Cadusafos (2- utan-2-ylsulfanyl(ethoxy)phosphorylulfanylbutane) is a chemical insecticide and

nematicide A nematicide is a type of chemical pesticide used to kill plant-parasitic nematodes. Nematicides have tended to be broad-spectrum toxicants possessing high volatility or other properties promoting migration through the soil. Aldicarb (Temik), a ...

often used against

parasitic Parasitism is a close relationship between species, where one organism, the parasite, lives on or inside another organism, the host, causing it some harm, and is adapted structurally to this way of life. The entomologist E. O. Wilson ha ...

nematode populations. The compound acts as a

acetylcholinesterase inhibitor 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 ...

. It belongs the chemical class of synthetic organic

thiophosphate Thiophosphates (or phosphorothioates, PS) are chemical compounds and anions with the general chemical formula (''x'' = 0, 1, 2, or 3) and related derivatives where organic groups are attached to one or more O or S. Thiophosphates feature tetrahedr ...

s 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 The European Commission (EC) is the executive of the European Union (EU). It operates as a cabinet government, with 27 members of the Commission (informally known as "Commissioners") headed by a President. It includes an administrative body ...

for use in the EU. Exposure can occur through

inhalation Inhalation (or Inspiration) happens when air or other gases enter the lungs. Inhalation of air Inhalation of air, as part of the cycle of breathing, is a vital process for all human life. The process is autonomic (though there are exceptions ...

ingestion Ingestion is the consumption of a substance by an organism. In animals, it normally is accomplished by taking in a substance through the mouth into the gastrointestinal tract, such as through eating or drinking. In single-celled organisms ingest ...

or contact with the skin. The compound is highly toxic to

nematodes The nematodes ( or grc-gre, Νηματώδη; la, Nematoda) or roundworms constitute the phylum Nematoda (also called Nemathelminthes), with plant-parasitic nematodes also known as eelworms. They are a diverse animal phylum inhabiting a broa ...

earthworms An earthworm is a terrestrial invertebrate that belongs to the phylum Annelida. They exhibit a tube-within-a-tube body plan; they are externally segmented with corresponding internal segmentation; and they usually have setae on all segments. T ...

and birds but poses no

carcinogenic A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive sub ...

risk to humans.

History

patent application A patent application is a request pending at a patent office for the grant of a patent for an invention described in the patent specification and a set of one or more claims stated in a formal document, including necessary official forms and rel ...

for Cadusafos was first filed in Europe on August 13, 1982 by

FMC Corporation FMC Corporation is an American chemical manufacturing company headquartered in Philadelphia, Pennsylvania, which originated as an insecticide producer in 1883 and later diversified into other industries. In 1941 at the beginning of US involvemen ...

, 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.” The patent is expired, meaning that the compound is commercially available from chemical vendors such as

Sigma Aldrich Sigma-Aldrich (formally MilliporeSigma) is an American chemical, life science, and biotechnology company that is owned by the German chemical conglomerate Merck Group. Sigma-Aldrich was created in 1975 by the merger of Sigma Chemical Company ...

. However, the pesticide is not approved for use in Europe due to the lack of information on consumer exposure and the risk to groundwater.

Structure and reactivity

Cadusafos is a synthetic organic

compound which is observed as a

volatile Volatility or volatile may refer to: Chemistry * Volatility (chemistry), a measuring tendency of a substance or liquid to vaporize easily * Relative volatility, a measure of vapor pressures of the components in a liquid mixture * Volatiles, a gr ...

and persistent clear liquid. The toxin is an

organothiophosphate Organothiophosphates or organophosphorothioates are a subclass of organophosphorus compounds. Many are used as pesticides, some have medical applications, and some are used as oil additives. They generally have the chemical formula (RO)3PS, RO)2P( ...

insecticide. Organothiophosphorus compounds are identified as compounds which contain carbonphosphorus bonds where the

phosphorus Phosphorus is a chemical element with the symbol P and atomic number 15. Elemental phosphorus exists in two major forms, white phosphorus and red phosphorus, but because it is highly reactive, phosphorus is never found as a free element on Ea ...

atom is also bound to

sulphur Sulfur (or sulphur in British English) is a chemical element with the symbol S and atomic number 16. It is abundant, multivalent and nonmetallic. Under normal conditions, sulfur atoms form cyclic octatomic molecules with a chemical formula ...

. Many of these compounds serve as insecticides and

cholinergic agents Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word " choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cation ...

. 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 In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again b ...

group. The exact reactivity of Cadusafos as well as that of organothiophosphate compounds in general is, as of yet, unknown. However, the

cholinesterase The enzyme cholinesterase (EC 3.1.1.8, choline esterase; systematic name acylcholine acylhydrolase) catalyses the hydrolysis of choline-based esters: : an acylcholine + H2O = choline + a carboxylate Several of these serve as neurotransmitters ...

enzyme inhibition mechanism of action of these compounds works similarly to other organophosphates. Examples of organophosphates include

nerve gas Nerve agents, sometimes also called nerve gases, are a class of organic chemicals that disrupt the mechanisms by which nerves transfer messages to organs. The disruption is caused by the blocking of acetylcholinesterase (AChE), an enzyme tha ...

ses such as

sarin Sarin (NATO designation GB G-series, "B"">Nerve_agent#G-series.html" ;"title="hort for Nerve agent#G-series">G-series, "B" is an extremely toxic synthetic organophosphorus compound.VX as well as pesticides like

malathion 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. Pesticide use Malathion is a pe ...

Synthesis

The synthesis of Cadusafos can be performed via the

substitution reaction A substitution reaction (also known as single displacement reaction or single substitution reaction) is a chemical reaction during which one functional group in a chemical compound is replaced by another functional group. Substitution reactions ar ...

of ''O''-ethyl phosphoric dichloride and two equivalents of 2-butanethiol.

Mechanism of action

Cadusafos is an

inhibitor Inhibitor or inhibition may refer to: In biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotra ...

of the enzyme

acetylcholinesterase Acetylcholinesterase (HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme that catalyzes the breakdown of acety ...

. This enzyme binds to acetylcholine and cleaves it into

choline Choline is an essential nutrient for humans and many other animals. Choline occurs as a cation that forms various salts (X− in the depicted formula is an undefined counteranion). Humans are capable of some ''de novo synthesis'' of choline but ...

and

acetate An acetate is a salt formed by the combination of acetic acid with a base (e.g. alkaline, earthy, metallic, nonmetallic or radical base). "Acetate" also describes the conjugate base or ion (specifically, the negatively charged ion called ...

. Acetylcholine is a

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neur ...

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 Accumulation may refer to: Finance * Accumulation function, a mathematical function defined in terms of the ratio future value to present value * Capital accumulation, the gathering of objects of value Science and engineering * Accumulate (highe ...

of acetylcholine. This might result in excessive nervous stimulation,

respiratory failure Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a rise ...

and death. Cadusafos is an organothiophosphate, which is a subclass of

organophosphates In organic chemistry, organophosphates (also known as phosphate esters, or OPEs) are a class of organophosphorus compounds with the general structure , a central phosphate molecule with alkyl or aromatic substituents. They can be considered a ...

. Organophosphates can act as an inhibitor for acetylcholinesterase in a way for which the mechanism is known. The active site of acetylcholinesterase contains an

anionic An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...

site and an esteratic site. This esteratic side contains a

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − for ...

at the 200th position, which usually binds acetylcholine. Organophosphate inhibitors can

phosphorylate In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, ...

this serine and with that inhibit the enzyme.

Metabolism and biotransformation

In a study, 14C

radiolabeled A radioactive tracer, radiotracer, or radioactive label is a chemical compound in which one or more atoms have been replaced by a radionuclide so by virtue of its radioactive decay it can be used to explore the mechanism of chemical reactions by tr ...

Cadusafos was administered

orally The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or oral ...

to rats. The excretion of feces, urine and CO₂ was monitored for seven days. This showed that cadusafos is readily absorbed (90-100%) 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%. The majority of this radioactivity was found in fat, liver, kidney and lung tissue and no evidence of accumulation was found. A different study was performed in order to identify the

metabolites In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

formed in rats after receiving either an oral or intravenous dose of Cadusafos. The metabolic products were analyzed using several analysis methods (

HPLC High-performance liquid chromatography (HPLC), formerly referred to as high-pressure liquid chromatography, is a technique in analytical chemistry used to separate, identify, and quantify each component in a mixture. It relies on pumps to pa ...

, TLC, GC-MS, ¹H-NMR and

liquid scintillation A liquid is a nearly incompressible fluid that conforms to the shape of its container but retains a (nearly) constant volume independent of pressure. As such, it is one of the four fundamental states of matter (the others being solid, gas, a ...

). 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 In organic chemistry, sulfonic acid (or sulphonic acid) refers to a member of the class of organosulfur compounds with the general formula , where R is an organic alkyl or aryl group and the group a sulfonyl hydroxide. As a substituent, it ...

, which then form conjugates.

Toxicity

A study has been conducted by the Joint

FAO The Food and Agriculture Organization of the United Nations (FAO)french: link=no, Organisation des Nations unies pour l'alimentation et l'agriculture; it, Organizzazione delle Nazioni Unite per l'Alimentazione e l'Agricoltura is an intern ...

WHO Who or WHO may refer to: * Who (pronoun), an interrogative or relative pronoun * Who?, one of the Five Ws in journalism * World Health Organization Arts and entertainment Fictional characters * Who, a creature in the Dr. Seuss book ''Horton Hear ...

Meeting on Pesticide Residues (JMPR), on rats in which the

lethal dose In toxicology, the lethal dose (LD) is an indication of the lethal toxicity of a given substance or type of radiation. Because resistance varies from one individual to another, the "lethal dose" represents a dose (usually recorded as dose per kilog ...

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 The dermis or corium is a layer of skin between the epidermis (with which it makes up the cutis) and subcutaneous tissues, that primarily consists of dense irregular connective tissue and cushions the body from stress and strain. It is divided in ...

pathway, lower median lethal doses were found; mg/kg bw in males and 41.8 mg/kg bw in females. 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 The Environmental Protection Agency (EPA) is an independent executive agency of the United States federal government tasked with environmental protection matters. President Richard Nixon proposed the establishment of EPA on July 9, 1970; it ...

(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.”

Effects on animals

Cadusafos has been proved to be toxic to fish, aquatic invertebrates, bees,

and other

arthropods Arthropods (, (gen. ποδός)) are invertebrate animals with an exoskeleton, a segmented body, and paired jointed appendages. Arthropods form the phylum Arthropoda. They are distinguished by their jointed limbs and cuticle made of chitin, oft ...

. Further research was conducted on terrestrial vertebrates, and it is expected to have toxic effects on mammals. Besides its direct toxicity to multiple species, Cadusafos also has a potential to

bioaccumulate Bioaccumulation is the gradual accumulation of substances, such as pesticides or other chemicals, in an organism. Bioaccumulation occurs when an organism absorbs a substance at a rate faster than that at which the substance is lost or eliminated ...

secondary poisoning Secondary poisoning, or relay toxicity, is the poisoning that results when one organism comes into contact with or ingests another organism that has poison in its system. It typically occurs when a predator eats an animal, such as a mouse, rat, or ...

for earthworm eating mammals and birds should also be taken into consideration. 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 The no-observed-adverse-effect level (NOAEL) denotes the level of exposure of an organism, found by experiment or observation, at which there is no biologically or statistically significant increase in the frequency or severity of any adverse effec ...

) of 0.03 mg/kg bw per day for the inhibition of cholinesterase activity in

plasma Plasma or plasm may refer to: Science * Plasma (physics), one of the four fundamental states of matter * Plasma (mineral), a green translucent silica mineral * Quark–gluon plasma, a state of matter in quantum chromodynamics Biology * Blood plas ...

and

erythrocytes Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...

. There has been no adequate evidence that Cadusafos could prove a

genotoxic Genotoxicity is the property of chemical agents that damage the genetic information within a cell causing mutations, which may lead to cancer. While genotoxicity is often confused with mutagenicity, all mutagens are genotoxic, but some genotoxic sub ...

compound. Due to this and additional research on mice and rats which proved Cadusafos as non-

, 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 ''Rotylenchulus reniformis'', the reniform nematode, is a species of parasitic nematode of plants with a worldwide distribution in the tropical and subtropical regions.Ferris, H''Rotylenchulus reniformis''.Nemaplex. Department of Nematology. U ...

'' and ''

Meloidogyne incognita ''Meloidogyne incognita'' (root-knot nematode - RKN), also known as the "southern root-nematode" or "cotton root-knot nematode" is a plant-parasitic roundworm in the family Heteroderidae. This nematode is one of the four most common species world ...

''. It showed to be more effective against

endoparasitic Parasitism is a close relationship between species, where one organism, the parasite, lives on or inside another organism, the host, causing it some harm, and is adapted structurally to this way of life. The entomologist E. O. Wilson ha ...

nematodes than

ectoparasitic Parasitism is a close relationship between species, where one organism, the parasite, lives on or inside another organism, the host, causing it some harm, and is adapted structurally to this way of life. The entomologist E. O. Wilson ha ...

nematodes and when compared to other nematicides like

triazophos Triazofos is a chemical compound used in acaricides, insecticides, and nematicides. History Triazofos has been registered in the Federal Office of Consumer Protection and Food Safety since 1975 and authorized as an insecticide in the EU unt ...

methyl bromide Bromomethane, commonly known as methyl bromide, is an organobromine compound with formula C H3 Br. This colorless, odorless, nonflammable gas is produced both industrially and biologically. It has a tetrahedral shape and it is a recognized ozo ...

aldicarb Aldicarb is a carbamate insecticide which is the active substance in the pesticide Temik. It is effective against thrips, aphids, spider mites, lygus, fleahoppers, and leafminers, but is primarily used as a nematicide. Aldicarb is a choli ...

carbofuran Carbofuran is a carbamate pesticide, widely used around the world to control insects on a wide variety of field crops, including potatoes, corn and soybeans. It is a systemic insecticide, which means that the plant absorbs it through the roots ...

and phorate, Cadusafos proved to be the most efficient. The effectiveness of Cadusafos improves when increasing the dosage or the exposure time. 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.

References

{{reflist Nematicides Ethyl esters Phosphorodithioates Insecticides Thioesters Sec-Butyl compounds