rats and four male and four female ddY mice were given single oral doses of ((14)C-carbonyl)-, ((14)C-benzyl)- or ((14)C-cyano)-fenvalerate at 7 mg/kg bw or ((14)C-chlorophenyl)-, ((14)C-phenoxybenzyl)- or ((14)C-cyano)-esfenvalerate at 4.2 mg/kg bw. Each of the labelled compounds was also administered to two male and two female rats at a dose of 30 mg/kg bw. Urine and feces were collected daily for 6-7 days, and CO2 was collected from those rats and mice that received ((14)C-cyano)-labelled compound. ... The two rats given low doses of ((14)C-chlorophenyl)- or ((14)C-phenoxybenzyl)-esfenvalerate and fenvalerate ... /had an excretion/ half-life of ... 0.5-0.6 days. ... /The excretion/ half-life of radioactivity /for mice at the same dose levels/ was 0.5-0.6 days. The rats given ((14)C-chlorophenyl)- or ((14)C-phenoxybenzyl)-esfenvalerate at 30 mg/kg bw ... /had an excretion/ half-life of 0.6-0.9 days. In rats given the lower doses of ((14)C-cyano)-fenvalerate and esfenvalerate, the excretion ... half-life /was/ 1.7-2.0 days. In similarly treated mice, the excretion ... half-life /was/ 1-1.7 days. ...

[1]. Anne-Marie Saillenfait, et al. The Pyrethroid Insecticides Permethrin and Esfenvalerate Do Not Disrupt Testicular Steroidogenesis in the Rat Fetus. Toxicology. 2018 Dec 1;410:116-124.

Esfenvalerate is a fenvalerate. It has a role as a pyrethroid ester insecticide and an agrochemical.

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Mechanism of Action
Esfenvalerate is a type two synthetic pyrethroid. The primary mechanism of action of pyrethroids is interference with the closing of voltage-dependent sodium channels, resulting in repetitive firing of neurons. After exposure the organism may exhibit hyperexcitation, tremors, convulsions, and/or salivation, followed by lethargy, paralysis, and death. Type two pyrethroids, those that contain a cyano group in the alcohol and halogen in the acid, are also reported to have effects at the presynaptic membrane of voltage-dependent calcium channels and to interfere with ATPase enzymes involved with maintaining ionic concentration gradients across membranes.
Interaction with sodium channels is not the only mechanism of action proposed for the pyrethroids. Their effects on the central nervous system have led various workers to suggest actions via antagonism of gamma-aminobutyric acid (GABA)-mediated inhibition, modulation of nicotinic cholinergic transmission, enhancement of noradrenaline release, or actions on calcium ions. Since neurotransmitter specific pharmacological agents offer only poor or partical protection against poisoning, it is unlikely that one of these effects represents the primary mechanism of action of the pyrethroids, and most neurotransmitter release is secondary to increased sodium entry. /Pyrethroids/
The biochemical process by which various pyrethroid insecticides alter membrane-bound ATPase activities of the squid nervous system was examined. Of the 5 ATP-hydrolyzing systems tested, only Ca(2+)-stimulated ATPase activities were clearly affected by the pyrethroids. The natural type /I/ pyrethroid, allethrin, primarily inhibits Ca-ATPase activity. /Pyrethroids/
The interactions of natural pyrethrins and 9 pyrethroids with the nicotinic acetylcholine (ACh) receptor/channel complex of Torpedo electronic organ membranes were studied. None reduced (3)H-ACh binding to the receptor sites, but all inhibited (3)H-labeled perhydrohistrionicotoxin binding to the channel sites in presence of carbamylcholine. Allethrin inhibited binding noncompetitively, but (3)H-labeled imipramine binding competitively, suggesting that allethrin binds to the receptor's channel sites that bind imipramine. The pyrethroids were divided into 2 types according to their action: type A, which included allethrin, was more potent in inhibiting (3)H-H12-HTX binding and acted more rapidly. Type B, which included permethrin, was less potent and their potency increased slowly with time. The high affinities that several pyrethroids have for this nicotinic ACh receptor suggest that pyrethroids may have a synaptic site of action in addition to their well known effects on the axonal channels. /Pyrethrins and Pyrethroids/
For more Mechanism of Action (Complete) data for ESFENVALERATE (7 total), please visit the HSDB record page.

C25H22CLNO3

419.91

419.128

66230-04-4

10342051

White crystalline solid
Colorless crystals
Clear viscous liquid at 23 °C

1.2±0.1 g/cm3

538.9±50.0 °C at 760 mmHg

59°C

279.7±30.1 °C

0.0±1.4 mmHg at 25°C

1.586

6.68

0

4

8

30

586

2

CC(C)[C@@H](C1=CC=C(C=C1)Cl)C(=O)O[C@H](C#N)C2=CC(=CC=C2)OC3=CC=CC=C3

NYPJDWWKZLNGGM-RPWUZVMVSA-N

InChI=1S/C25H22ClNO3/c1-17(2)24(18-11-13-20(26)14-12-18)25(28)30-23(16-27)19-7-6-10-22(15-19)29-21-8-4-3-5-9-21/h3-15,17,23-24H,1-2H3/t23-,24+/m1/s1

[(S)-cyano-(3-phenoxyphenyl)methyl] (2S)-2-(4-chlorophenyl)-3-methylbutanoate

Asana Esfenvalerate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~238.15 mM)

Solubility in Formulation 1: 2.5 mg/mL (5.95 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (5.95 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.95 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)