Tricresyl phosphate

Last updated
Tri-ortho-cresyl phosphate
Tri-o-cresyl phosphate.svg
O-Tricresyl phosphate 3D ball.png
Names
Preferred IUPAC name
Tris(2-methylphenyl) phosphate
Other names
tri-o-cresyl phosphate
TOCP
tritolyl phosphate, ortho-isomer
tri-o-tolyl ester of phosphoric acid
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.014.136 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
RTECS number
  • o-:TD0350000
UNII
UN number 2574
  • InChI=1S/C21H21O4P/c1-16-10-4-7-13-19(16)23-26(22,24-20-14-8-5-11-17(20)2)25-21-15-9-6-12-18(21)3/h4-15H,1-3H3 Yes check.svgY
    Key: YSMRWXYRXBRSND-UHFFFAOYSA-N Yes check.svgY
  • o-:InChI=1/C21H21O4P/c1-16-10-4-7-13-19(16)23-26(22,24-20-14-8-5-11-17(20)2)25-21-15-9-6-12-18(21)3/h4-15H,1-3H3
    Key: YSMRWXYRXBRSND-UHFFFAOYAP
  • o-:Cc3ccccc3OP(=O)(Oc1ccccc1C)Oc2ccccc2C
Properties
C21H21O4P
Molar mass 368.37 g/mol
Appearancecolourless liquid
Melting point −40 °C (−40 °F; 233 K)
Boiling point 255 °C (491 °F; 528 K) (10 mmHg)
Hazards
GHS labelling:
GHS-pictogram-silhouette.svg GHS-pictogram-pollu.svg
Danger
H370, H411
P260, P264, P270, P273, P307+P311, P321, P391, P405, P501
NFPA 704 (fire diamond)
NFPA 704.svgHealth 1: Exposure would cause irritation but only minor residual injury. E.g. turpentineFlammability 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
1
1
0
Flash point >225 °C (437 °F; 498 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Tricresyl phosphate (TCP), is a mixture of three isomeric organophosphate compounds most notably used as a flame retardant. [1] Other uses include as a plasticizer in manufacturing for lacquers and varnishes and vinyl plastics and as an antiwear additive 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, hexane, and diethylether among others. It was synthesized by Alexander Williamson in 1854 upon reacting phosphorus pentachloride with cresol (a mixture of para-, ortho-, and meta- isomers of methylphenol), though today's manufacturers can prepare TCP by mixing cresol with phosphorus oxychloride or phosphoric acid 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.

Contents

Isomers

The most dangerous isomers are considered to be those containing ortho isomers, such as tri-ortho-cresyl phosphate, TOCP. The World Health Organization 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." [2] 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. [3] However, researchers at the University of Washington found that non-ortho TCP isomers present in synthetic jet engine oils do inhibit certain enzymes. [4]

Health calamities from TCP

TCP was the source of a 1977 epidemic of acute polyneuropathy in Sri Lanka where 20 Tamil girls were poisoned by TCP-contaminated gingili oil. It is a toxic substance that causes neuropathy, 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 compound. Pharmacist Jules Brissonet had synthesized this compound in the hopes of treating tuberculosis, but soon after administration all six patients developed polyneuropathy. [5] The original paper described this phosphocresote to be: [6]

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 into the popular drink "Ginger Jake" (or Jamaica "Jake") during the United States Prohibition era. [5] Although the drink was a primary substitute for alcohol during that period, when all alcoholic drinks had been outlawed, under the Eighteenth Amendment to the United States Constitution, it was also listed as a cure for "assorted ailments" in the U.S. Pharmocopoeia and thus easy to acquire. [7] 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. [8] The exact reason for why TOCP was found in Ginger Jake is disputed; one source claims it was to further extract the Jamaica root, [5] another source claims it was to water the drink down, [9] and yet another source claims it was a result of contamination from lubricating oils. [10] 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 that followed with 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." [11]

The chemical structure of apiole, a constituent of Apiol Apiol structure.svg
The chemical structure of apiole, a constituent of Apiol
Parsley Leaves Parsley Leaves.jpg
Parsley Leaves

In 1932, 60 European women experienced TOCP poisoning by means of the abortion-inducing (abortifacient) drug apiol. [5] This drug, formed by the phenylpropanoid compound extracted from parsley leaves, was exploited throughout history—and even known to Hippocrates himself—as an agent to terminate pregnancies. [12] The contamination of the modern drug in 1932 was not accidental, but rather included as an "additional stimulus." [5] Those who took the pill experienced comas, convulsions, paralysis of the lower body (paraplegia) and often death [13] Apiol was subsequently criticized by doctors, journalists, and activists alike until its discontinuation, citing that the dangers were too great and the number of poisonings was likely higher than accounted for. [14]

Other mass poisonings [8] include:

Aerotoxic syndrome

TCP is used as an additive in turbine engine oil and can potentially contaminate an airliner cabin via a bleed air "fume event". Aerotoxic syndrome is the name given to the alleged ill effects (with symptoms including memory loss, depression and schizophrenia) caused by exposure to engine chemicals. However, industry-funded studies in the UK have not found a link between TCP and long-term health problems. [15]

Safety

Animals

In studies on slow lorises (Nyticebus coucang coucang), numerous chronic effects observed from topical applications. [16] Mammalian placental development were also negatively affected. [11]

Metabolism

Although TOCP is mainly excreted through urine and feces, it is partially metabolized by the hepatic cytochrome P450 system. Pathways include hydroxylation at one or more methyl groups, dearylation (removal of a o-cresyl group) and conversion of the hydroxymethyl groups to an aldehyde or a carboxylic acid.[ citation needed ]

The first step results in a saligenin cyclic o-tolyl phosphate (SCOTP) intermediate, a neurotoxin. 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 (NTE) and results in the classic organophosphate-induced delayed neuropathy (OPIDN). In tandem, TOCP exerts physical damage by causing axon al destruction and myelin disintegration within specialized cells that transmit nerve impulses (neurons). [17]

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)-4H-1,2,3-benzodioxaphosphoran-2-one (CBDP). [18] 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." [19] Upon inactivation, acetylcholine can no longer be broken down in the body and results in uncontrollable muscle spasms, paralyzed breathing (bradycardia), convulsions, and/or death. [20] Luckily, TOCP is considered a weak AChE inhibitor. [21]

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) and a sensation of pins-and-needles (paraesthesia). [22] Onset typically occurs between 3–28 days from initial exposure. [5] 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. [23]

Exposure to TOCP has been characterized by a list of observations: [5]

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<span class="mw-page-title-main">Jamaica ginger</span>

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, since it contained approximately 70% to 80% ethanol by weight. In the 1930s, a large number of users of Jamaica ginger were afflicted with a paralysis of the hands and feet that quickly became known as Jamaica ginger paralysis or jake paralysis.

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

Chlorfenvinphos is the common name of 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 cancelled in 1991.

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<span class="mw-page-title-main">Organophosphate</span> Organic compounds with the structure O=P(OR)3

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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 doses, it can cause liver and kidney damage. Cases of death due to attempted abortion using apiol have been reported.

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

Apiole is a phenylpropene, also known as apiol, parsley apiol, or parsley camphor. Its chemical name is 1-allyl-2,5-dimethoxy-3,4-methylenedioxybenzene. It is found in the essential oils of celery leaf and all parts of parsley. Heinrich Christoph Link, an apothecary in Leipzig, discovered the substance in 1715 as greenish crystals reduced by steam from oil of parsley. In 1855 Joret and Homolle discovered that apiol was an effective treatment of amenorrea or lack of menstruation.

<span class="mw-page-title-main">Pralidoxime</span> Chemical compound as an antidote

Pralidoxime or 2-PAM, usually as the chloride or iodide salts, belongs to a family of compounds called oximes that bind to organophosphate-inactivated acetylcholinesterase. It is used to treat organophosphate poisoning in conjunction with atropine and either diazepam or midazolam. It is a white solid.

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References

  1. ↑ Weil, Edward D. (1978). "Phosphorus-Based Flame Retardants". Flame - Retardant Polymeric Materials: 103–131. doi:10.1007/978-1-4684-6973-8_4. ISBN   978-1-4684-6975-2.
  2. ↑ "Tricresyl Phosphate Environmental Health Criteria A110". International Programme On Chemical Safety. WHO Geneva. 1990.
  3. ↑ Ramsden, J. J. (2013). "On the proportion of ortho isomers in the tricresyl phosphates contained in jet oil". Journal of Biological Physics and Chemistry. 13 (2): 69–72. doi:10.4024/03RA13L.jbpc.13.02.
  4. ↑ Baker, Paul E.; Cole, Toby B.; Cartwright, Megan; Suzuki, Stephanie M.; Thummel, Kenneth E.; Lin, Yvonne S.; Co, Aila L.; Rettie, Allan E.; Kim, Jerry H.; Furlong, Clement E. (2013). "Identifying safer anti-wear triaryl phosphate additives for jet engine lubricants". Chemico-Biological Interactions. 203 (1): 257–264. doi:10.1016/j.cbi.2012.10.005. PMC   3618534 . PMID   23085349.
  5. 1 2 3 4 5 6 7 Susser, M.; Stein, Z. (1957-04-01). "An Outbreak of Tri-ortho-cresyl Phosphate (T.O.C.P.) Poisoning in Durban". Occupational and Environmental Medicine. 14 (2): 111–120. doi:10.1136/oem.14.2.111. ISSN   1351-0711. PMC   1037779 . PMID   13426434.
  6. ↑ Petroianu, G.A. (December 2016). "Neuropathic organophosphates: from Scrugham, Heim and Lorot to Jake leg paralysis". Die Pharmazie. Avoxa - Mediengruppe Deutscher Apotheker GmbH. 71 (12): 738–744. doi:10.1691/ph.2016.6080. PMID   29442005 – via Ingenta Connect.
  7. ↑ "Got the Jake Leg Too". www.fresnostate.edu. Retrieved 2020-04-24.
  8. 1 2 Organophosphates And Health. World Scientific. 2001. p. 159. ISBN   1783261439.
  9. ↑ "The Jake Walk Effect". Moonshine.
  10. ↑ Neurotoxicity: Identifying and Controlling Poisons of the Nervous System : New Developments in Neuroscience. Congress of the U.S., Office of Technology Assessment. 1990. p. 47.
  11. 1 2 Yang, Bei; Wang, Xinlu; Ma, Yilin; Yan, Lei; Ren, Yuan; Yu, Dainan; Qiao, Bo; Shen, Xin; Liu, Hui; Zhang, Dalei; Kuang, Haibin (January 2020). "Tri‐ortho‐cresyl phosphate (TOCP)‐induced reproductive toxicity involved in placental apoptosis, autophagy and oxidative stress in pregnant mice". Environmental Toxicology. 35 (1): 97–107. Bibcode:2020EnTox..35...97Y. doi: 10.1002/tox.22846 . ISSN   1520-4081. PMID   31566301.
  12. ↑ Pizzato, Margherita (2012-07-16). "Apiol: abortive and toxic effects".
  13. ↑ HERMANN K; LE ROUX A; FIDDES FS (16 June 1956). "Death from Apiol Used as Abortifacient". The Lancet. 267 (6929): 937–9. doi:10.1016/S0140-6736(56)91522-7. PMID   13320936.
  14. ↑ Quinn, L. J.; Harris, C.; Joron, G. E. (April 15, 1958). "Letters to the Editor: Apiol Poisoning". Canadian Medical Association Journal. 78 (8): 635–636. PMC   1829842 . PMID   20325694.
  15. ↑ "UK Parliament: Elements of healthy cabin air".
  16. ↑ Vij, S.; Kanagasuntheram, R. (1972). "Effect of tri-o-cresyl phosphate (TOCP) poisoning on sensory nerve terminations of slow loris: Nycticebus coucang coucang". Acta Neuropathologica. 20 (2): 150–159. doi:10.1007/BF00691131. ISSN   0001-6322. PMID   4336145. S2CID   519641.
  17. ↑ Prineas, J. (1969-08-01). "Triorthocresyl Phosphate Myopathy". Archives of Neurology. 21 (2): 150–156. doi:10.1001/archneur.1969.00480140050005. ISSN   0003-9942. PMID   5797349.
  18. ↑ Reinen, Jelle; Nematollahi, Leyla; Fidder, Alex; Vermeulen, Nico P. E.; Noort, Daan; Commandeur, Jan N. M. (2015-04-20). "Characterization of Human Cytochrome P450s Involved in the Bioactivation of Tri- ortho -cresyl Phosphate (ToCP)". Chemical Research in Toxicology. 28 (4): 711–721. doi:10.1021/tx500490v. ISSN   0893-228X. PMID   25706813.
  19. ↑ Masson, Patrick; Lockridge, Oksana (February 2010). "Butyrylcholinesterase for protection from organophosphorus poisons: Catalytic complexities and hysteretic behavior". Archives of Biochemistry and Biophysics. 494 (2): 107–120. doi:10.1016/j.abb.2009.12.005. PMC   2819560 . PMID   20004171.
  20. ↑ "Cholinesterase Inhibition". Extoxnet. Cornell University. September 1993.
  21. ↑ Oh, Shin J. (2010). Treatment and Management of Disorders of the Neuromuscular Junction. ISBN   978-1-4377-0372-6.
  22. ↑ "Tricresyl phosphate (EHC 110, 1990)". www.inchem.org. Retrieved 2020-05-05.
  23. ↑ Inoue, N.; Fujishiro, K.; Mori, K.; Matsuoka, M. (December 1, 1988). "Triorthocresyl phosphate poisoning--a review of human cases". Journal of UOEH. 10 (4): 433–42. doi: 10.7888/juoeh.10.433 . PMID   3062730.
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