Mode of Action of Insecticides, Metabolism and Selectivity of O,O-Dimethyl 2,2,2-Trichloro-1-hydroxyethyl Phosphonate and Its Acetyl and Vinyl Derivatives

Abstract

0,O-dimethyl 2,2,2-trichloro-l -hydroxyethyl phosphonate (L13/59) and its acetyl derivative (0,O-dimethyl 2,2,2-trichloro-l -acetoxyethyl phosphonate), and vinyl derivative formed on dehydrochlorination (0,O-dimethyl 2,2-dichlorovinyl phosphate) were investigated with phosphorus-32-tagged materials in relation to their metabolism and selective toxicity. A marked variation in species susceptibility was demonstrated; the vinyl phosphate was generally more toxic but less selectively toxic than the two phosphonates. Antiesterase activity of the three compounds appeared to be due to dimethyl phosphorylation of the enzymatically active sites. Acetyl L13/59 may be enzymatically deacetylated in vivo to form the more active antiesterase, L13/59. The greater activity with the free a-hydroxyl may be due to hydrogen bonding between the L13/59 and the esterase. Although several different types of experimental approaches were utilized, no evidence was obtained for in vivo L13/59 dehydrochlorination and rearrangement to the more toxic vinyl phosphate. The low mammalian toxicity of L13/59 appears to be due to phosphonate hydrolysis b y serum esterases and elimination of the trichloro-portion of the molecule in the urine as trichloroethyl glucuronide. Studies are reported on the rate and products of acid and alkaline hydrolysis of the three derivatives, as are observations on their phytotoxicity, volatility, and in vivo distribution in certain insects and plants.A 2 , 2 , 2 -tric hloro-1 -hydroxyethyl phosphonate (L13/59) has attracted considerable interest for housefly control and for potential use as a systemic in the treatment of animals infested with endo-and ectoparasitic arthropods (7, 7, 27, 37). In the presence of dilute alkali, this trichlorohydroxyethyl phosphonate undergoes a dehydrochlorination and rearrangement reaction, yielding the highly insecticidal vinyl derivative. 0,O-dimethyl 2,2-dichlorovinyl phosphate (DDVP) (5, 29, 37). The formation of an acetyl derivative, 0,O-dimethyl 2,2,2-trichloro -1-acetoxyethyl phosphonate, involves blocking the active hydrogen taking part in dehydrochlorination and possibly in hydrogen bonding reactions.Mammals poisoned with L13/59 display a rapid recovery of cholinesterase activity of serum and brain compared with the phosphate and phosphorothioate insecticides now being used (24). DuBois and Cotter (76) postulated that this rapid in vivo reactivation of the cholinesterase and possibly the low toxicity to mammals may be due to the ease of metabolic degradation and a rapid dissociation of the enzyme-inhibitor combination.This investigation concerns the metabolism and selective toxicity of L13/59 and its acetyl phosphonate and vinyl phosphate derivatives.Radio-phosphorus-labeled insecticides were used to investigate the in vivo and in vitro metabolism of thrse materials. Materials and Methods 0,O-Dimethyl 2,-Synthesis of 2,Z-Tr ic hlor o-lRadiophosphorus h y d r o x y e t h y lPhosphonate (desInsecticides ignated as the hydroxyethyl phosphonate or L13/59 based on the Bayer code num...

Newly Observed Spontaneous Activation of Ethephon as a Butyrylcholinesterase Inhibitor

“…Increasing the pH of the preincubation buffer above 7 increases the rate of conversion. 32 The principal differences between the two inhibitors are that 62% of the trichlorphon is converted to its activated form, 33 while only 3% of the ethephon appears to be converted to its effective activated form, and dichlorvos is stable in aqueous media.…”

Pesticide Toxicity, Biological Activity of Several O,O-Dialkyl Alpha-Acyloxyethyl Phosphonates

“…Chromatography of the chloroform-soluble ma-terials of the reaction mixture on silica gel with «-hexane, followed by chloroform elutrients, yielded more than 99% of the total radioactivity7 in the chloroform fraction. This major fraction was identical to known Dipterex in infrared absorption spectrum, and the total phosphorus (colorimetric analysis) and total radioactivity were present in the same compound based on chromatographic behavior, partition distribution between chloroform and water, dehydrochlorination rate (4, 20), and hydrolysis rate in alkali (2).…”

“…The dialkyl -hydroxyethyl phosphonates shown in Table I w'ere prepared by the addition of chloral to equimolar dialkyl hydrogen phosphites (5,79). Carboxylic esters were synthesized by esterification of the -hydroxyethyl phosphonates with equimolar acid anhydrides or acyl chlorides (2,5). A single acyloxy derivative, butonate, was also prepared in very low yields by coupling a-chloro-/3-trichloroethyl n-butyrate (70) with equimolar dimethyl phosphite and by the addition of methanol and phosphorus trichloride to the a-chloro-/3-trichloroethyl n-butyrate intermediate in a 3 to 1 to 1 molar ratio.…”

“…The reaction mixtures were partially purified by adding water, extracting with n-hexane to recover the a-acyloxyethyl phosphonates and then with chloroform to recover the a-hydroxyethyl phosphonates. These separated fractions were then chromatographed on silica gel (2) and the acyloxyethyl derivatives eluted with hexane and the hydroxyethyl derivatives with chloroform. Elementary analyses of 0,0diethyl 2,2,2-trichloro-l -acetoxyethyl phosphonate purified in this way gave carbon, 29.36%; hydrogen, 4.43%; chlorine, 32.70%; and phosphorus, 9.29%.…”

Trichlorfon Residues in Lettuce

“…It is hydrolyzed rapidly in plant tissues to a number of metabolites (Arthur & Casida, 1957;Bull & Ridgeway, 1969). The Joint Meeting of the F A 0 Working Party of Experts on Pesticide Residues and WHO Expert Committee on Pestii cide Residues stated in their report (WHO, 1971) that more information is needed on the disappearance of trichlorfon in leaf and head lettuce under different climatic conditions.…”