Tetraethyl pyrophosphate toxicity

Phosphoric Acid and Phosphorothioic Acid Anhydrides. The aUphatic organophosphoms esters originally developed by Schrader (27) are extremely toxic to mammals and are largely of historic interest. Tetraethyl pyrophosphate [107-49-3] (40) (bp 104—110°C at 10.7 Pa, d 1.185, vp 6.1 mPa at 30°C) is miscible with water and hydrolyzes very rapidly with a half-life of 6.8 h at 25°C. The rat LD qS ate 1.1 (oral) and 2.4 (dermal) mg/kg. 

Of the three organic phosphorus insecticides—hexaethyl tetraphosphate, tetraethyl pyrophosphate, and parathion—the first two have been shown to be mixtures (36) that contain tetraethyl pyrophosphate as the principal active ingredient. Several methods have been proposed for the determination of this compound in the commercial products (25, 35). All are based on the separation of the tetraethyl pyrophosphate from the related ethyl phosphates, followed by its hydrolysis to diethyl orthophosphoric acid and titration with standard alkali. Both hexaethyl tetraphosphate and tetraethyl pyrophosphate are soluble in water and are rapidly hydrolyzed to monoethyl and diethyl orthophosphoric acid. This rapid hydrolysis to nontoxic products greatly limits the duration of the in- secticidal effectiveness of tetraethyl pyrophosphate, but it also eliminates the danger of toxic residues on the crops treated. 

The purpose of this work was to determine the toxicity to mosquito larvae of insecticide spray residues. That certain insecticides are translocated in plants (4, 5) adds impetus to this study. Fresh orchard fruit sprayed or dusted with preparations containing parathion (0,0-diethyl O-p-nitrophenyl thiophosphate), tetraethyl pyrophosphate (TEPP, HEPP), DDD [2,2-bis(p-chlorophenyl)-l,l-dichloroethane], DDT [2,2-bis(p-chlorophenyl)-l,l,l-trichloroethane], chlorinated camphene, and basic lead arsenate were shipped from California to Yonkers, N. Y., by air express for bioassay. 

In addition to the tests made on peaches and apricots, samples of prunes from trees that had been sprayed with parathion, DDT, DDD, basic lead arsenate, and toxaphene at the rate of from 1 to 2 pounds of these insecticides per 100 gallons of water were tested on larvae of Aedes aegypti. The trees had been sprayed on April 20 and June 16, 1948. The fruit was harvested on or about September 10. Prunes from trees that had been treated with 1 quart of tetraethyl pyrophosphate and 12 pounds of sulfur dust per acre on June 15, and harvested about July 6, were tested on larvae of the above named species. None of the prune samples tested in this study exhibited any significant toxicity to mosquito larvae as compared with the unsprayed check. 

The purified tetraethyl pyrophosphate is a colorless, odorless, water-soluble, hygroscopic liquid (24, 4 )- It possesses a very high acute toxicity (28), exceeding that of parathion, and is rapidly absorbed through the skin. There is no spray-residue problem, however, for tetraethyl pyrophosphate hydrolyzes even in the absence of alkali to nontoxic diethyl phosphoric acid. Hall and Jacobson (24) and Toy (47) have measured its rate of hydrolysis, which is a first-order reaction. Its half-life at 25° C. is 6.8 hours and at 38° C. is 3.3 hours. Coates (10) determined the over-all velocity constant at 25° C. k = 160 [OH-] + 1.6 X 10 3 min.-1 Toy (47) has described an elegant method for preparing this ester as well as other tetraalkyl pyrophosphates, based upon the controlled hydrolysis of 2 moles of dialkyl chlorophosphate ... 

Tetraisopropyl Pyrophosphate. This ester, a water-white liquid, has been prepared by Toy (47) in 94% yield from diisopropyl chlorophosphate and water in the presence of pyridine. The ester is insecticidal and is about one tenth as toxic to white mice as tetraethyl pyrophosphate. An insecticidal dust of much greater stability than tetraethyl pyrophosphate dust can be formulated from tetraisopropyl pyrophosphate, inasmuch as the tetraisopropyl ester hydrolyzes at approximately V50th the rate at which the tetraethyl ester breaks down in the presence of moisture. 

Since selenium and all its compounds are toxic in some degree they are of no use as systemic insecticides because condition (4) is not realized. Parathion,3 however, has a low water-solubility and tetraethyl pyrophosphate (T.E.P.P.)4 is very readily hydrolysed by water. Therefore, although they have powerful insecticidal action, they are not considered by some workers as successful systemic insecticides. 

Toxicology. Tetraethyl pyrophosphate (TEPP) is a highly toxic anticholinesterase agent. 

The characteristic high group transfer potential of a phospho group in pyrophosphate linkage, which makes ATP so useful in cells, also permits tetraethyl pyrophosphate to phosphorylate active sites of acetylcholinesterases. While TEPP is very toxic, it is rapidly hydrolyzed all harmful residues are gone within a few hours after use. 

When heated to decomposition it emits toxic fumes of POx. See also TETRAETHYL PYROPHOSPHATE. 

However, our procedure is more versatile in making the homologs of tetraethyl pyrophosphate and we made a few of them and studied their properties (18). We were very much interested in the toxicity of these homologs to warm-blooded animals. The standard quick test in those days was by intraperitoneal injections into white mice to determine the MLDjq, the minimum lethal doze to kill 50% of the mice. As shown in the data in chart III, the homologs are less toxic, but for practical purposes, they are still highly toxic. We felt that they would not have any advantage over the crude tetraethyl pyrophosphate in the market at that time. 

Tetraethyl pyrophosphate. Very toxic anticholinesterase originally synthesized as a potential insecticide. Lethal dose oral 1.1 mg/kg, dermal 2.4 mg/kg. 

The first organophosphorus ChE inhibitor was probably tetraethyl pyrophosphate (TEPP), synthesized by Wurtz and tasted (with no ill results) by Clermont in 1854.4 During the next 80 years, chemists (such as Michaelis, Arbusow, and Nylen) made numerous advances in organophosphorus chemistry, but generally they did not realize the toxicity of the substances with which they were working.4... 

Pyrophosphates, such as tetraethyl pyrophosphate, of which all are extremely toxic. 

Blocking of the hydrolytic enzymes by selective hydrolase-inhibitors such as tetraethyl pyrophosphate (TEPP [1215]) or diethyl p-nitrophenylphosphate (paraoxon). However, aU of these inhibitors are highly toxic and have to be handled with extreme caution. 

The hydrogen chloride is removed either by reduced pressure or by salt formation with pyridine or sodium bicarbonate the latter procedure gave high yields of the pure ester. Toy (47) also measured the hydrolysis rates and compared the toxicities of a series of tetraalkyl pyrophosphates. Of these tested, the tetraethyl ester was the most toxic to white mice. 

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