Cadusafos

Last updated
Cadusafos
Cadusafos structure.svg
Clinical data
Trade names Cadusafos
Legal status
Legal status
  • US:eligible for reregistration
  • EU:not approved
Pharmacokinetic data
Bioavailability 90-100%
Metabolism >90%
Metabolites hydroxy sulfones, phosphorothioic and sulfonic acids
Elimination half-life not available
Excretion kidney, renal
Identifiers
  • S,S-di-sec-butyl O-ethyl phosphorodithioate
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.108.705 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C10H23O2PS2
Molar mass 270.39 g·mol−1
3D model (JSmol)
Density 1.054 g/cm3
Boiling point 112–114 °C (234–237 °F)
Solubility in water 0.248 g/L
  • CCC(C)SP(=O)(OCC)SC(C)CC
  • InChI=1S/C10H23O2PS2/c1-6-9(4)14-13(11,12-8-3)15-10(5)7-2/h9-10H,6-8H2,1-5H3
  • Key:KXRPCFINVWWFHQ-UHFFFAOYSA-N

Cadusafos (2-[butan-2-ylsulfanyl(ethoxy)phosphoryl]sulfanylbutane) 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. [1] [2] [3] [4] [5] [6]

Contents

History

A patent application for Cadusafos was first filed in Europe on August 13, 1982 by FMC Corporation, an American chemical company which originated as an insecticide producer. In their patent application, they claimed that the compound should preferably be used to “control nematodes and soil insects, but may also control some insects which feed on the above ground portions of the plant.” [7] The patent is expired, meaning that the compound is commercially available from chemical vendors such as Sigma Aldrich. [8] However, the pesticide is not approved for use in Europe due to the lack of information on consumer exposure and the risk to groundwater. [9]

Structure and reactivity

Cadusafos is a synthetic organic thiophosphate compound which is observed as a volatile and persistent clear liquid. The toxin is an organothiophosphate insecticide. [1] Organothiophosphorus compounds are identified as compounds which contain carbonphosphorus bonds where the phosphorus atom is also bound to sulphur. Many of these compounds serve as insecticides and cholinergic agents. [10] Cadusafos contains the phosphorus atom bound to two sulphurs which are attached to iso-butyl substituents. The phosphorus is also connected to oxygen by a double bond and is bound to an ethyl ether group. The exact reactivity of Cadusafos as well as that of organothiophosphate compounds in general is, as of yet, unknown. However, the cholinesterase enzyme inhibition mechanism of action of these compounds works similarly to other organophosphates. [11] Examples of organophosphates include nerve gasses such as sarin and VX as well as pesticides like malathion. [12]

Synthesis

The synthesis of Cadusafos can be performed via the substitution reaction of O-ethyl phosphoric dichloride and two equivalents of 2-butanethiol. [13]

Mechanism of action

Cadusafos is an inhibitor of the enzyme acetylcholinesterase. This enzyme binds to acetylcholine and cleaves it into choline and acetate. Acetylcholine is a neurotransmitter which is used in neurons to pass on a neural stimulus. Cadusafos inhibits the function of acetylcholinesterase by occupying the active site of the enzyme which will no longer be able to function properly, resulting in the accumulation of acetylcholine. This might result in excessive nervous stimulation, respiratory failure and death. [14] Cadusafos is an organothiophosphate, which is a subclass of organophosphates. Organophosphates can act as an inhibitor for acetylcholinesterase in a way for which the mechanism is known. [1] The active site of acetylcholinesterase contains an anionic site and an esteratic site. This esteratic side contains a serine at the 200th position, which usually binds acetylcholine. Organophosphate inhibitors can phosphorylate this serine and with that inhibit the enzyme. [15]

Metabolism and biotransformation

In a study, 14C radiolabeled Cadusafos was administered orally to rats. The excretion of feces, urine and CO2 was monitored for seven days. This showed that cadusafos is readily absorbed (90-100%) [16] and mainly eliminated via urine (around 75%), followed by elimination via expired air (10-15%) and via feces (5-15%). Over 90% of the administered dose was eliminated within 48 hours after administration. Analysis of tissue and blood samples collected after seven days showed a remaining radioactivity between 1-3%. [2] The majority of this radioactivity was found in fat, liver, kidney and lung tissue and no evidence of accumulation was found. [2] [17] A different study was performed in order to identify the metabolites formed in rats after receiving either an oral or intravenous dose of Cadusafos. The metabolic products were analyzed using several analysis methods (HPLC, TLC, GC-MS, 1H-NMR and liquid scintillation). This indicated the presence of the parent compound, Cadusafos, as well as 10 other metabolites. The main pathway of metabolism involves the cleavage of the thio-(sec-butyl) group, forming two primary products: Sec-butyl mercaptan and Oethyl-S-(2-butyl) phosphorothioic acid (OSPA). These intermediate compounds are then degraded further into several metabolites. The major metabolites were hydroxysulfones, followed by phosphorothionic acids and sulfonic acids, which then form conjugates. [2]

Toxicity

A study has been conducted by the Joint FAO/WHO Meeting on Pesticide Residues (JMPR), on rats in which the lethal dose of Cadusafos was investigated. The researchers found a median lethal dose via the oral pathway of 68.4 mg/kg bodyweight (bw) in male rats and 82.1 mg/kg bw in female rats. The rats died of typical symptoms of acetylcholinesterase inhibition. Via the dermal pathway, lower median lethal doses were found; mg/kg bw in males and 41.8 mg/kg bw in females. [18] Considering the toxicity in humans, there is no data available yet regarding the median lethal dose for a human. The United States Environmental Protection Agency (EPA), did publish a report on the safety concerns of Cadusafos used as a pesticide on bananas and concluded that “Potential acute and chronic dietary exposures from eating bananas treated with Cadusafos are below the level of concern for the entire U.S. population, including infants and children.” [19]

Effects on animals

Cadusafos has been proved to be toxic to fish, aquatic invertebrates, bees, earthworms and other arthropods. Further research was conducted on terrestrial vertebrates, and it is expected to have toxic effects on mammals. [3] Besides its direct toxicity to multiple species, Cadusafos also has a potential to bioaccumulate so secondary poisoning for earthworm eating mammals and birds should also be taken into consideration. [17] The estimated risk to bees and aquatic organisms is low due to the application of Cadusafos, even though the toxicity to bees is high. The compound is also estimated to be highly toxic to earthworms and birds. A multigeneration study in rats has established a No Adverse Effect Level (NOAEL) of 0.03 mg/kg bw per day for the inhibition of cholinesterase activity in plasma and erythrocytes. [2] There has been no adequate evidence that Cadusafos could prove a genotoxic compound. Due to this and additional research on mice and rats which proved Cadusafos as non-carcinogenic, it can be concluded that Cadusafos is non-carcinogenic for humans.

Efficacy

Cadusafos proved to be very effective against parasitic nematode populations such as Rotylenchulus reniformis and Meloidogyne incognita . It showed to be more effective against endoparasitic nematodes than ectoparasitic nematodes [4] and when compared to other nematicides like triazophos, methyl bromide, aldicarb, carbofuran and phorate, Cadusafos proved to be the most efficient. The effectiveness of Cadusafos improves when increasing the dosage or the exposure time. [20] [5] Efficacy after application for several successive cropping seasons seemed to remain the same for up to four seasons. However, when it is used for more than 4 consecutive seasons, this can cause a linear decrease in the efficacy. [4]

Related Research Articles

<span class="mw-page-title-main">Soman</span> Chemical compound (nerve agent)

Soman is an extremely toxic chemical substance. It is a nerve agent, interfering with normal functioning of the mammalian nervous system by inhibiting the enzyme cholinesterase. It is an inhibitor of both acetylcholinesterase and butyrylcholinesterase. As a chemical weapon, it is classified as a weapon of mass destruction by the United Nations according to UN Resolution 687. Its production is strictly controlled, and stockpiling is outlawed by the Chemical Weapons Convention of 1993 where it is classified as a Schedule 1 substance. Soman was the third of the so-called G-series nerve agents to be discovered along with GA (tabun), GB (sarin), and GF (cyclosarin).

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

Malathion is an organophosphate insecticide which acts as an acetylcholinesterase inhibitor. In the USSR, it was known as carbophos, in New Zealand and Australia as maldison and in South Africa as mercaptothion.

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

Chlorfenvinphos is an organophosphorus compound that was widely used as an insecticide and an acaricide. 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.

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

Ethion (C9H22O4P2S4) is an organophosphate insecticide. It is known to affect the neural enzyme acetylcholinesterase and disrupt its function.

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

Diazinon, a colorless to dark brown liquid, is a thiophosphoric acid ester developed in 1952 by Ciba-Geigy, a Swiss chemical company. It is a nonsystemic organophosphate insecticide formerly used to control cockroaches, silverfish, ants, and fleas in residential, non-food buildings. Diazinon was heavily used during the 1970s and early 1980s for general-purpose gardening use and indoor pest control. A bait form was used to control scavenger wasps in the western U.S. Diazinon is used in flea collars for domestic pets in Australia and New Zealand. Diazinon is a major component in the "Golden Fleece" brand sheep dip. Residential uses of diazinon were outlawed in the U.S. in 2004 because of human health risks but it is still approved for agricultural uses. An emergency antidote is atropine.

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

Diisopropyl fluorophosphate (DFP) or Isoflurophate is an oily, colorless liquid with the chemical formula C6H14FO3P. It is used in medicine and as an organophosphorus insecticide. It is stable, but undergoes hydrolysis when subjected to moisture.

<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">Dimethoate</span> Chemical compound

Dimethoate is a widely used organophosphate insecticide and acaricide. It was patented and introduced in the 1950s by American Cyanamid. Like other organophosphates, dimethoate is an acetylcholinesterase inhibitor which disables cholinesterase, an enzyme essential for central nervous system function. It acts both by contact and through ingestion. It is readily absorbed and distributed throughout plant tissues, and is degraded relatively rapidly. One of the breakdown products of dimethoate is omethoate, a potent cholinesterase inhibitor, is ten times more toxic than its parent compound.

<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">Methiocarb</span> Chemical compound

Methiocarb is a carbamate pesticide which is used as an insecticide, bird repellent, acaricide and molluscicide since the 1960s. Methiocarb has contact and stomach action on mites and neurotoxic effects on molluscs. Seeds treated with methiocarb also affect birds. Other names for methiocarb are mesurol and mercaptodimethur.

<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">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">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">Triazofos</span> Chemical compound

Triazofos is a chemical compound used in acaricides, insecticides, and nematicides.

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

Prothioconazole is a synthetic chemical produced primarily for its fungicidal properties. It is a member of the class of compounds triazoles, and possesses a unique toxophore in this class of fungicides. Its effective fungicidal properties can be attributed to its ability to inhibit CYP51A1. This enzyme is required to biosynthesize ergosterol, a key component in the cell membrane of fungi.

References

  1. 1 2 3 "Cadusafos". pubchem.ncbi.nlm.nih.gov. Retrieved 16 March 2023.
  2. 1 2 3 4 5 Donovan W. "Cadusafos (174)" (PDF). fao.org. Food and Agriculture Organisation of the United Nations. Retrieved 24 March 2023.
  3. 1 2 Lewis KA, Tzilivakis J, Warner DJ, Green A (18 May 2016). "An international database for pesticide risk assessments and management". Human and Ecological Risk Assessment. 22 (4): 1050–1064. Bibcode:2016HERA...22.1050L. doi:10.1080/10807039.2015.1133242. hdl: 2299/17565 . S2CID   87599872.
  4. 1 2 3 Meher HC, Gajbhiye VT, Singh G, Kamra A, Chawla G (1 January 2010). "Nematicidal efficacy, enhanced degradation and cross adaptation of carbosulfan, cadusafos and triazophos under tropical conditions". Nematology. 12 (2): 211–224. doi:10.1163/138855409x12465264245574.
  5. 1 2 Anwar S (March 2012). "Incidence and Population Density of Plant-Parasitic Nematodes Infecting Vegetable Crops and Associated Yield Losses in Punjab, Pakistan". Pakistan Journal of Zoology. 44 (2). Retrieved 16 March 2023.
  6. ↑ "Cadusafos". ec.europa.eu. Eu Pesticides Database. Retrieved 24 March 2023.
  7. ↑ US 4535077,Fahmy, Mohamed A. H.,"O-ethyl S,S-dialkyl phosphorodithioates for use as pesticides",published 1985-08-13, assigned to FMC Corp.
  8. ↑ "Cadusafos". Sigma Aldrich. Retrieved 14 March 2023.
  9. ↑ Kyprianou M (2007-06-21). "2007/428/EC: Commission Decision of 18 June 2007 concerning the non-inclusion of cadusafos in Annex I to Council Directive 91/414/EEC and the withdrawal of authorisations for plant protection products containing that substance (notified under document number C(2007) 2511) (Text with EEA relevance)". Official Journal of the European Union. 160: 26–27.
  10. ↑ "Organothiophosphorus Compounds". meshb.nlm.nih.gov. National Library of Medicine. Retrieved 24 March 2023.
  11. ↑ "Fenthion. Uses, Interactions, Mechanism of Action". go.drugbank.com. DrugBank Online. Retrieved 24 March 2023.
  12. ↑ English BA, Webster AA (1 January 2012). "Chapter 132 - Acetylcholinesterase and its Inhibitors". Primer on the Autonomic Nervous System (Third Edition): 631–633. doi:10.1016/B978-0-12-386525-0.00132-3. ISBN   9780123865250.
  13. ↑ EP 0086826,Fahmy, Mohamed A. H.,"Alpha-branched alkylthiophosphate pesticides",published 1983-08-31, assigned to FMC Corp.
  14. ↑ Organophosphorus insecticides : a general introduction. Geneva: World Health Organization. 1986. hdl:10665/40198. ISBN   9241542632.
  15. ↑ Dvir H, Silman I, Harel M, Rosenberry TL, Sussman JL (September 2010). "Acetylcholinesterase: from 3D structure to function". Chemico-Biological Interactions. 187 (1–3): 10–22. Bibcode:2010CBI...187...10D. doi:10.1016/j.cbi.2010.01.042. PMC   2894301 . PMID   20138030.
  16. ↑ Puhl RJ (1987). FMC 67825 rat metabolism: single and multiple low-dose test regimen. Hazleton Laboratories America, Inc., Madison, WI, USA.: Unpublished report No. PC-0077 (Cd 6.1.1/3). Submitted to WHO by FMC Corporation.
  17. 1 2 "Conclusion regarding the peer review of the pesticide risk assessment of the active substance cadusafos". EFSA Journal. 4 (5). May 2006. doi: 10.2903/j.efsa.2006.68r .
  18. ↑ JMPR (2009). Pesticide residues in Food – 2009. Report of the Joint Meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Core Assessment Group on Pesticide Residues. Geneva: WHO and FAO.
  19. ↑ Report on FQPA Tolerance Reassessment Progress and Interim Risk Management Decision Cadusafos. United States Environmental Protection Agency. 2000.
  20. ↑ Meher HC, Gajbhiye VT, Singh G, Kamra A, Chawla G (February 2010). "Persistence and nematicidal efficacy of carbosulfan, cadusafos, phorate, and triazophos in soil and uptake by chickpea and tomato crops under tropical conditions". Journal of Agricultural and Food Chemistry. 58 (3): 1815–1822. doi:10.1021/jf903609d. PMID   20085277.
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