Chlorfenvinphos

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Chlorfenvinphos
Chlorfenvinphos Structures V.1.svg
Chlorfenvinphos 3D spacefill.png
Names
IUPAC name
[(EZ)-2-Chloro-1-(2,4-dichlorophenyl)ethenyl] diethyl phosphate
Other names
Clofenvinfos; Chlorfenvinfos; Chlorphenvinfos; Chlofenvinphos; Chlofenvinfos; Vinylphate; Apachlor; Birlane; Dermaton; Enolofos; Haptarax; Haptasol; Dermaton; Sapercon; Steladone; Supona
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.006.758 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 207-432-0
KEGG
PubChem CID
RTECS number
  • TB8750000
UNII
UN number 3018
  • InChI=1S/C12H14Cl3O4P/c1-3-17-20(16,18-4-2)19-12(8-13)10-6-5-9(14)7-11(10)15/h5-8H,3-4H2,1-2H3/b12-8- Yes check.svgY
    Key: FSAVDKDHPDSCTO-WQLSENKSSA-N Yes check.svgY
  • InChI=1/C12H14Cl3O4P/c1-3-17-20(16,18-4-2)19-12(8-13)10-6-5-9(14)7-11(10)15/h5-8H,3-4H2,1-2H3/b12-8-
    Key: FSAVDKDHPDSCTO-WQLSENKSBC
  • Clc1cc(Cl)ccc1C(OP(=O)(OCC)OCC)=[C@H]Cl
Properties
C12H14Cl3O4P
Molar mass 359.56 g·mol−1
AppearanceAmber liquid
145 mg/L
Hazards
GHS labelling: [1]
GHS-pictogram-skull.svg GHS-pictogram-pollu.svg
Danger
H300, H311, H330, H410
P260, P262, P264, P270, P271, P273, P280, P284, P301+P316, P302+P352, P304+P340, P316, P320, P321, P330, P361+P364, P391, P403+P233, P405, P501
NFPA 704 (fire diamond)
NFPA 704.svgHealth 4: Very short exposure could cause death or major residual injury. E.g. VX gasFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
4
1
0
Lethal dose or concentration (LD, LC):
15  mg/kg (rat, oral)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Chlorfenvinphos is an organophosphorus compound that was widely used as an insecticide and an acaricide. [2] The molecule itself can be described as an enol ester derived from dichloroacetophenone and diethylphosphonic acid. Chlorfenvinphos has been included in many products since its first use in 1963. However, because of its toxic effect as a cholinesterase inhibitor it has been banned in several countries, including the United States and the European Union. Its use in the United States was discontinued in 1991. [3]

Contents

The pure chemical is a colorless solid, but for commercial purposes, it is often marketed as an amber liquid. The insecticides, mostly used in liquid form, contain between 50% and 90% chlorfenvinphos. The substance easily mixes with acetone, ethanol, and propylene glycol. Furthermore, chlorfenvinphos is corrosive to metal and hydrolyzes in the environment. [4]

It is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002), and is subject to strict reporting requirements by facilities which produce, store, or use it in significant quantities. [5]

Pesticide use

History

Dermaton was the first registered product containing chlorfenvinphos. It was introduced in the United States in 1963 and was used as an insecticide and acaricide for controlling fleas and ticks on domestic pets and other animals. Between 1963 and 1970, additional uses were registered, including the use as fly spray, surface spray and larvicide. Because of these effects, chlorfenvinphos was often used on farms to control adult flies in dairy barns, milk rooms, poultry houses and yards, and in other animal buildings. Furthermore, it was used to control larval flies in manure storage pits and piles and other refuse accumulation areas around dairies and feedlots. [3] In the early 1980s, chlorfenvinphos was registered for additional uses in a dust formulation for use in dog kennels and in dog collars for the control of fleas and ticks. [6]

Outside the United States, chlorfenvinphos, registered under the trade names Birlane, C8949, CGA 26351, Sapecron, Steladone and Supona, was used as a soil insecticide for controlling root maggots, root worms and cutworms. Chlorfenvinphos was also used against Colorado beetles on potatoes and scale insects and mite eggs on citrus. Furthermore, the compound had the same uses as in the United States.

There is no quantitative information on the total volume of chlorfenvinphos really used as a pesticide in the United States or elsewhere. Since all uses of the chemical in the United States were canceled in 1991, use is likely to have declined, although there are no data showing this trend.

Regulation and advisories

No international regulations exist for the use of chlorfenvinphos, although standards and guidelines have been set to protect people from the possible harmful effects of the toxin. No regulation exists for inhalation exposure, but multiple minimal risk levels (MRL) have been estimated for oral exposure. These data have been developed from lowest observed adverse effect levels (LOAEL) in test rats, based on adverse neurological effects. The acute oral MRL has been established at 0.002 mg/kg/day, while the chronic MRL has been established somewhat lower, at 0.0007 mg/kg/day.

Furthermore, chlorfenvinphos is one of the chemicals regulated under “The Emergency Planning and Community Right-to-Know act of 1986”. This means that owners and operators of certain facilities that manufacture, import, process or otherwise use the chemical, are obligated to report their annual release of the chemical to any environmental media. [4]

However, the use of chlorfenvinphos has now been banned in the European Union and in the United States. In Europe it is banned as a plant protection product. An exception is Switzerland, where chlorfenvinphos is still allowed for use in crops and certain vegetables under the brand name Birlane. In Australia, chlorfenvinphos is partially banned. Thus, it was withdrawn in alfalfa, potatoes and mushrooms, while it is still used in veterinary medicine for combating ectoparasites until 2013. [7]

Production

Chlorfenvinphos was first introduced in the United States in 1963, by the Shell International Chemical Company Ltd., Ciba AG (now Ciba-Geigy AG) and by Allied Chemical Corporation. Its main use was as an insecticide and acaricide used to control insect pests on livestock and household pests such as flies, fleas, and mites. [8] Since its first application, many manufacturers included chlorfenvinphos in their products. Some common trade names are Birlane, Dermaton, Sapercon, Steladone, and Supona. [4] Since 1991, however, information on current production of chlorfenvinphos has been conflicting. One source lists base producers of the compound as the American Cyanamid Company. [8] However, no producers of chlorfenvinphos were identified in a 1993 Directory of Chemical Producers for the United States of America. [9] Moreover, there have been no registered uses for this compound as a pesticide in the United States since 1995. [3]

Chlorfenvinphos is produced by reaction of triethylphosphite (P(OEt)3) with 2,2,2,4-tetrachloro acetophenone (C8H4Cl4O). In the production process, both the Z and E isomers are formed in a ratio (Z:E) of 8.5:1. The technical grade material therefore contains over 92% chlorfenvinphos. [10]

Unfortunately, no data is available in the Toxics Release Inventory (TRI) database on total environment releases of this compound from facilities. This is mainly because chlorfenvinphos was not considered a dangerous toxin until the early 1990s. Therefore, chlorfenvinphos is not one of the compounds about which facilities were required to report to the Toxic Release Inventory. [6]

Toxicokinetics

Chlorfenvinphos is most commonly absorbed into the body through either ingestion of food products that have been treated with the pesticide, or through dermal absorption, though the latter is much less efficient.

Once absorbed, chlorfenvinphos is widely distributed throughout the body, and has been detected in a variety of bodily fluids. [11] However, as an organophosphorus compound, it does not accumulate well in tissues.

The first and most important step of metabolism of chlorfenvinphos in humans is accomplished by the enzyme cytochrome P450 in liver microsomes. This enzyme facilitates oxidative dealkylation of the compound to acetaldehyde and 2-chloro-1-(2,4-dichlorophenyl) vinylethylhydrogen phosphate, the latter of which quickly breaks down to acetophenone. Acetophenone is then reduced to an alcohol and conjugated by glutathione transferases., [12] [13]

Excretion of chlorfenvinphos is fairly rapid. In rats, an administered dose is excreted in 4 days, mostly in urine. [14]

Mechanism of toxicity

The toxicity of chlorfenvinphos is primarily caused by its inhibition of cholinesterase activity. Chlorfenvinphos reacts with the acetylcholine binding sites of enzymes that hydrolyze acetylcholine, thereby preventing their catalysis of this reaction. The reaction itself is a phosphorylation, which is reversible. The phosphorylated enzymes can undergo conformational changes and additional reactions however, which prevent the dephosphorylation. This “aging” results in irreversible inhibition of the cholinesterase. [4]

Acetylcholine is a neurotransmitter in the nervous system, it targets muscarinic and nicotinic receptors and receptors in the central nervous system. These receptors are used to pass on an action potential across the synaptic cleft between neurons. Inhibition of acetylcholinesterase enzymes results in the accumulation of acetylcholine at its receptors. This leads to continuous or excessive stimulation of neurons that respond to acetylcholine. Cholinergic poisoning leads to different symptoms, depending on the part of the nervous system that is affected. The most likely cause of death in chlorfenvinphos is respiratory failure due to paralysis and bronchoconstriction. [4]

Toxicity

Toxic effects

The toxic effects of accumulation of acetylcholine can be divided into three categories, based upon its actions in different parts of the nervous system. Muscarinic receptors that respond to acetylcholine are found in smooth muscles, the heart and exocrine glands. The muscarinic symptoms of cholinergic poisoning are therefore tightness in the chest, wheezing due to bronchoconstriction, bradycardia, miosis, increased salivation, lacrimation and sweating and increased peristalsis, which leads to nausea, vomiting and diarrhea.

Nicotinic receptors responding to acetylcholine can be found in skeletal muscle and the autonomic ganglia. The nicotinic symptoms of cholinergic poisoning are therefore fatigue, involuntary twitching, muscular weakness, hypertension and hyperglycemia.

Symptoms of accumulation of acetylcholine in the central nervous system are diverse and include tension, anxiety, ataxia, convulsions, depression of the respiratory and circulatory centers and coma. [15]

Acute toxicity

The acute toxicity of chlorfenvinphos varies widely between species. Oral LD50 values range from 9.6–39 mg/kg in rats to >12,000 mg/kg in dogs. [16] Though no direct data on the acute toxicity in humans is available, an in vitro study of the detoxification of chlorfenvinphos has shown that human liver enzymes were almost as effective as those of rabbits, who have an oral LD50 of 412-4,700 mg/kg., [16] [17]

Long-term toxicity

Prolonged exposure to chlorfenvinphos has been observed to decrease plasma and erythrocyte cholinesterase activity in humans. [18] No significant genotoxicity, carcinogenicity or teratogenicity has been reported. On the basis of a NOAEL of 0.05 mg/kg observed in rats, an acceptable daily intake for humans of 0.0005 mg/kg has been established. [19]

Biomarkers

Biomarkers of exposure

Traces of unchanged chlorfenvinphos and its polar metabolites can be detected in animals, which have been exposed to chlorfenvinphos. These small amounts can be used to prove that chlorfenvinphos exposure has occurred and the method of analysis is non-invasive.

Another method to assess chlorfenvinphos exposure is to measure the activity of cholinesterases in the blood. Two pools of cholinesterases exist in the blood: acetylcholinesterase in erythrocytes and pseudocholinesterase in plasma. The acetylcholinesterase in erythrocytes is identical to the acetylcholinesterase found in neuromuscular tissue. The function of plasma pseudocholinesterase is unknown, but its activity is considered to be a more sensitive biomarker for organophosphate exposure than erythrocyte cholinesterase activity. The inhibition of the individual cholinesterases or the inhibition of their combined activity can be used as a marker of exposure. However, cholinesterase inhibition is caused by all anticholinesterase compounds and is therefore not a specific biomarker for chlorfenvinphos. In addition, the activity of cholinesterases in the blood varies in populations and there are no studies which have measured a correlation between chlorfenvinphos exposure and cholinesterase inhibition. There have been suggestions that chlorfenvinphos or its metabolites would be a better biomarker of exposure than its cholinesterase activity inhibition. [18]

Biomarkers of effect

In combination with analysis of reductions in cholinesterase activity in the blood, symptoms of organophosphate poisoning can be used to identify victims of organophosphate poisoning. These symptoms are not specific for chlorfenvinphos, but for anticholinesterase compounds in general. [18]

Treatments of exposure

Ingestion of chlorfenvinphos, either by accident or through suicidal intent, can be treated as with other acute organophosphate poisonings. This includes a combination of three approaches: [20] [21] [22]

  1. Administration of an anticholinergic such as atropine, considered an antidote;
  2. Administration of a cholinesterase reactivator, in the pyridinium oxime family, usually pralidoxime;
  3. Administration of anticonvulsants, e.g. benzodiazepines (of which diazepam is most effective).

The efficacy of oxime treatment is controversial. [22] Ingestion of organophosphates as residues on food rarely reaches clinically relevant doses. [20]

Related Research Articles

<span class="mw-page-title-main">Cholinesterase</span> Esterase that lyses choline-based esters

The enzyme cholinesterase (EC 3.1.1.8, choline esterase; systematic name acylcholine acylhydrolase) catalyses the hydrolysis of choline-based esters:

<span class="mw-page-title-main">Ethion</span> Chemical compound

Ethion (C9H22O4P2S4) is an organophosphate insecticide. It is known to affect a neural enzyme called acetylcholinesterase and prevent it from functioning.

Demeton-S-methyl is an organic compound with the molecular formula C6H15O3PS2. It was used as an organothiophosphate acaricide and organothiophosphate insecticide. It is flammable. With prolonged storage, Demeton-S-methyl becomes more toxic due to formation of a sulfonium derivative which has greater affinity to the human form of the acetylcholinesterase enzyme, and this may present a hazard in agricultural use.

<span class="mw-page-title-main">Azinphos-methyl</span> Chemical compound

Azinphos-methyl (Guthion) is a broad spectrum organophosphate insecticide manufactured by Bayer CropScience, Gowan Co., and Makhteshim Agan. Like other pesticides in this class, it owes its insecticidal properties to the fact that it is an acetylcholinesterase inhibitor. It is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act, and is subject to strict reporting requirements by facilities which produce, store, or use it in significant quantities.

<span class="mw-page-title-main">Phosmet</span> Organophosphate non-systemic insecticide

Phosmet is a phthalimide-derived, non-systemic, organophosphate insecticide used on plants and animals. It is mainly used on apple trees for control of codling moth, though it is also used on a wide range of fruit crops, ornamentals, and vines for the control of aphids, suckers, mites, and fruit flies.

<span class="mw-page-title-main">Organophosphate poisoning</span> Toxic effect of pesticides

Organophosphate poisoning is poisoning due to organophosphates (OPs). Organophosphates are used as insecticides, medications, and nerve agents. Symptoms include increased saliva and tear production, diarrhea, vomiting, small pupils, sweating, muscle tremors, and confusion. While onset of symptoms is often within minutes to hours, some symptoms can take weeks to appear. Symptoms can last for days to weeks.

<span class="mw-page-title-main">Chlorethoxyfos</span> Chemical compound

Chlorethoxyfos is an organophosphate acetylcholinesterase inhibitor used as an insecticide. It is registered for the control of corn rootworms, wireworms, cutworms, seed corn maggot, white grubs and symphylans on corn. The insecticide is sold under the trade name Fortress by E.I. du Pont de Nemours & Company.

<span class="mw-page-title-main">Disulfoton</span> Chemical compound

Disulfoton is an organophosphate acetylcholinesterase inhibitor used as an insecticide. It is manufactured under the name Di-Syston by Bayer CropScience. Disulfoton in its pure form is a colorless oil but the technical product used in vegetable fields is dark and yellowish with a sulfur odor. Disulfoton is processed as a liquid into carrier granules, these granules are mixed with fertilizer and clay to be made into a spike, designed to be driven into the ground. The pesticide is absorbed over time by the roots and translocated to all parts of the plant. The pesticide acts as a cholinesterase inhibitor and gives long lasting control.

<span class="mw-page-title-main">Acetylcholinesterase inhibitor</span> Drugs that inhibit acetylcholinesterase

Acetylcholinesterase inhibitors (AChEIs) also often called cholinesterase inhibitors, inhibit the enzyme acetylcholinesterase from breaking down the neurotransmitter acetylcholine into choline and acetate, thereby increasing both the level and duration of action of acetylcholine in the central nervous system, autonomic ganglia and neuromuscular junctions, which are rich in acetylcholine receptors. Acetylcholinesterase inhibitors are one of two types of cholinesterase inhibitors; the other being butyryl-cholinesterase inhibitors. Acetylcholinesterase is the primary member of the cholinesterase enzyme family.

<span class="mw-page-title-main">Demeton</span> Chemical compound

Demeton, sold as an amber oily liquid with a sulphur like odour under the name Systox, is an organophosphate derivative causing irritability and shortness of breath to individuals repeatedly exposed. It was used as a phosphorothioate insecticide and acaricide and has the chemical formula C8H19O3PS2. Although it was previously used as an insecticide, it is now largely obsolete due to its relatively high toxicity to humans. Demeton consists of two components, demeton-S and demeton-O in a ratio of approximately 2:1 respectively. The chemical structure of demeton is closely related to military nerve agents such as VX and a derivative with one of the ethoxy groups replaced by methyl was investigated by both the US and Soviet chemical-weapons programs under the names V-sub x and GD-7.

<span class="mw-page-title-main">Carbophenothion</span> Chemical compound

Carbophenothion also known as Stauffer R 1303 as for the manufacturer, Stauffer Chemical, is an organophosphorus chemical compound. It was used as a pesticide for citrus fruits under the name of Trithion. Carbophenothion was used as an insecticide and acaricide. Although not used anymore it is still a restricted use pesticide in the United States. The chemical is identified in the US as an extremely hazardous substance according to the Emergency Planning and Community Right-to-Know Act.

<span class="mw-page-title-main">Tetraethyl pyrophosphate</span> Chemical compound

Tetraethyl pyrophosphate, abbreviated TEPP, is an organophosphate compound with the formula [(C2H5O)2P(O)]2O. It is the tetraethyl derivative of pyrophosphate (P2O74-). It is a colorless oil that solidifies near room temperature. It is used as an insecticide. The compound hydrolyzes rapidly.

<span class="mw-page-title-main">Sulfotep</span> Chemical compound

Sulfotep (also known as tetraethyldithiopyrophosphate and TEDP) is a pesticide commonly used in greenhouses as a fumigant. The substance is also known as Dithione, Dithiophos, and many other names. Sulfotep has the molecular formula C8H20O5P2S2 and belongs to the organophosphate class of chemicals. It has a cholinergic effect, involving depression of the cholinesterase activity of the peripheral and central nervous system of insects. The transduction of signals is disturbed at the synapses that make use of acetylcholine. Sulfotep is a mobile oil that is pale yellow-colored and smells like garlic. It is primarily used as an insecticide.

<span class="mw-page-title-main">Ethoprophos</span> Chemical compound

Ethoprophos (or ethoprop) is an organophosphate ester with the formula C8H19O2PS2. It is a clear yellow to colourless liquid that has a characteristic mercaptan-like odour. It is used as an insecticide and nematicide and it is an acetylcholinesterase inhibitor.

<span class="mw-page-title-main">Terbufos</span> Chemical compound

Terbufos is a chemical compound used in insecticides and nematicides. It is part of the chemical family of organophosphates. It is a clear, colourless to pale yellow or reddish-brown liquid and sold commercially as granulate.

<span class="mw-page-title-main">Triamiphos</span> Chemical compound

Triamiphos (chemical formula: C12H19N6OP) is an organophosphate used as a pesticide and fungicide. It is used to control powdery mildews on apples and ornamentals. It was discontinued by the US manufacturer in 1998.

<span class="mw-page-title-main">EPN (insecticide)</span> Chemical compound

EPN is an insecticide of the phosphonothioate class. It is used against pests such as European corn borer, rice stem borer, bollworm, tobacco budworm, and boll weevil.

Carbamate poisoning is poisoning due to exposure to carbamates, which are commonly sold as pesticides around the world. In most respects, it is similar to organophosphate poisoning, though typically less severe or requiring a larger amount of the chemical before symptoms appear.

<span class="mw-page-title-main">Cadusafos</span> Thiosulfate insecticide against nematodes

Cadusafos is a chemical insecticide and nematicide often used against parasitic nematode populations. The compound acts as a acetylcholinesterase inhibitor. It belongs the chemical class of synthetic organic thiophosphates and it is a volatile and persistent clear liquid. It is used on food crops such as tomatoes, bananas and chickpeas. It is currently not approved by the European Commission for use in the EU. Exposure can occur through inhalation, ingestion or contact with the skin. The compound is highly toxic to nematodes, earthworms and birds but poses no carcinogenic risk to humans.

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  22. 1 2 King, Andrew M.; Aaron, Cynthia K. (February 2015). "Organophosphate and Carbamate Poisoning". Emergency Medicine Clinics of North America. 33 (1): 133–151. doi:10.1016/j.emc.2014.09.010. PMID   25455666.