Tricresyl Phosphate
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Tricresyl phosphate (TCP), is a mixture of three isomeric
organophosphate 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 ...
compounds most notably used as a
flame retardant Flame retardants are a diverse group of chemicals that are added to manufactured materials, such as plastics and textiles, and surface finishes and coatings. Flame retardants are activated by the presence of an combustion, ignition source and pr ...
. Other uses include as a
plasticizer A plasticizer ( UK: plasticiser) is a substance that is added to a material to make it softer and more flexible, to increase its plasticity, to decrease its viscosity, and/or to decrease friction during its handling in manufacture. Plasticizer ...
in manufacturing for
lacquer Lacquer is a type of hard and usually shiny coating or finish applied to materials such as wood or metal. It is most often made from resin extracted from trees and waxes and has been in use since antiquity. Asian lacquerware, which may be c ...
s and
varnish Varnish is a clear Transparency (optics), transparent hard protective coating or film. It is not to be confused with wood stain. It usually has a yellowish shade due to the manufacturing process and materials used, but it may also be pigmente ...
es and vinyl plastics and as an
antiwear additive AW additives, or antiwear additives, are additives for lubricants to prevent metal-to-metal contact between parts of gears. EP additives are used in applications such as gearboxes, while AW additives are used with lighter loads such as bushings. ...
in lubricants. Pure tricresyl phosphate is a colourless, viscous liquid, although commercial samples are typically yellow. It is virtually insoluble in water, but easily soluble in organic solvents like
toluene Toluene (), also known as toluol (), is a substituted aromatic hydrocarbon with the chemical formula , often abbreviated as , where Ph stands for the phenyl group. It is a colorless, water Water is an inorganic compound with the c ...
,
hexane Hexane () or ''n''-hexane is an organic compound, a straight-chain alkane with six carbon atoms and the molecular formula C6H14. Hexane is a colorless liquid, odorless when pure, and with a boiling point of approximately . It is widely used as ...
, and
diethyl ether Diethyl ether, or simply ether, is an organic compound with the chemical formula , sometimes abbreviated as . It is a colourless, highly Volatility (chemistry), volatile, sweet-smelling ("ethereal odour"), extremely flammable liquid. It belongs ...
among others. It was synthesized by Alexander Williamson in 1854 upon reacting
phosphorus pentachloride Phosphorus pentachloride is the chemical compound with the formula . It is one of the most important phosphorus chlorides/oxychlorides, others being and . finds use as a chlorinating reagent. It is a colourless, water-sensitive solid, althoug ...
with
cresol Cresols (also known as hydroxytoluene, toluenol, benzol or cresylic acid) are a group of aromatic organic compounds. They are widely-occurring phenols (sometimes called ''phenolics'') which may be either natural or manufactured. They are also c ...
(a mixture of para-, ortho-, and meta- isomers of methylphenol), though today's manufacturers can prepare TCP by mixing cresol with
phosphorus oxychloride Phosphoryl chloride (commonly called phosphorus oxychloride) is a colourless liquid with the formula . It hydrolyses in moist air releasing phosphoric acid and fumes of hydrogen chloride. It is manufactured industrially on a large scale from phos ...
or
phosphoric acid Phosphoric acid (orthophosphoric acid, monophosphoric acid or phosphoric(V) acid) is a colorless, odorless phosphorus-containing solid, and inorganic compound with the chemical formula . It is commonly encountered as an 85% aqueous solution, ...
as well. TCP, especially the all-ortho isomer, is the causative agent in a number of acute poisonings. Its chronic toxicity is also of concern. The ortho-isomer is rarely used on its own outside of laboratory studies that require isomeric purity, due to its extremely toxic nature, and is generally excluded from commercial products where TCP is involved.


Isomers

The most dangerous isomers are considered to be those containing ''ortho'' isomers, such as tri-''ortho''-cresyl phosphate, TOCP. The
World Health Organization The World Health Organization (WHO) is a list of specialized agencies of the United Nations, specialized agency of the United Nations which coordinates responses to international public health issues and emergencies. It is headquartered in Gen ...
stated in 1990 that "Because of considerable variation among individuals in sensitivity to TOCP, it is not possible to establish a safe level of exposure" and "TOCP are therefore considered major hazards to human health." Therefore, strenuous efforts have been made to reduce the content of the ''ortho'' isomers in commercial TCP if there is a risk of human exposure. However, researchers at the
University of Washington The University of Washington (UW and informally U-Dub or U Dub) is a public research university in Seattle, Washington, United States. Founded in 1861, the University of Washington is one of the oldest universities on the West Coast of the Uni ...
found that non-''ortho'' TCP isomers present in synthetic jet engine oils do inhibit certain enzymes.


Health calamities from TCP

TCP was the source of a 1977 epidemic of acute
polyneuropathy Polyneuropathy () is damage or disease affecting peripheral nerves (peripheral neuropathy) in roughly the same areas on both sides of the body, featuring weakness, numbness, and burning pain. It usually begins in the hands and feet and may prog ...
in Sri Lanka where 20 Tamil girls were poisoned by TCP-contaminated gingili oil. It is a toxic substance that causes
neuropathy Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropa ...
, paralysis in the hands and feet, and/or death for humans and animals alike. It can be ingested, inhaled, or even absorbed through the skin. Its ortho-isomer is notoriously known as a source of several delayed neurotoxic outbreaks across recent history. Contemporary commercial products typically contain only the para- and meta- isomers of TCP due to the lack of neurotoxic potential within these isomers. The earliest known mass poisoning event by TOCP occurred in 1899 when six French hospital patients were given a phosphocresote cough mixture containing the
organophosphate 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 ...
compound. Pharmacist Jules Brissonet had synthesized this compound in the hopes of treating
tuberculosis Tuberculosis (TB), also known colloquially as the "white death", or historically as consumption, is a contagious disease usually caused by ''Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can al ...
, but soon after administration all six patients developed
polyneuropathy Polyneuropathy () is damage or disease affecting peripheral nerves (peripheral neuropathy) in roughly the same areas on both sides of the body, featuring weakness, numbness, and burning pain. It usually begins in the hands and feet and may prog ...
. The original paper described this phosphocresote to be:
''A bland, limpid liquid, nearly tasteless and odourless, which is not irritating to the gastric mucous membranes. When creosote is combined with phosphoric acid the metabolic action produced is much more marked, and Phosote can be tolerated in larger doses and for a longer continuance than Creosote or Guaiacol. Dose of the preparation, one to two grammes three times a day.''
The greatest mass poisoning by TOCP occurred in 1930 when it was added as an
adulterant An adulterant is a substance secretly added to another that may compromise the safety or effectiveness. Typical substances that are adulterated include food, cosmetics, pharmaceuticals or fuels. Definition Adulteration is the practice of secre ...
to the popular drink
Jamaica ginger Jamaica ginger extract, known in the United States by the slang name Jake, was a late 19th-century patent medicine that provided a convenient way to obtain alcohol during the era of Prohibition in the United States, Prohibition, since it conta ...
, also known as Ginger Jake, during the United States Prohibition era, when all alcoholic drinks had been outlawed by the
Eighteenth Amendment to the United States Constitution The Eighteenth Amendment (Amendment XVIII) to the United States Constitution established the prohibition of alcohol in the United States. The amendment was proposed by Congress on December 18, 1917, and ratified by the requisite number of sta ...
. Jake was listed as a cure for "assorted ailments" in the U.S. Pharmocopoeia and thus easy to obtain; as it had a high alcohol content it was used as a way to obtain alcohol legally. Up to 100,000 people were poisoned and 5,000 paralyzed when a manufacturer of Ginger Jake added Lindol—a compound that consisted mainly of TOCP—to their product. The exact reason for why TOCP was found in Ginger Jake is disputed; one source claims it was to further extract the Jamaica root, another source claims it was to water the drink down, and yet another source claims it was a result of contamination from lubricating oils. Binges of Ginger Jake resulted in what was known to be a "Jake walk", in which patients experienced a highly irregular gait caused by numbness in the legs, followed by eventual paralysis of the wrists and feet. In medical journals it was described to have produced an organophosphate-induced delayed neuropathy (OPIDN) neurodegenerative syndrome, "characterized by distal axonal lesions, ataxia, and neuronal degeneration in the spinal cord and peripheral nervous systems." In 1932, 60 European women experienced TOCP poisoning due to the abortion-inducing (abortifacient) drug
apiol Apiol, also known as liquid apiol or green oil of parsley is the extracted oleoresin of parsley, rather than the distilled oil. Due to its similarity to the term apiole, care should be taken to avoid confusion. Apiol is an irritant and, in high do ...
. This drug, formed by the
phenylpropanoid The phenylpropanoids are a diverse family of organic compounds that are biosynthesized by plants from the amino acids phenylalanine and tyrosine in the shikimic acid pathway. Their name is derived from the six-carbon, aromatic phenyl group and ...
compound extracted from
parsley Parsley, or garden parsley (''Petroselinum crispum''), is a species of flowering plant in the family Apiaceae that is native to Greece, Morocco and the former Yugoslavia. It has been introduced and naturalisation (biology), naturalized in Eur ...
leaves, was exploited throughout history—and even known to
Hippocrates Hippocrates of Kos (; ; ), also known as Hippocrates II, was a Greek physician and philosopher of the Classical Greece, classical period who is considered one of the most outstanding figures in the history of medicine. He is traditionally referr ...
—as an agent to terminate pregnancies. The contamination of the modern drug in 1932 was not accidental, but rather included as an "additional stimulus." Those who took the pill experienced comas, convulsions, paralysis of the lower body (paraplegia) and often death. Apiol was subsequently criticized by doctors, journalists, and activists until it was discontinued, citing that the dangers were too great and the number of poisonings was likely higher than accounted for. Other mass poisonings include: * In 1937, 60 South Africans were poisoned after using contaminated cooking oil that had been stored in drums that previously stored lubricating oil. * In two separate incidents in 1940, 74, and at least 17, men in units of the Swiss army experienced a similar outbreak when their cooking oil was contaminated with machine gun oil. They became known as the "
Oil soldiers Oil soldiers (German ''Ölsoldaten'') is the name given to soldiers of the Swiss Army poisoned by accident in 1940, when they were served ''Käseschnitten'' (fried bread with cheese) in which mineral oil mixed with tricresyl phosphate, intended as ...
". * In the 1950s, 11 South Africans used water from drums from a paint factory that previously stored TOCP. * 10,000 people in Morocco were poisoned in 1959, when they consumed cooking oil contaminated with jet-plane lubricating oil. * Hundreds of Germans in the cities of
Eckernförde Eckernförde (; , sometimes also ; , sometimes also ) is a city located in the of Rendsburg-Eckernförde, Schleswig-Holstein, northern Germany. Situated on the coast of the Baltic Sea, approximately 30 km north-west of Kiel, it has a populat ...
(1941) and
Kiel Kiel ( ; ) is the capital and most populous city in the northern Germany, German state of Schleswig-Holstein. With a population of around 250,000, it is Germany's largest city on the Baltic Sea. It is located on the Kieler Förde inlet of the Ba ...
(1945) when torpedo-lubricants were used as a cooking oil replacement, "organised" from the "black market". That was common, for example after
World War I World War I or the First World War (28 July 1914 – 11 November 1918), also known as the Great War, was a World war, global conflict between two coalitions: the Allies of World War I, Allies (or Entente) and the Central Powers. Fighting to ...
, because torpedo oil was of natural origin but, in
World War II World War II or the Second World War (1 September 1939 – 2 September 1945) was a World war, global conflict between two coalitions: the Allies of World War II, Allies and the Axis powers. World War II by country, Nearly all of the wo ...
, TOCP was added for thermic purposes. Severe physical and neurological damage was experienced, and the illness was called the .


Aerotoxic syndrome

TCP is used as an additive in turbine engine oil and can potentially contaminate an airliner cabin via a
bleed air Bleed air in aerospace engineering is compressed air taken from the compressor stage of a gas turbine, upstream of its fuel-burning sections. Automatic air supply and cabin pressure controller (ASCPC) valves bleed air from low or high stage engine ...
"
fume event A fume event occurs when bleed air used for cabin pressurisation and air conditioning in a pressurised aircraft is contaminated by fluids such as engine oil, hydraulic fluid, anti-icing fluid, and other potentially hazardous chemicals. How c ...
". Aerotoxic syndrome is the name given to the alleged ill effects (with symptoms including
memory loss Amnesia is a deficit in memory caused by brain damage or brain diseases,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be temporarily caused by t ...
, depression and
schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
) caused by exposure to engine chemicals. However, industry-funded studies in the UK discussed in 1999–2000 did not find a link between TCP and long-term health problems.


Safety


Animals

In studies on
slow loris Slow lorises are a group of several species of Nocturnality, nocturnal Strepsirrhini, strepsirrhine primates that make up the genus ''Nycticebus''. Found in Southeast Asia and nearby areas, they range from Bangladesh and Northeast India in the ...
es (''Nyticebus coucang coucang''), numerous chronic effects observed from topical applications. Mammalian placental development were also negatively affected.


Metabolism

Although TOCP is mainly excreted through urine and feces, it is partially metabolized by the hepatic cytochrome P450 system. Pathways include
hydroxylation In chemistry, hydroxylation refers to the installation of a hydroxyl group () into an organic compound. Hydroxylations generate alcohols and phenols, which are very common functional groups. Hydroxylation confers some degree of water-solubility ...
at one or more methyl groups, dearylation (removal of a o-cresyl group) and conversion of the
hydroxymethyl The hydroxymethyl group is a substituent with the structural formula . It consists of a methylene bridge ( unit) bonded to a hydroxyl group (). This makes the hydroxymethyl group an alcohol. It has the identical chemical formula with the methoxy g ...
groups to an
aldehyde In organic chemistry, an aldehyde () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...
or a
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...
. The first step results in a ''saligenin cyclic o-tolyl phosphate (''SCOTP'')'' intermediate'','' a
neurotoxin Neurotoxins are toxins that are destructive to nervous tissue, nerve tissue (causing neurotoxicity). Neurotoxins are an extensive class of exogenous chemical neurological insult (medical), insultsSpencer 2000 that can adversely affect function ...
. To the right, the first step of TOCP metabolism is depicted by means of chemical structures. This intermediate is able to inhibit
neuropathy target esterase Neuropathy target esterase, also known as patatin-like phospholipase domain-containing protein 6 (PNPLA6), is an esterase enzyme that in humans is encoded by the ''PNPLA6'' gene. Neuropathy target esterase is a phospholipase that deacetylates in ...
(NTE) and results in the classic organophosphate-induced delayed neuropathy ( OPIDN). In tandem, TOCP exerts physical damage by causing
axon An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see American and British English spelling differences#-re, -er, spelling differences) is a long, slender cellular extensions, projection of a nerve cell, or neuron, ...
al destruction and
myelin Myelin Sheath ( ) is a lipid-rich material that in most vertebrates surrounds the axons of neurons to insulate them and increase the rate at which electrical impulses (called action potentials) pass along the axon. The myelinated axon can be lik ...
disintegration within specialized cells that transmit nerve impulses (
neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
s). In addition to the formation of SCOTP, the interactions between TOCP and two different human cytochrome P450 complexes (1A2 and 3A4) can further produce 2-(''ortho''-cresyl)-4''H''-1,2,3-benzodioxaphosphoran-2-one (CBDP). This metabolite can bind to butyrylcholinesterase (BuChE) and/or acetylcholinesterase (AChE). Binding to BuChE results in no adverse effects, for its typical role is to covalently bind to organophosphate poisons and detoxify them by inactivation. The dangers in metabolizing TOCP to CBDP occur when its potential to bind to AChE become imminent, for inactivation of the enzyme in nerve synapses can be lethal. The enzyme plays a tantamount role in terminating nerve impulse transmission "by hydrolyzing the neurotransmitter acetylcholine." Upon inactivation, acetylcholine can no longer be broken down in the body and results in uncontrollable muscle spasms, paralyzed breathing (
bradycardia Bradycardia, also called bradyarrhythmia, is a resting heart rate under 60 beats per minute (BPM). While bradycardia can result from various pathological processes, it is commonly a physiological response to cardiovascular conditioning or due ...
), convulsions, and/or death. Luckily, TOCP is considered a weak AChE inhibitor.


Onset and treatment

In humans, the first symptoms are weakness/paralysis of the hands and feet on both sides of the body due to damage to the peripheral nervous system (
polyneuropathy Polyneuropathy () is damage or disease affecting peripheral nerves (peripheral neuropathy) in roughly the same areas on both sides of the body, featuring weakness, numbness, and burning pain. It usually begins in the hands and feet and may prog ...
) and a sensation of pins-and-needles (
paresthesia Paresthesia is a sensation of the skin that may feel like numbness (''hypoesthesia''), tingling, pricking, chilling, or burning. It can be temporary or Chronic condition, chronic and has many possible underlying causes. Paresthesia is usually p ...
). Onset typically occurs between 3–28 days from initial exposure. If ingested, this can be preceded by gastrointestinal symptoms that include nausea, vomiting, and diarrhea. Rates of metabolism vary by species and by individual; some people developed severe polyneuropathy after ingesting 0.15g of TOCP, whereas others have been reported asymptomatic after 1-2g. Though death is uncommon in acute exposure cases, the result of paralysis can last for months or years due to differences in gender, age, and route of exposure. The cardinal treatment is physical therapy to restore the use of the hands and feet, though it can take up to 4 years to only regain a fraction of motor control. Exposure to TOCP has been characterized by a list of observations: *
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 neurotransmitte ...
levels will remain unchanged or show no significant changes. *
Electromyography Electromyography (EMG) is a technique for evaluating and recording the electrical activity produced by skeletal muscles. EMG is performed using an instrument called an electromyograph to produce a record called an electromyogram. An electromyo ...
will show partial or complete reactions of degeneration. * An increase of protein in
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...
. * Swelling of the
parotid gland The parotid gland is a major salivary gland in many animals. In humans, the two parotid glands are present on either side of the mouth and in front of both ears. They are the largest of the salivary glands. Each parotid is wrapped around the m ...
s (non-tender).


References

{{Acetylcholine metabolism and transport modulators Acetylcholinesterase inhibitors Flame retardants Fuel additives Neurotoxins Organophosphates Phosphate esters Plasticizers Prohibition in the United States Solvents