What Is Nitrophenol? (besides something mentioned in ‘Scientific Opinion on the re‐evaluation of aspartame as a food additive’)

Nitrophenols are compounds of the formula HOC₆H_5−x(NO₂)_x. The conjugate bases are called nitrophenolates. Nitrophenols are more acidic than phenol itself.

Wikipedia

Mono-nitrophenols

with the formula HOC₆H₄NO₂. Three isomeric nitrophenols exist:

• o-Nitrophenol (2-nitrophenol; OH and NO₂ groups are neighboring; CAS number: 88-75-5), a yellow crystalline solid (m.p. 46 °C).
• m-Nitrophenol (3-nitrophenol, CAS number: 554-84-7), a yellow solid (m.p. 97 °C) and precursor to the drug mesalazine (5-aminosalicylic acid).
  • Mesalazine, also known as mesalamine or 5-aminosalicylic acid (5-ASA), is a medication used to treat inflammatory bowel disease, including ulcerative colitis and Crohn’s disease. It is generally used for mildly to moderately severe disease. It is taken by mouth or rectally. ^[“Mesalamine Monograph for Professionals”. Drugs.com. American Society of Health-System Pharmacists^] The formulations which are taken by mouth appear to be similarly effective.
    • Side Effects – There are no data on use in pregnant women, but the drug does cross the placenta and is excreted in breast milk. The drug should not be used in children under two years of age, people with kidney disease, or people who are allergic to aspirin. ^{[“Asacol HD- mesalamine tablet, delayed release”. DailyMed. 15 April 2018. Retrieved 30 December 2019.]}
    • Side effects are primarily gastrointestinal but may also include headache; GI effects include nausea, diarrhea and abdominal pain. There have been scattered reports of various problems when the oral form is used, including: problems caused by myelosuppression (leukopenia, neutropenia, agranulocytosis, aplastic anaemia, and thrombocytopenia), as well as hair loss, peripheral neuropathy, pancreatitis, liver problems, myocarditis and pericarditis, allergic and fibrotic lung reactions, lupus erythematosus-like reactions and rash (including urticaria), drug fever, interstitial nephritis and nephrotic syndrome, usually reversible on withdrawal. Very rarely, use of mesalazine has been associated with an exacerbation of the symptoms of colitis, Stevens Johnson syndrome and erythema multiforme.^{[“Asacol HD- mesalamine tablet, delayed release”. DailyMed. 15 April 2018. Retrieved 30 December 2019.]}
    • Mesalazine is the active moiety of sulfasalazine, which is metabolized to sulfapyridine and mesalazine. ^{[Richard Finkel R, Clark MA, Cubeddu LX (2009). Lippincott’s Illustrated Reviews: Pharmacology (Fourth ed.). ISBN 978-0-7817-7155-9.]} 
    • It is also the active component of the prodrug balsalazide along with the inert carrier molecule 4-aminobenzoyl-beta-alanine. ^{[“Balsalazide: increasing the choice for patients with ulcerative colitis”. Drugs & Therapy Perspectives. 19 (1–4): 1–4. 2003. doi:10.2165/00042310-200319100-00001. S2CID 195230977]} 
    • It is in the category of disease-modifying antirheumatic drugs (DMARDs) family of medications. It is unclear exactly how it works. ^{[“Sulfasalazine”. The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.]}

• p-Nitrophenol (4-nitrophenol, CAS number: 100-02-7), yellow crystals (m.p. 114 °C). It is a precursor to the rice herbicide fluorodifen, the pesticide parathion, and the human analgesic paracetamol (also known as acetaminophen).
  • Fluorodifen – no page at wikipedia but listed as a protox inhibitor at the bottom of the herbicides page
    • Clicking on protox inhibitor redirects to Protoporphyrinogen oxidase
    • Protoporphyrinogen oxidase or protox is an enzyme that in humans is encoded by the PPOX gene.^{[Taketani S, Inazawa J, Abe T, Furukawa T, Kohno H, Tokunaga R, et al. (October 1995). “The human protoporphyrinogen oxidase gene (PPOX): organization and location to chromosome 1”. Genomics. 29 (3): 698–703. doi:10.1006/geno.1995.9949. PMID 8575762][Frank J, McGrath JA, Poh-Fitzpatrick MB, Hawk JL, Christiano AM (July 1999). “Mutations in the translation initiation codon of the protoporphyrinogen oxidase gene underlie variegate porphyria”. Clinical and Experimental Dermatology. 24 (4): 296–301. doi:10.1046/j.1365-2230.1999.00484.x. PMID 10457135. S2CID 40509390][“Entrez Gene: PPOX protoporphyrinogen oxidase”]}
    • Protoporphyrinogen oxidase is responsible for the seventh step in biosynthesis of protoporphyrin IX. This porphyrin is the precursor to hemoglobin, the oxygen carrier in animals, and chlorophyll, the dye in plants. The enzyme catalyzes the dehydrogenation (removal of hydrogen atoms) of protoporphyrinogen IX (the product of the sixth step in the production of heme) to form protoporphyrin IX. One additional enzyme must modify protoporphyrin IX before it becomes heme. Inhibition of this enzyme is a strategy used in certain herbicides.
    • The PPOX gene is located on the long (q) arm of chromosome 1 at position 22, from base pair 157,949,266 to base pair 157,954,082.
    • This gene encodes the penultimate enzyme of heme biosynthesis, which catalyzes the 6-electron oxidation of protoporphyrinogen IX to form protoporphyrin IX. This protein is a flavoprotein associated with the outer surface of the inner mitochondrial membrane.^{[“Entrez Gene: PPOX protoporphyrinogen oxidase”]}
    • The following genes encode enzymes that catalyze the various steps in the heme biosynthetic pathway:
      • ALAD: aminolevulinate, delta-, dehydratase
      • ALAS1: aminolevulinate, delta-, synthase 1
      • ALAS2: aminolevulinate, delta-, synthase 2 (sideroblastic/hypochromic anemia)
      • CPOX: coproporphyrinogen oxidase
      • FECH: ferrochelatase (protoporphyria)
      • HMBS: hydroxymethylbilane synthase
      • PPOX: protoporphyrinogen oxidase
      • UROD: uroporphyrinogen decarboxylase
      • UROS: uroporphyrinogen III synthase (congenital erythropoietic porphyria)
    • Variegate porphyria is caused by mutations in the PPOX gene. More than 100 mutations that can cause variegate porphyria have been identified in the PPOX gene. One mutation, a substitution of the amino acid tryptophan for arginine at position 59 (also written as Arg59Trp or R59W), is found in about 95 percent of South African families with variegate porphyria. Mutations in the PPOX gene reduce the activity of the enzyme made by the gene, allowing byproducts of heme production to build up in the body. This buildup, in combination with nongenetic factors (such as certain drugs, alcohol and dieting), causes this type of porphyria.
    • Inhibition of protoporphyrinogen oxidase is a mechanism of action for several commercial herbicides including the nitrophenyl ethers 
      • acifluorfen and 
        • In California, acifluorfen is listed as “known to the state to cause cancer or reproductive toxicity” according to Proposition 65.^{[ The Proposition 65 List]}
      • fomesafen and
      • the pyrimidinediones 
        • butafenacil and 
        • saflufenacil.
      • In the United States, the Environmental Protection Agency (EPA) is responsible for regulating pesticides under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), the Food Quality Protection Act (FQPA) and the Pesticide Registration Improvement Act (PRIA).^{[“About Pesticide Registration”. US EPA. Retrieved 2021-02-27.]} A pesticide can only be used legally according to the directions on the label that is included at the time of the sale of the pesticide. The purpose of the label is “to provide clear directions for effective product performance while minimizing risks to human health and the environment”. A label is a legally binding document that mandates how the pesticide can and must be used and failure to follow the label as written when using the pesticide is a federal offence.^{[“Registration Review Label Mitigation for Sodium Acifluorfen” (PDF). United States Environmental Protection Agency. 2020-06-02. Retrieved 2021-03-05.][United Phosphorus, Inc (2012). “Ultra Blazer herbicide” (PDF). Retrieved 2021-03-06.]}
      • The visible symptoms of treatment are chlorosis and desiccation. The damage is caused by an accumulation of protoporphyrin IX in the plant cells by inhibiting protox within the tetrapyrrole biosynthesis pathway.^{[Brzezowski P, Ksas B, Havaux M, Grimm B, Chazaux M, Peltier G, et al. (2019-05-03). “The function of PROTOPORPHYRINOGEN IX OXIDASE in chlorophyll biosynthesis requires oxidised plastoquinone in Chlamydomonas reinhardtii“. Communications Biology. 2 (1): 159. doi:10.1038/s42003-019-0395-5. PMC 6499784. PMID 31069268]} 
      • This is a potent photosensitizer which activates oxygen, leading to lipid peroxidation. Both light and oxygen are required for this process to kill the plant.^{[ Dayan FE, Reddy KN, Duke SO (1999). “Structure-Activity Relationships of Diphenyl Ethers and Other Oxygen-Bridged Protoporphyrinogen Oxidase Inhibitors”. Peroxidizing Herbicides. pp. 141–161. doi:10.1007/978-3-642-58633-0_5. ISBN 978-3-642-63674-5.][Nagano E (1999). “Herbicidal Efficacy of Protoporphyrinogen Oxidase Inhibitors”. Peroxidizing Herbicides. pp. 293–302. doi:10.1007/978-3-642-58633-0_11. ISBN 978-3-642-63674-5][ Dayan FE, Duke SO (2010). “Protoporphyrinogen Oxidase-Inhibiting Herbicides”. Hayes’ Handbook of Pesticide Toxicology. pp. 1733–1751. doi:10.1016/B978-0-12-374367-1.00081-1. ISBN 9780123743671.]}
    • See Also Porphyrin
  • Parathion
    • Parathion, also called parathion-ethyl or diethyl parathion and locally known as “Folidol“, is an organophosphate insecticide and acaricide. It was originally developed by IG Farben in the 1940s. It is highly toxic to non-target organisms, including humans, so its use has been banned or restricted in most countries. The basic structure is shared by parathion methyl.^[5]
    • Parathion was developed by Gerhard Schrader for the German trust IG Farben in the 1940s. After World War II and the collapse of IG Farben due to the war crime trials, the Western allies seized the patent, and parathion was marketed worldwide by different companies and under different brand names. The most common German brand was E605 (banned in Germany after 2002); this was not a food-additive “E number” as used in the EU today. “E” stands for Entwicklungsnummer (German for “development number”). It is an irreversible acetylcholinesterase inhibitor.
    • Safety concerns have later led to the development of parathion methyl, which is somewhat less toxic.
    • In the EU, Parathion was banned after 2001. ^[6] In Switzerland, the substance is no longer approved as a pesticide.
    • Pure parathion is a white crystalline solid. It is commonly distributed as a brown liquid that smells of rotting eggs or garlic. The insecticide is somewhat stable, although it darkens when exposed to sunlight.
    • Parathion is synthesized from diethyl dithiophosphoric acid (C₂H₅O)₂PS₂H by chlorination to generate diethylthiophosphoryl chloride ((C₂H₅O)₂P(S)Cl), and then the chloride is treated with sodium 4-nitrophenolate (the sodium salt of 4-nitrophenol).^[7]
    • As a pesticide, parathion is generally applied by spraying. It is often applied to cotton, rice and fruit trees. The usual concentrations of ready-to-use solutions are 0.05 to 0.1%. The chemical is banned for use on many food crops.
    • Parathion acts on the enzyme acetylcholinesterase indirectly. After an insect (or a human) ingests parathion, an oxidase replaces the double bonded sulfur with oxygen to give paraoxon. The phosphate ester is more reactive in organisms than the phosphorothiolate ester, as the phosphorus atoms become much more electropositive.^{[Metcalf, R. L. (2002). “Insect Control”. Ullmann’s Encyclopedia of Industrial Chemistry. New York: Wiley-VCH Verlag GmbH & Co. KGaA. doi:10.1002/14356007.a14_263. ISBN 978-3527306732.]}
    • Degradation of parathion leads to more water-soluble products. Hydrolysis, which deactivates the molecule, occurs at the aryl ester bond resulting in diethyl thiophosphate and 4-nitrophenol. Degradation proceeds differently under anaerobic conditions: the nitro group on parathion is reduced to the amine. [Metcalf, R. L. (2002). “Insect Control”. Ullmann’s Encyclopedia of Industrial Chemistry. New York: Wiley-VCH Verlag GmbH & Co. KGaA. doi:10.1002/14356007.a14_263. ISBN 978-3527306732.]
    • Parathion is a cholinesterase inhibitor. It generally disrupts the nervous system by inhibiting acetylcholinesterase. It is absorbed via skin, mucous membranes, and orally. Absorbed parathion is rapidly metabolized to paraoxon, as described in Insecticidal activity. Paraoxon exposure can result in headaches, convulsions, poor vision, vomiting, abdominal pain, severe diarrhea, unconsciousness, tremor, dyspnea, and finally pulmonary edema as well as respiratory arrest. Symptoms of poisoning are known to last for extended periods, sometimes months. The most common and very specific antidote is atropine, in doses of up to 100 mg daily. Because atropine may also be toxic, it is recommended that small frequently repeated doses be used in treatment. If human poisoning is detected early and the treatment is prompt (atropine and artificial respiration), fatalities are infrequent. Insufficient oxygen will lead to cerebral hypoxia and permanent brain damage. Peripheral neuropathy including paralysis is noticed as late sequelae after recovery from acute intoxication. Parathion and related organophosphorus pesticides are used in hundreds of thousands of poisonings annually, especially suicides.^{[Litchfield, M.H. “Estimates of acute pesticide poisoning in agricultural workers in less developed countries” Toxicology Reviews 2005, volume 24, pp. 271-8. PMID 16499408]} It is known as Schwiegermuttergift (mother-in-law poison) in Germany. For this reason, most formulations contain a blue dye providing warning.
    • Parathion was used as a chemical warfare agent, most notably by an element of the British South Africa Police (BSAP) attached to the Selous Scouts during the Rhodesian Bush War. They used it to poison clothing that was then supplied to anti-government guerrillas. When the enemy soldiers put on the clothes, they were poisoned by absorption through the skin.^{[ “Poison in Rhodesia” (PDF). 31 January 2019.][ “Dirty War: Rhodesia and Chemical Biological Warfare 1975-1980 (Book Review)”. PRISM | National Defense University.][Cross, Glenn (2017). Dirty War: Rhodesia and Chemical Biological Warfare, 1975–1980. Solihull, UK: Helion & Company. ISBN 978-1-911512-12-7]}
    • Based on animal studies, parathion is considered by the U.S. Environmental Protection Agency to be a possible human carcinogen.^{[ “Parathion”. Integrated Risk Information System. U. S. Environmental Protection Agency. 26 January 2007.]} Studies show that parathion is toxic to fetuses, but does not cause birth defects.^{[“Pesticide Information Profiles – Parathion”. Extension Toxicology Network. Oregon State University. September 1993.]}
    • It is classified by the United Nations Environment Programme (UNEP) as a persistent organic pollutant^{[citation needed]} and by the World Health Organization (WHO) as Toxicity Class Ia (extremely hazardous).^{[citation needed]}
    • Parathion is toxic to bees, fish, birds, and other forms of wildlife.^{[“Pesticide Information Profiles – Parathion”. Extension Toxicology Network. Oregon State University. September 1993.]}
    • To provide the end user with a minimum standard of protection, suitable protective gloves, clothing, and a respirator with organic-vapour cartridges is normally worn. Industrial safety during the production process requires special ventilation and continuous measurement of air contamination in order not to exceed PEL levels, as well as careful attention to personal hygiene. Frequent analysis of workers’ serum acetylcholinesterase activity is also helpful with regards to occupational safety, because the action of parathion is cumulative. Also, atropine has been used as a specific antidote.
    • See Also Pesticide toxicity to bees and Parathion methyl
  • Paracetamol
    • Paracetamol, also known as acetaminophen,^{[ Commonly called “acetaminophen” in the US and Canada.]} is a medication used to treat fever and mild to moderate pain.^{[Warwick C (November 2008). “Paracetamol and fever management”. J R Soc Promot Health. 128 (6): 320–3. doi:10.1177/1466424008092794. PMID 19058473. S2CID 25702228][Saragiotto BT, Abdel Shaheed C, Maher CG (December 2019). “Paracetamol for pain in adults”. BMJ. 367: l6693. doi:10.1136/bmj.l6693. PMID 31892511. S2CID 209524643]} Common brand names include Tylenol and Panadol.
    • Paracetamol safety in pregnancy has been under increased scrutiny. There appears to be no link between paracetamol use in the first trimester and adverse pregnancy outcomes or birth defects. However, indications exist of a possible increase of asthma and developmental and reproductive disorders in the offspring of women with prolonged use of paracetamol during pregnancy.^{[McCrae JC, Morrison EE, MacIntyre IM, Dear JW, Webb DJ (October 2018). “Long-term adverse effects of paracetamol – a review”. Br J Clin Pharmacol. 84 (10): 2218–2230. doi:10.1111/bcp.13656. PMC 6138494. PMID 29863746]}
    • Paracetamol use by the mother during pregnancy is associated with an increased risk of childhood asthma,^{[Eyers S, Weatherall M, Jefferies S, Beasley R (April 2011). “Paracetamol in pregnancy and the risk of wheezing in offspring: a systematic review and meta-analysis”. Clinical and Experimental Allergy. 41 (4): 482–9. doi:10.1111/j.1365-2222.2010.03691.x. PMID 21338428. S2CID 205275267][Fan G, Wang B, Liu C, Li D (2017). “Prenatal paracetamol use and asthma in childhood: A systematic review and meta-analysis”. Allergol Immunopathol (Madr). 45 (6): 528–533. doi:10.1016/j.aller.2016.10.014. PMID 28237129]} but so are the maternal infections for which paracetamol may be used, and separating these influences is difficult. Paracetamol, in a small scale meta analysis was also associated with 20–30% increase in autism spectrum disorder, attention deficit hyperactivity disorder, hyperactivity symptoms, and conduct disorder, with the association being lower in a meta analysis where a larger demographic was used, but it is unclear whether this is a causal relationship and there was potential bias in the findings.^{[McCrae JC, Morrison EE, MacIntyre IM, Dear JW, Webb DJ (October 2018). “Long-term adverse effects of paracetamol – a review”. Br J Clin Pharmacol. 84 (10): 2218–2230. doi:10.1111/bcp.13656. PMC 6138494. PMID 29863746][Masarwa R, Levine H, Gorelik E, Reif S, Perlman A, Matok I (August 2018). “Prenatal Exposure to Acetaminophen and Risk for Attention Deficit Hyperactivity Disorder and Autistic Spectrum Disorder: A Systematic Review, Meta-Analysis, and Meta-Regression Analysis of Cohort Studies”. Am J Epidemiol. 187 (8): 1817–1827. doi:10.1093/aje/kwy086. PMID 29688261.][Ji Y, Azuine RE, Zhang Y, Hou W, Hong X, Wang G, Riley A, Pearson C, Zuckerman B, Wang X (February 2020). “Association of Cord Plasma Biomarkers of In Utero Acetaminophen Exposure With Risk of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in Childhood”. JAMA Psychiatry. 77 (2): 180–189. doi:10.1001/jamapsychiatry.2019.3259. PMC 6822099. PMID 31664451]} There is also an argument that the large number, consistency, and the robust designs of the studies provide a strong evidence in favor of paracetamol causing the increased risk of these neurodevelopmental disorders.^{[Bauer AZ, Kriebel D, Herbert MR, Bornehag CG, Swan SH (May 2018). “Prenatal paracetamol exposure and child neurodevelopment: A review”. Horm Behav. 101: 125–147. doi:10.1016/j.yhbeh.2018.01.003. PMID 29341895. S2CID 4822468][Gou X, Wang Y, Tang Y, Qu Y, Tang J, Shi J, Xiao D, Mu D (March 2019). “Association of maternal prenatal acetaminophen use with the risk of attention deficit/hyperactivity disorder in offspring: A meta-analysis”. Aust N Z J Psychiatry. 53 (3): 195–206. doi:10.1177/0004867418823276. PMID 30654621. S2CID 58575048]} In animal experiments, paracetamol disrupts fetal testosterone production, and several epidemiological studies linked cryptorchidism with mother’s paracetamol use for more than two weeks in the second trimester. On the other hand, several studies did not find any association. The consensus recommendation appears to be to avoid prolonged use of paracetamol in pregnancy and use it only when necessary, at the lowest effective dosage and for the shortest time.^{[McCrae JC, Morrison EE, MacIntyre IM, Dear JW, Webb DJ (October 2018). “Long-term adverse effects of paracetamol – a review”. Br J Clin Pharmacol. 84 (10): 2218–2230. doi:10.1111/bcp.13656. PMC 6138494. PMID 29863746][Toda K (October 2017). “Is acetaminophen safe in pregnancy?”. Scand J Pain. 17: 445–446. doi:10.1016/j.sjpain.2017.09.007. PMID 28986045. S2CID 205183310][Black E, Khor KE, Kennedy D, Chutatape A, Sharma S, Vancaillie T, Demirkol A (November 2019). “Medication Use and Pain Management in Pregnancy: A Critical Review”. Pain Pract. 19 (8): 875–899. doi:10.1111/papr.12814. PMID 31242344. S2CID 195694287]}
    • Paracetamol toxicity is the foremost cause of acute liver failure in the Western world, and accounts for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand.^{[Daly FF, Fountain JS, Murray L, Graudins A, Buckley NA (March 2008). “Guidelines for the management of paracetamol poisoning in Australia and New Zealand—explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres”. The Medical Journal of Australia. 188 (5): 296–301. doi:10.5694/j.1326-5377.2008.tb01625.x. PMID 18312195. S2CID 9505802][Khashab M, Tector AJ, Kwo PY (2007). “Epidemiology of acute liver failure”. Curr Gastroenterol Rep. 9 (1): 66–73. doi:10.1007/s11894-008-0023-x. PMID 17335680. S2CID 30068892.][Hawkins LC, Edwards JN, Dargan PI (2007). “Impact of restricting paracetamol pack sizes on paracetamol poisoning in the United Kingdom: a review of the literature”. Drug Saf. 30 (6): 465–79. doi:10.2165/00002018-200730060-00002. PMID 17536874. S2CID 36435353][Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, et al. (2005). “Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study”. Hepatology. 42 (6): 1364–72. doi:10.1002/hep.20948. PMID 16317692. S2CID 24758491]} 
    • Paracetamol overdose results in more calls to poison control centers in the US than overdose of any other pharmacological substance.^{[Lee WM (2004). “Acetaminophen and the U.S. Acute Liver Failure Study Group: lowering the risks of hepatic failure”. Hepatology. 40 (1): 6–9. doi:10.1002/hep.20293. PMID 15239078. S2CID 15485538]} According to the FDA, in the United States, “56,000 emergency room visits, 26,000 hospitalizations, and 458 deaths per year [were] related to acetaminophen-associated overdoses during the 1990s. Within these estimates, unintentional acetaminophen overdose accounted for nearly 25% of the emergency department visits, 10% of the hospitalizations, and 25% of the deaths.“^[“Prescription Drug Products Containing Acetaminophen: Actions to Reduce Liver Injury from Unintentional Overdose”. regulations.gov. US Food and Drug Administration. 14 January 2011. Archived from the original on 25 September 2012. Retrieved 23 February 2014. This article incorporates text from this source, which is in the public domain.^]
  • • Overdoses are frequently related to high-dose recreational use of prescription opioids, as these opioids are most often combined with paracetamol.^{[Yan H (16 January 2014). “FDA: Acetaminophen doses over 325 mg may lead to liver damage”. CNN. Archived from the original on 16 February 2014. Retrieved 18 February 2014.]} The overdose risk may be heightened by frequent consumption of alcohol.^{[Lee WM (December 2017). “Acetaminophen (APAP) hepatotoxicity—Isn’t it time for APAP to go away?”. Journal of Hepatology. 67 (6): 1324–1331. doi:10.1016/j.jhep.2017.07.005. PMC 5696016. PMID 28734939]}
    • Untreated paracetamol overdose results in a lengthy, painful illness. Signs and symptoms of paracetamol toxicity may initially be absent or non-specific symptoms. The first symptoms of overdose usually begin several hours after ingestion, with nausea, vomiting, sweating, and pain as acute liver failure starts.^{[Rumack B, Matthew H (1975). “Acetaminophen poisoning and toxicity”. Pediatrics. 55 (6): 871–76. doi:10.1542/peds.55.6.871. PMID 1134886. S2CID 45739342]} People who take overdoses of paracetamol do not fall asleep or lose consciousness, although most people who attempt suicide with paracetamol wrongly believe that they will be rendered unconscious by the drug.^{[ “Paracetamol”. University of Oxford Centre for Suicide Research. 25 March 2013. Archived from the original on 20 March 2013. Retrieved 20 April 2013.]}
    • Treatment is aimed at removing the paracetamol from the body and replenishing glutathione.^{[ Mehta S (25 August 2012). “Metabolism of Paracetamol (Acetaminophen), Acetanilide and Phenacetin”. PharmaXChange.info. Archived from the original on 28 October 2019. Retrieved 27 October 2019.]} Activated charcoal can be used to decrease absorption of paracetamol if the person comes to the hospital soon after the overdose. While the antidote, acetylcysteine (also called N-acetylcysteine or NAC), acts as a precursor for glutathione, helping the body regenerate enough to prevent or at least decrease the possible damage to the liver; a liver transplant is often required if damage to the liver becomes severe.^{[Daly FF, Fountain JS, Murray L, Graudins A, Buckley NA (March 2008). “Guidelines for the management of paracetamol poisoning in Australia and New Zealand—explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres”. The Medical Journal of Australia. 188 (5): 296–301. doi:10.5694/j.1326-5377.2008.tb01625.x. PMID 18312195. S2CID 9505802.][101]} NAC was usually given following a treatment nomogram (one for people with risk factors, and one for those without), but the use of the nomogram is no longer recommended as evidence to support the use of risk factors was poor and inconsistent, and many of the risk factors are imprecise and difficult to determine with sufficient certainty in clinical practice.^{[ “Paracetamol overdose: new guidance on treatment with intravenous acetylcysteine”. Drug Safety Update. September 2012. pp. A1. Archived from the original on 27 October 2012.][“Treating paracetamol overdose with intravenous acetylcysteine: new guidance”. Medicines and Healthcare products Regulatory Agency (MHRA). 11 December 2014. Archived from the original on 28 October 2019. Retrieved 27 October 2019.][ “Treating paracetamol overdose with intravenous acetylcysteine: new guidance”. GOV.UK. 11 December 2014. Archived from the original on 28 October 2019. Retrieved 24 January 2021.]} 
    • Toxicity of paracetamol is due to its quinone metabolite NAPQI and NAC also helps in neutralizing it.^{[Mehta S (25 August 2012). “Metabolism of Paracetamol (Acetaminophen), Acetanilide and Phenacetin”. PharmaXChange.info. Archived from the original on 28 October 2019. Retrieved 27 October 2019.]} Kidney failure is also a possible side effect.^{[Lee WM (December 2017). “Acetaminophen (APAP) hepatotoxicity—Isn’t it time for APAP to go away?”. Journal of Hepatology. 67 (6): 1324–1331. doi:10.1016/j.jhep.2017.07.005. PMC 5696016. PMID 28734939]}
    • Paracetamol is available in oral, suppository, and intravenous forms.^{[ “Acetaminophen”. Physicians’ Desk Reference (63rd ed.). Montvale, N.J.: Physicians’ Desk Reference. 2009. pp. 1915–1916. ISBN978-1-56363-703-2. OCLC276871036]} Intravenous paracetamol is sold under the brand name Ofirmev in the United States.^{[Nam S. “IV, PO, and PR Acetaminophen: A Quick Comparison”. Pharmacy Times. Archived from the original on 24 October 2019. Retrieved 24 October 2019.]}
    • Paracetamol was first marketed in the United States in 1950 under the name Triagesic, a combination of paracetamol, aspirin, and caffeine. Reports in 1951 of three users stricken with the blood disease agranulocytosis led to its removal from the marketplace, and it took several years until it became clear that the disease was unconnected.^{[Silverman M, Lydecker M, Lee PR (1992). Bad Medicine: The Prescription Drug Industry in the Third World. Stanford University Press. pp. 88–90. ISBN 978-0804716697.]} The following year, 1952, paracetamol returned to the US market as a prescription drug.^{[Ameer B, Greenblatt DJ (August 1977). “Acetaminophen”. Ann Intern Med. 87 (2): 202–9. doi:10.7326/0003-4819-87-2-202. PMID 329728]} In the United Kingdom, marketing of paracetamol began in 1956 by Sterling-Winthrop Co. as Panadol, available only by prescription, and promoted as preferable to aspirin since it was safe for children and people with ulcers. In 1963, paracetamol was added to the British Pharmacopoeia, and has gained popularity since then as an analgesic agent with few side-effects and little interaction with other pharmaceutical agents.^{[Spooner JB, Harvey JG (1976). “The history and usage of paracetamol”. J Int Med Res. 4 (4 Suppl): 1–6. doi:10.1177/14732300760040S403. PMID 799998. S2CID 11289061][Silverman M, Lydecker M, Lee PR (1992). Bad Medicine: The Prescription Drug Industry in the Third World. Stanford University Press. pp. 88–90. ISBN 978-0804716697.]}
    • Acetanilide was the first aniline derivative serendipitously found to possess analgesic as well as antipyretic properties, and was quickly introduced into medical practice under the name of Antifebrin by Cahn & Hepp in 1886.^{[Cahn A, Hepp P (1886). “Das Antifebrin, ein neues Fiebermittel” [Antifebrin, a new antipyretic]. Centralblatt für klinische Medizin (in German). 7: 561–4. Archived from the original on 1 September 2020. Retrieved 21 February 2019.]} But its unacceptable toxic effects—the most alarming being cyanosis due to methemoglobinemia, an increase of hemoglobin in its ferric [Fe³⁺] state, called methemoglobin, which cannot bind oxygen, and thus decreases overall carriage of oxygen to tissue—prompted the search for less toxic aniline derivatives.^{[Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S (2006). “Paracetamol: New vistas of an old drug”. CNS Drug Reviews. 12 (3–4): 250–75. doi:10.1111/j.1527-3458.2006.00250.x. PMC 6506194. PMID 17227290]} Some reports state that Cahn & Hepp or a French chemist called Charles Gerhardt first synthesized paracetamol in 1852.^{[Eyers SJ (April 2012). The effect of regular paracetamol on bronchial responsiveness and asthma control in mild to moderate asthma (Ph.D. thesis). University of Otago). Archived from the original on 24 August 2021. Retrieved 24 August 2021.][Roy J (2011). “Paracetamol – the best selling antipyretic analgesic in the world”. An introduction to pharmaceutical sciences: production, chemistry, techniques and technology. Oxford: Biohealthcare. p. 270. ISBN 978-1-908818-04-1. Archived from the original on 24 August 2021. Retrieved 24 August 2021.]}
    • Harmon Northrop Morse synthesized paracetamol at Johns Hopkins University via the reduction of p-nitrophenol with tin in glacial acetic acid in 1877,^{[Morse HN (1878). “Ueber eine neue Darstellungsmethode der Acetylamidophenole” [On a new method of preparing acetylamidophenol]. Berichte der deutschen chemischen Gesellschaft (in German). 11 (1): 232–233. doi:10.1002/cber.18780110151. Archived from the original on 6 November 2018.][Silverman M, Lydecker M, Lee PR (1992). Bad Medicine: The Prescription Drug Industry in the Third World. Stanford University Press. pp. 88–90. ISBN 978-0804716697.]} but it was not until 1887 that clinical pharmacologist Joseph von Mering tried paracetamol on humans.^{[Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S (2006). “Paracetamol: New vistas of an old drug”. CNS Drug Reviews. 12 (3–4): 250–75. doi:10.1111/j.1527-3458.2006.00250.x. PMC 6506194. PMID 17227290]} In 1893, von Mering published a paper reporting on the clinical results of paracetamol with phenacetin, another aniline derivative.^{[von Mering J (1893). “Beitrage zur Kenntniss der Antipyretica”. Ther Monatsch. 7: 577–587.]} Von Mering claimed that, unlike phenacetin, paracetamol had a slight tendency to produce methemoglobinemia. Paracetamol was then quickly discarded in favor of phenacetin. The sales of phenacetin established Bayer as a leading pharmaceutical company.^{[Sneader W (2005). Drug Discovery: A History. Hoboken, NJ: Wiley. p. 439. ISBN 978-0471899808. Archived from the original on 18 August 2016.]}
    • Von Mering’s claims remained essentially unchallenged for half a century, until two teams of researchers from the United States analyzed the metabolism of acetanilide and phenacetin.^{[Sneader W (2005). Drug Discovery: A History. Hoboken, NJ: Wiley. p. 439. ISBN 978-0471899808. Archived from the original on 18 August 2016.]} In 1947, David Lester and Leon Greenberg found strong evidence that paracetamol was a major metabolite of acetanilide in human blood, and in a subsequent study they reported that large doses of paracetamol given to albino rats did not cause methemoglobinemia.^{[ Lester D, Greenberg LA, Carroll RP (1947). “The metabolic fate of acetanilid and other aniline derivatives: II. Major metabolites of acetanilid appearing in the blood”. J. Pharmacol. Exp. Ther. 90 (1): 68–75. PMID 20241897. Archived from the original on 2 December 2008.]} In 1948, Bernard Brodie, Julius Axelrod and Frederick Flinn confirmed that paracetamol was the major metabolite of acetanilide in humans, and established that it was just as efficacious an analgesic as its precursor.^{[Brodie BB, Axelrod J (1948). “The estimation of acetanilide and its metabolic products, aniline, N-acetyl p-aminophenol and p-aminophenol (free and total conjugated) in biological fluids and tissues”. J. Pharmacol. Exp. Ther. 94 (1): 22–28. PMID 18885610][Brodie BB, Axelrod J (1948). “The fate of acetanilide in man” (PDF). J. Pharmacol. Exp. Ther. 94 (1): 29–38. PMID 18885611. Archived (PDF) from the original on 7 September 2008.][Flinn FB, Brodie BB (1948). “The effect on the pain threshold of N-acetyl p-aminophenol, a product derived in the body from acetanilide”. J. Pharmacol. Exp. Ther. 94 (1): 76–77. PMID 18885618]} They also suggested that methemoglobinemia is produced in humans mainly by another metabolite, phenylhydroxylamine. A follow-up paper by Brodie and Axelrod in 1949 established that phenacetin was also metabolized to paracetamol.^{[ Brodie BB, Axelrod J (1949). “The fate of acetophenetidin (phenacetin) in man and methods for the estimation of acetophenitidin and its metabolites in biological material”. J Pharmacol Exp Ther. 94 (1): 58–67.]} This led to a “rediscovery” of paracetamol.^{[Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S (2006). “Paracetamol: New vistas of an old drug”. CNS Drug Reviews. 12 (3–4): 250–75. doi:10.1111/j.1527-3458.2006.00250.x. PMC 6506194. PMID 17227290]}
    • Concerns about paracetamol’s safety delayed its widespread acceptance until the 1970s, but in the 1980s paracetamol sales exceeded those of aspirin in many countries, including the United Kingdom. This was accompanied by the commercial demise of phenacetin, blamed as the cause of analgesic nephropathy and hematological toxicity.^{[Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S (2006). “Paracetamol: New vistas of an old drug”. CNS Drug Reviews. 12 (3–4): 250–75. doi:10.1111/j.1527-3458.2006.00250.x. PMC 6506194. PMID 17227290]} Available in the US without a prescription since 1955^{[Ameer B, Greenblatt DJ (August 1977). “Acetaminophen”. Ann Intern Med. 87 (2): 202–9. doi:10.7326/0003-4819-87-2-202. PMID 329728]} (1960, according to another source^{[ “Our Story”. McNEIL-PPC, Inc. Archived from the original on 8 March 2014. Retrieved 8 March 2014.]}) paracetamol has become a common household drug.^{[ “Medication and Drugs”. MedicineNet. 1996–2010. Archived from the original on 22 April 2010. Retrieved 22 April 2010.]} In 1988, Sterling Winthrop was acquired by Eastman Kodak which sold the over the counter drug rights to SmithKline Beecham in 1994.^{[“SEC Info – Eastman Kodak Co – ‘8-K’ for 6/30/94”. Archived from the original on 4 March 2016. Retrieved 3 March 2016.]}
    • In June 2009, an FDA advisory committee recommended that new restrictions be placed on paracetamol use in the United States to help protect people from the potential toxic effects. The maximum single adult dosage would be decreased from 1000 mg to 650 mg, while combinations of paracetamol and other products would be prohibited. Committee members were particularly concerned by the fact that the then-present maximum dosages of paracetamol had been shown to produce alterations in liver function.^{[ “FDA May Restrict Acetaminophen”. Webmd. 1 July 2009. Archived from the original on 21 March 2011. Retrieved 19 March 2011.]}
    • In January 2011, the FDA asked manufacturers of prescription combination products containing paracetamol to limit its amount to no more than 325 mg per tablet or capsule and began requiring manufacturers to update the labels of all prescription combination paracetamol products to warn of the potential risk of severe liver damage.^{[ “FDA limits acetaminophen in prescription combination products; requires liver toxicity warnings” (Press release). U.S. Food and Drug Administration (FDA). 13 January 2011. Archived from the original on 15 January 2011. Retrieved 13 January 2011. This article incorporates text from this source, which is in the public domain.][ “FDA Drug Safety Communication: Prescription Acetaminophen Products to be Limited to 325 mg Per Dosage Unit; Boxed Warning Will Highlight Potential for Severe Liver Failure”. U.S. Food and Drug Administration (FDA). 13 January 2011. Archived from the original on 18 January 2011. Retrieved 13 January 2011. This article incorporates text from this source, which is in the public domain.][ Perrone M (13 January 2011). “FDA orders lowering pain reliever in Vicodin”. The Boston Globe. Associated Press. Archived from the original on 2 November 2012. Retrieved 13 January 2011.][Harris G (13 January 2011). “F.D.A. Plans New Limits on Prescription Painkillers”. The New York Times. Archived from the original on 9 June 2012. Retrieved 13 January 2011.][ “FDA limits acetaminophen in prescription combination products; requires liver toxicity warnings”. U.S. Food and Drug Administration (FDA) (Press release). 15 January 2011. Archived from the original on 15 January 2011. Retrieved 23 February 2014. This article incorporates text from this source, which is in the public domain.]} Manufacturers had three years to limit the amount of paracetamol in their prescription drug products to 325 mg per dosage unit.^{[ “FDA Drug Safety Communication: Prescription Acetaminophen Products to be Limited to 325 mg Per Dosage Unit; Boxed Warning Will Highlight Potential for Severe Liver Failure”. U.S. Food and Drug Administration (FDA). 13 January 2011. Archived from the original on 18 January 2011. Retrieved 13 January 2011. This article incorporates text from this source, which is in the public domain.][Harris G (13 January 2011). “F.D.A. Plans New Limits on Prescription Painkillers”. The New York Times. Archived from the original on 9 June 2012. Retrieved 13 January 2011.]}
    • In November 2011, the Medicines and Healthcare products Regulatory Agency revised UK dosing of liquid paracetamol for children.^{[ “Liquid paracetamol for children: revised UK dosing instructions introduced” (PDF). Medicines and Healthcare products Regulatory Agency (MHRA). 14 November 2011. Archived from the original (PDF) on 28 October 2019. Retrieved 27 October 2019.]}
    • In September 2013, “Use Only as Directed”, an episode of the radio program This American Life^{[ “Use Only as Directed”. This American Life. Episode 505. Chicago. 20 September 2013. Public Radio International. WBEZ. Archived from the original on 27 September 2013. Retrieved 24 September 2013.]} highlighted deaths from paracetamol overdose. This report was followed by two reports by ProPublica alleging that the “FDA has long been aware of studies showing the risks of acetaminophen. So has the maker of Tylenol, McNeil Consumer Healthcare, a division of Johnson & Johnson”^{[Gerth J, Miller TC (20 September 2013). “Use Only as Directed”. ProPublica. Archived from the original on 24 September 2013. Retrieved 24 September 2013.]} and “McNeil, the maker of Tylenol, … has repeatedly opposed safety warnings, dosage restrictions and other measures meant to safeguard users of the drug.”^{[ Miller TC, Gerth J (20 September 2013). “Dose of Confusion”. ProPublica. Archived from the original on 24 September 2013. Retrieved 24 September 2013.]}
    • During the COVID-19 pandemic it was considered by some in the scientific community that it was an effective analgesic medication to treat symptoms of COVID-19, but this was found to be unsubstantiated.^{[Orso D, Federici N, Copetti R, Vetrugno L, Bove T (October 2020). “Infodemic and the spread of fake news in the COVID-19-era”. European Journal of Emergency Medicine. 27 (5): 327–328. doi:10.1097/MEJ.0000000000000713. PMC 7202120. PMID 32332201][Torjesen I (April 2020). “Covid-19: ibuprofen can be used for symptoms, says UK agency, but reasons for change in advice are unclear”. BMJ. 369: m1555. doi:10.1136/bmj.m1555. PMID 32303505.][Rinott E, Kozer E, Shapira Y, Bar-Haim A, Youngster I (September 2020). “Ibuprofen use and clinical outcomes in COVID-19 patients”. Clinical Microbiology and Infection. 26 (9): 1259.e5–1259.e7. doi:10.1016/j.cmi.2020.06.003. PMC 7289730. PMID 32535147.][ Day M (March 2020). “Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists”. BMJ. 368: m1086. doi:10.1136/bmj.m1086. PMID32184201]}
    • In some formulations, paracetamol is combined with the opiate codeine, sometimes referred to as co-codamol (BAN) and Panadeine in Australia. In the US, this combination is available only by prescription.^{[ “Acetaminophen and Codeine (Professional Patient Advice)”. Drugs.com. 29 June 2019. Archived from the original on 20 May 2020. Retrieved 25 February 2020.]} As of 1 February 2018, medications containing codeine also became prescription-only in Australia.^{[“Codeine information hub”. Therapeutic Goods Administration, Australian Government. 10 April 2018. Archived from the original on 8 December 2021. Retrieved 9 December 2021]} Paracetamol is also combined with other opioids such as dihydrocodeine,^{[“Acetaminophen, Caffeine, and Dihydrocodeine (Professional Patient Advice)”. Drugs.com. 2 October 2019. Archived from the original on 19 May 2020. Retrieved 25 February 2020.]} referred to as co-dydramol (British Approved Name (BAN)), oxycodone^{[ “Oxycodone and Acetaminophen (Professional Patient Advice)”. Drugs.com. 11 November 2019. Archived from the original on 20 May 2020. Retrieved 25 February 2020.]} or hydrocodone.^{[“Hydrocodone and Acetaminophen (Professional Patient Advice)”. Drugs.com. 2 January 2020. Archived from the original on 21 May 2020. Retrieved 25 February 2020.]} Another very commonly used analgesic combination includes paracetamol in combination with propoxyphene napsylate.^{[“Propoxyphene and Acetaminophen Tablets”. Drugs.com. 21 June 2019. Archived from the original on 20 May 2020. Retrieved 25 February 2020.]} A combination of paracetamol, codeine, and the doxylamine succinate is also available.^{[ “APOHealth Paracetamol Plus Codeine & Calmative”. Drugs.com. 3 February 2020. Archived from the original on 25 February 2020. Retrieved 25 February 2020.]}
    • Paracetamol is sometimes combined with phenylephrine hydrochloride.^{[Atkinson HC, Stanescu I, Anderson BJ (2014). “Increased Phenylephrine Plasma Levels with Administration of Acetaminophen”. New England Journal of Medicine. 370 (12): 1171–1172. doi:10.1056/NEJMc1313942. PMID 24645960.]} Sometimes a third active ingredient, such as ascorbic acid,^{[Atkinson HC, Stanescu I, Anderson BJ (2014). “Increased Phenylephrine Plasma Levels with Administration of Acetaminophen”. New England Journal of Medicine. 370 (12): 1171–1172. doi:10.1056/NEJMc1313942. PMID 24645960.][“Ascorbic acid/Phenylephrine/Paracetamol”. NHS Choices. National Health Service. Archived from the original on 26 March 2014. Retrieved 25 March 2014.]} caffeine,^{[“Phenylephrine/Caffeine/Paracetamol dual relief”. NHS Choices. National Health Service. Archived from the original on 26 March 2014. Retrieved 25 March 2014.][“Beechams Decongestant Plus With Paracetamol”. NHS Choices. National Health Service. Archived from the original on 26 March 2014. Retrieved 25 March 2014.]} chlorpheniramine maleate,^{[Senyuva H, Ozden T (2002). “Simultaneous High-Performance Liquid Chromatographic Determination of Paracetamol, Phenylephrine HCl, and Chlorpheniramine Maleate in Pharmaceutical Dosage Forms”. Journal of Chromatographic Science. 40 (2): 97–100. doi:10.1093/chromsci/40.2.97. PMID 11881712.]} or guaifenesin^{[Janin A, Monnet J (2014). “Bioavailability of paracetamol, phenylephrine hydrochloride and guaifenesin in a fixed-combination syrup versus an oral reference product”. Journal of International Medical Research. 42 (2): 347–359. doi:10.1177/0300060513503762. PMID 24553480.][“Paracetamol – phenylephrine hydrochloride – guaifenesin”. NPS MedicineWise. National Prescribing Service (Australia). Archived from the original on 26 March 2014. Retrieved 25 March 2014][“Phenylephrine/Guaifenesin/Paracetamol”. NHS Choices. National Health Service. Archived from the original on 12 September 2013. Retrieved 25 March 2014.]} is added to this combination.
    • See also: Paracetamol brand names
    • Paracetamol is lethal to snakes, and has been suggested as a chemical control program for the invasive brown tree snake (Boiga irregularis) in Guam.^{[Johnston J, Savarie P, Primus T, Eisemann J, Hurley J, Kohler D (2002). “Risk assessment of an acetaminophen baiting program for chemical control of brown tree snakes on Guam: evaluation of baits, snake residues, and potential primary and secondary hazards”. Environ Sci Technol. 36 (17): 3827–33. Bibcode:2002EnST…36.3827J. doi:10.1021/es015873n. PMID 12322757][Lendon B (7 September 2010). “Tylenol-loaded mice dropped from air to control snakes”. CNN. Archived from the original on 9 September 2010. Retrieved 7 September 2010.]} Doses of 80 mg are inserted into dead mice that are scattered by helicopter,^{[Richards S (1 May 2012). “It’s Raining Mice”. The Scientist. Archived from the original on 15 May 2012.]} as lethal bait to be consumed by the snakes.
    • Paracetamol appears to exert its effects through two mechanisms: the inhibition of cyclooxygenase and actions of its metabolite AM404.^{[Ghanem CI, Pérez MJ, Manautou JE, Mottino AD (July 2016). “Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity”. Pharmacological Research. 109: 119–31. doi:10.1016/j.phrs.2016.02.020. PMC 4912877. PMID 26921661.]}
    • Supporting the first mechanism, pharmacologically and in its side effects, paracetamol is close to classical nonsteroidal anti-inflammatory drugs (NSAIDs) that act by inhibiting COX-1 and COX-2 enzymes and especially similar to selective COX-2 inhibitors.^{[Graham GG, Davies MJ, Day RO, Mohamudally A, Scott KF (June 2013). “The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings”. Inflammopharmacology. 21 (3): 201–32. doi:10.1007/s10787-013-0172-x. PMID 23719833. S2CID 11359488]} Paracetamol inhibits prostaglandin synthesis by reducing the active form of COX-1 and COX-2 enzymes. This occurs only when the concentration of arachidonic acid and peroxides is low. Under these conditions, COX-2 is the predominant form of cyclooxygenase, which explains the apparent COX-2 selectivity of paracetamol. Under the conditions of inflammation, the concentration of peroxides is high, which counteracts the reducing effect of paracetamol. Accordingly, the anti-inflammatory action of paracetamol is slight.^{[Ghanem CI, Pérez MJ, Manautou JE, Mottino AD (July 2016). “Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity”. Pharmacological Research. 109: 119–31. doi:10.1016/j.phrs.2016.02.020. PMC 4912877. PMID 26921661.][Graham GG, Davies MJ, Day RO, Mohamudally A, Scott KF (June 2013). “The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings”. Inflammopharmacology. 21 (3): 201–32. doi:10.1007/s10787-013-0172-x. PMID 23719833. S2CID 11359488]} The anti-inflammatory action of paracetamol (via COX inhibition) has also been found to primarily target the central nervous system and not peripheral areas of the body, explaining the lack of side effects associated with conventional NSAIDs such as gastric bleeding.
    • The second mechanism centers on the paracetamol metabolite AM404. This metabolite has been detected in the brains of animals and cerebrospinal fluid of humans taking paracetamol.^{[Ghanem CI, Pérez MJ, Manautou JE, Mottino AD (July 2016). “Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity”. Pharmacological Research. 109: 119–31. doi:10.1016/j.phrs.2016.02.020. PMC 4912877. PMID 26921661.][Sharma CV, Long JH, Shah S, Rahman J, Perrett D, Ayoub SS, Mehta V (2017). “First evidence of the conversion of paracetamol to AM404 in human cerebrospinal fluid”. J Pain Res. 10: 2703–2709. doi:10.2147/JPR.S143500. PMC 5716395. PMID 29238213]} Apparently, it is formed in the brain from another paracetamol metabolite 4-aminophenol by action of fatty acid amide hydrolase. AM404 is a weak agonist of cannabinoid receptors CB1 and CB2, an inhibitor of endocannabinoid transporter, and a potent activator of TRPV1 receptor. This and other research indicate that cannabinoid system and TRPV1 may play an important role in the analgesic effect of paracetamol.^{[Ghanem CI, Pérez MJ, Manautou JE, Mottino AD (July 2016). “Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity”. Pharmacological Research. 109: 119–31. doi:10.1016/j.phrs.2016.02.020. PMC 4912877. PMID 26921661.][Ohashi N, Kohno T (2020). “Analgesic Effect of Acetaminophen: A Review of Known and Novel Mechanisms of Action”. Front Pharmacol. 11: 580289. doi:10.3389/fphar.2020.580289. PMC 7734311. PMID 33328986]}

The mononitrated phenols are often hydrogenated to the corresponding aminophenols that are also useful industrially.^{[Gerald Booth (2007). “Nitro Compounds, Aromatic”. Ullmann’s Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a17_411. ISBN 978-3527306732.]}

Di- and trinitrophenols

• 2,4-Dinitrophenol (m.p. 83 °C) is a moderately strong acid (pK_a = 4.89).
  • 2,4-Dinitrophenol (2,4-DNP or simply DNP) is an organic compound with the formula HOC₆H₃(NO₂)₂. It is a yellow, crystalline solid that has a sweet, musty odor. It sublimes, is volatile with steam, and is soluble in most organic solvents as well as aqueous alkaline solutions.^{[Budavari, Susan; et al., eds. (1989). The Merck index : an encyclopedia of chemicals, drugs, and biologicals (11th ed.). Rahway, N.J.: Merck. pp. 1900. ISBN 978-0911910285. OCLC 21297020]} When in a dry form, it is a high explosive and has an instantaneous explosion hazard.^{[“DINITROPHENOL, WETTED WITH NOT LESS THAN 15% WATER | CAMEO Chemicals | NOAA”. cameochemicals.noaa.gov. Retrieved 20 September 2019.]} 
  • It is a precursor to other chemicals and is biochemically active, uncoupling oxidative phosphorylation from the electron transport chain in cells with mitochondria, by allowing protons to pass from the intermembrane space into the mitochondrial matrix. Oxidative phosphorylation is a highly regulated step in aerobic respiration that is inhibited, among other factors, by normal cellular levels of ATP. Uncoupling it results in chemical energy from diet and energy stores such as triglycerides being wasted as heat with minimal regulation, leading to dangerously high body temperatures that may develop into heatstroke. Its use as a dieting aid has been identified with severe side-effects, including a number of deaths.^{[Grundlingh J, Dargan PI, El-Zanfaly M, Wood DM (2011). “Summary of previously published fatalities relating to exposure to DNP including basic demographics, amount of exposure and maximal temperature recorded pre-death”. J Med Toxicol. 7 (3): 205–12. doi:10.1007/s13181-011-0162-6. PMC 3550200. PMID 21739343]}
    • Commercially, DNP is used as an antiseptic and as a non-selective bioaccumulating pesticide.
    • DNP is particularly useful as a herbicide alongside other closely related dinitrophenol herbicides like 2,4-dinitro-o-cresol (DNOC), dinoseb and dinoterb.^{[Gupta, Ramesh C., ed. (2011). Reproductive and developmental toxicology. London: Academic Press. p. 509. ISBN 9780123820327. OCLC 717387050]} Since 1998 DNP has been withdrawn from agricultural use.^{[ Pohanish, Richard P. (23 September 2011). Sittig’s Handbook of Toxic and Hazardous Chemicals and Carcinogens. William Andrew. ISBN 9781437778700.]} Currently, there are no actively registered pesticides containing DNP in the United States or Europe.^{[ “Toxicological Profile for Dinitrophenols” (PDF). Agency for Toxic Substances and Disease Registry. U.S. Department of Health and Human Services. August 2021.][Pohanish, Richard P. (6 September 2014). Sittig’s Handbook of Pesticides and Agricultural Chemicals. William Andrew. ISBN 9781455731572.]} Dinoseb is used industrially as a polymerisation inhibitor during styrene production.
    • It is a chemical intermediate in the production of sulfur dyes,^{[Gerald Booth “Nitro Compounds, Aromatic” in “Ullmann’s Encyclopedia of Industrial Chemistry” 2007; Wiley-VCH, Weinheim. doi:10.1002/14356007.a17_411]} wood preservatives^{[“2,4-Dinitrophenol” (PDF). Environmental Protection Agency. Retrieved 15 October 2017]} and picric acid.^{[Agrawal, Jai Prakash; Hodgson, Robert (11 January 2007). Organic Chemistry of Explosives. John Wiley & Sons. ISBN 9780470059357.]} DNP has also been used to make photographic developers and explosives (see shellite).^{[Grundlingh, Johann; Dargan, Paul I.; El-Zanfaly, Marwa; Wood, David M. (September 2011). “2,4-dinitrophenol (DNP): a weight loss agent with significant acute toxicity and risk of death”. Journal of Medical Toxicology. 7 (3): 205–212. doi:10.1007/s13181-011-0162-6. ISSN 1937-6995. PMC 3550200. PMID 21739343.]} DNP is classified as an explosive in the United Kingdom^{[Urben, Peter (18 March 2017). Bretherick’s Handbook of Reactive Chemical Hazards. Elsevier. ISBN 9780081010594.]} and the United States.^{[“Commerce in Explosives; 2017 Annual List of Explosive Materials”. Federal Register. 28 December 2017. Retrieved 22 July 2018.^]}
    • Although DNP is widely considered too dangerous for clinical use, its mechanism of action remains under investigation as a potential approach for treating obesity.^{[Harper JA, Dickinson K, Brand MD (2001). “Mitochondrial uncoupling as a target for drug development for the treatment of obesity”. Obesity Reviews. 2 (4): 255–265. doi:10.1046/j.1467-789X.2001.00043.x. PMID 12119996. S2CID 42349204]} As of 2015, research is being conducted on uncoupling proteins naturally found in humans.^{[Busiello, Rosa A.; Savarese, Sabrina; Lombardi, Assunta (10 February 2015). “Mitochondrial uncoupling proteins and energy metabolism”. Frontiers in Physiology. 6: 36. doi:10.3389/fphys.2015.00036. ISSN 1664-042X. PMC 4322621. PMID 25713540]}
    • In living cells, DNP acts as a proton ionophore, an agent that can shuttle protons (hydrogen cations) across biological membranes. It dissipates the proton gradient across mitochondria membranes, collapsing the proton motive force that the cell uses to produce most of its ATP chemical energy. Instead of producing ATP, the energy of the proton gradient is lost as heat.^{[Grundlingh J, Dargan PI, El-Zanfaly M, Wood DM (2011). “Summary of previously published fatalities relating to exposure to DNP including basic demographics, amount of exposure and maximal temperature recorded pre-death”. J Med Toxicol. 7 (3): 205–12. doi:10.1007/s13181-011-0162-6. PMC 3550200. PMID 21739343]}
    • DNP is often used in biochemistry research to help explore the bioenergetics of chemiosmotic and other membrane transport processes.
    • DNP acts as a protonophore, allowing protons to leak across the inner mitochondrial membrane and thus bypass ATP synthase. This makes ATP energy production less efficient. In effect, part of the energy that is normally produced from cellular respiration is wasted as heat. The inefficiency is proportional to the dose of DNP that is taken. As the dose increases and energy production is made more inefficient, metabolic rate increases (and more fat is burned) in order to compensate for the inefficiency and to meet energy demands. DNP is probably the best known agent for uncoupling oxidative phosphorylation. The “phosphorylation” of adenosine diphosphate (ADP) by ATP synthase gets disconnected or “uncoupled” from oxidation. From the Journal of Clinical Toxicology, Volume 44, Issue 3 (2006):
      • Dinitrophenol uncouples oxidative phosphorylation, causes release of calcium from mitochondrial stores and prevents calcium re-uptake. This leads to free intracellular calcium and causes muscle contraction and hyperthermia. Dantrolene inhibits calcium release from the sarcoplasmic reticulum which reduces intracellular calcium. The resulting muscle relaxation allows heat dissipation. There is little risk to dantrolene administration. Since dantrolene may be effective in reducing hyperthermia caused by agents that inhibit oxidative phosphorylation, early administration may improve outcome.^{[ Barker K, Seger D, Kumar S (2006). “Comment on “Pediatric fatality following ingestion of Dinitrophenol: postmortem identification of a ‘dietary supplement'””. Clin Toxicol. 44 (3): 351. doi:10.1080/15563650600584709. PMID16749560. S2CID3057662]}
    • Information about pharmacokinetics of DNP in humans is limited.^{[ “Ambient water quality criteria for nitrophenols, 440/5-80-063” (PDF). U.S. Environmental Protection Agency. 1980. Retrieved 9 June 2008.]} The ATSDR‘s Toxicological Profile for Dinitrophenols remarks that DNP elimination appears to be rapid except when liver function is impaired.^{[ Harris, M. O.; Cocoran, J. J. (1995). “Toxicological Profile for Dinitrophenols”. Agency for Toxic Substances and Disease Registry. Retrieved 23 April 2013.]} The NEJM remarks that DNP appears to be eliminated in around three to four days, except possibly when the liver and kidneys are damaged.^{[Edsall, G. (1934). “Biological actions of dinitrophenol and related compounds: a review”. The New England Journal of Medicine. 211 (9): 385–390. doi:10.1056/NEJM193408302110901]} Other papers give a wide array of possible half-lives, ranging from 3 hours^{[Korde AS, Pettigrew LC, Craddock SD, Maragos WF (September 2005). “The mitochondrial uncoupler 2,4-dinitrophenol attenuates tissue damage and improves mitochondrial homeostasis following transient focal cerebral ischemia”. J. Neurochem. 94 (6): 1676–1684. doi:10.1111/j.1471-4159.2005.03328.x. PMID 16045446. S2CID 36285159.]} to 5–14 days,^{[Hsiao AL, Santucci KA, Seo-Mayer P, et al. (2005). “Pediatric fatality following ingestion of dinitrophenol: postmortem identification of a “dietary supplement””. Clin Toxicol. 43 (4): 281–285. doi:10.1081/clt-200058946. PMID 16035205]} while still other, more recent papers maintain that the half-life in humans is unknown.^{[A. Hahn, K. Begemann, R. Burger, J. Hillebrand, H. Meyer, K. Preußner: “Cases of Poisoning Reported by Physicians in 2006”, page 40. BfR Press and Public Relations Office, 2006.]}
    • DNP is considered to have high acute toxicity.^{[ “2,4-Dinitrophenol” (PDF). Environmental Protection Agency. Retrieved 15 October 2017.]} In March 2020 a UK judge stated “there is no antidote or remedy for DNP once taken. In consequence, DNP has a high mortality rate ⁠— ⁠of those who presented at hospital between 2007 and 2019 with a history of having taken DNP, 18% died. This puts DNP close to cyanide in terms of its toxicity.”^{[R -v- Rebelo sentencing remarks” (PDF). Courts and Tribunals Judiciary. 11 March 2020. Retrieved 16 March 2020.]} The study published in 2021 indicates that the worldwide cases fatality overall was 11.9% between 2010 and 2020.^{[Gziut, Tomasz; Thomas, Simon H. L. (23 November 2021). “International trends in systemic human exposures to 2,4 dinitrophenol reported to poisons centres”. Clinical Toxicology. 60 (5): 628–631. doi:10.1080/15563650.2021.2005797. ISSN 1556-3650. PMID 34812657. S2CID 244490656]} Other than increasing metabolic rate, acute oral exposure to DNP has resulted in nausea, vomiting, sweating, dizziness, headache, and loss of weight. Chronic oral exposure to DNP can lead to the formation of cataracts and skin lesions and has caused effects on the bone marrow, central nervous system, and cardiovascular system.^{[“2,4-Dinitrophenol” (PDF). Environmental Protection Agency. Retrieved 15 October 2017.][ Public Health Service, U.S. Department of Health and Human Services (1995). “Toxicological Profile for Dinitrophenols”. Agency for Toxic Substances and Disease Registry.]} Contact with skin or inhalation can cause DNP poisoning. In 2009, an incident occurred in a Chinese chemical factory and 20 persons suffered acute DNP poisoning.^{[ Lu, Yuan-qiang; Jiang, Jiu-kun; Huang, Wei-dong (3 December 2011). “Clinical features and treatment in patients with acute 2,4-dinitrophenol poisoning”. Journal of Zhejiang University Science B. 12 (3): 189–192. doi:10.1631/jzus.B1000265. ISSN 1673-1581. PMC 3048933. PMID 21370503.]}
    • The factor that limits ever-increasing doses of DNP is not a lack of ATP energy production, but rather an excessive rise in body temperature due to the heat produced during uncoupling. Accordingly, DNP overdose will cause fatal hyperthermia, with body temperature rising to as high as 43.1 °C (109.6 °F)^{[ McGillis, Eric. “Page 83, ‘136. Rapid-onset hyperthermia and hypercapnea preceding rigor mortis and cardiopulmonary arrest in a DNP overdose'” (PDF). www.eapcct.org.]} shortly before death. Case reports have shown that an acute administration of 10–20 milligrams per kilogram of body weight in humans can be lethal.^{[Hsiao AL, Santucci KA, Seo-Mayer P, et al. (2005). “Pediatric fatality following ingestion of dinitrophenol: postmortem identification of a “dietary supplement””. Clin Toxicol. 43 (4): 281–285. doi:10.1081/clt-200058946. PMID 16035205][Holborow, Alexander; Purnell, Richard M; Wong, Jenny Frederina (4 April 2016). “Beware the yellow slimming pill: fatal 2,4-dinitrophenol overdose”. BMJ Case Reports. 2016: bcr2016214689. doi:10.1136/bcr-2016-214689. ISSN 1757-790X. PMC 4840695. PMID 27045052][ “Dantrolene is not the answer to 2,4-dinitrophenol poisoning: more heated debate”. ResearchGate. Retrieved 6 January 2019.][Veenendaal, A. van. “Surviving a life-threatening 2,4-DNP intoxication: ‘Almost dying to be thin'”. www.njmonline.nl.][ “Banned dinitrophenols still trigger both legal and forensic issues”. ResearchGate. Retrieved 16 February 2019.]} The lowest published fatal ingested dose is 4.3 mg/kg.^{[Grundlingh, Johann; Dargan, Paul I.; El-Zanfaly, Marwa; Wood, David M. (September 2011). “2,4-dinitrophenol (DNP): a weight loss agent with significant acute toxicity and risk of death”. Journal of Medical Toxicology. 7 (3): 205–212. doi:10.1007/s13181-011-0162-6. ISSN 1937-6995. PMC 3550200. PMID 21739343][Bateman, Nick; Jefferson, Robert; Thomas, Simon; Thompson, John; Vale, Allister (26 June 2014). Oxford Desk Reference: Toxicology. OUP Oxford. ISBN 9780191022487.]} In the three separate publicly published medical management cases, a single dose of few tablets from an online retailer (tablet dose unknown) has proven fatal.^{[ “Dantrolene is not the answer to 2,4-dinitrophenol poisoning: more heated debate”. ResearchGate. Retrieved 6 January 2019.][ “Page 1278, ‘Case 377’, American Association of Poison Control Centers (AAPCC) – 2013 Annual Report”. aapcc.org. Retrieved 30 December 2018.]}
    • The United Kingdom’s Food Standards Agency identifies DNP as “an industrial chemical known to have serious short-term and long-term effects, which can be extremely dangerous to human health” and advises “consumers not to take any product containing DNP at any level. This chemical is not suitable for human consumption.”^{[“Warning about ‘fat-burner’ substances containing DNP”. Food Standards Agency. Retrieved 23 April 2013.]} Since February 2017 DNP has been included in Australia SUSMP Schedule 10, “Substances of such a danger to health as to warrant prohibition of sale, supply and use”^{[Health. “Poisons Standard (No. 3) June 2020”. www.legislation.gov.au. Retrieved 19 October 2020.][“Request Rejected” (PDF). www.courts.sa.gov.au. Retrieved 19 October 2020.]} From December 2018 DNP has been classified as an “illegal poisonous substance” in Russia.^{[“Izvestia”: the government has decided to withdraw from free trade in some anabolics – Russian Reality”. Archived from the original on 30 December 2018. Retrieved 30 December 2018.][“О дополнении списка сильнодействующих и ядовитых веществ”. government.ru (in Russian). Retrieved 30 December 2018.]}
    • A dust explosion is possible with DNP in powder or granular form in the presence of air. DNP may explosively decompose when submitted to shock, friction or concussion, and may explode upon heating.^{[Stellman, Jeanne Mager (1998). Encyclopaedia of Occupational Health and Safety: Guides, indexes, directory. International Labour Organization. ISBN 9789221098171.]} DNP forms explosive salts with strong bases as well as ammonia, and emits toxic fumes of nitrogen dioxide when heated to decomposition.^{[Sax, N.Irving; Bruce, Robert D (1989). Dangerous properties of industrial materials. Vol. 3 (7th ed.). John Wiley & Sons. ISBN 0-442-27368-1.]} DNP’s explosive strength is 81% that of TNT, based on the Trauzl lead block test.^{[Meyer, Rudolf; Köhler, Josef; Homburg, Axel (9 May 2016). Explosives. John Wiley & Sons. ISBN 9783527689613.]} DNP was the cause of the 1916 Rainham Chemical Factory explosion which left 7 dead and 69 injured.^{[“Massive explosion that occurred at H.M. Factory, Rainham on 14th September 1916” (PDF).][“Report ID 2136, Past Accident Review, The Institute of Explosives Engineers”. Archived from the original on 27 January 2019. Retrieved 27 January 2019.]} DNP is listed on the Homeland Security Anti-Terrorism Chemicals of Interest list.^{[“Appendix A: Chemicals of Interest”. Department of Homeland Security. 6 July 2009. Retrieved 20 September 2019.]}
    • DNP was widely used in explosive mixtures around the world. Examples include Shellite in the UK, Tridite in the US, Tridita in Spain, MDPC/DD in France, MABT/MBT in Italy, and DNP in the Soviet Union.^{[Meyer, Rudolf; Köhler, Josef; Homburg, Axel (8 February 2008). Explosives. John Wiley & Sons. ISBN 9783527617036.]} During World War I, 36 munition factory workers in France and 27 in the US lost their lives through DNP poisoning.^{[ “Provisional peer peviewed toxicity values for 2,4-dinitrophenol (CASRN 51-28-5)” (PDF). EPA.]} 2,4-dinitrophenol was widely used by Red Army soldiers to make them more resilient to the cold during World War II.^{[Stilwell, Blake (29 April 2020). “This is the drug Russians took to beat the Nazis during World War II”. We Are The Mighty. Retrieved 14 May 2022.]}
    • Three fatalities were reported in dye factories, where DNP was used to make sulfur black dye.^{[Hamilton, Alice (1921). Industrial Poisoning in Making Coal-tar Dyes and Dye Intermediates. U.S. Government Printing Office. p. 25]}
    • DNP was used extensively in diet pills from 1933 to 1938 after Cutting and Tainter at Stanford University made their first report on how the compound substantially increased metabolic rate.^{[Cutting WC, Mehrtens HG, Tainter ML (1933). “Actions and uses of dinitrophenol: Promising metabolic applications”. J Am Med Assoc. 101 (3): 193–195. doi:10.1001/jama.1933.02740280013006][Tainter ML, Stockton AB, Cutting WC (1933). “Use of dinitrophenol in obesity and related conditions: a progress report”. J Am Med Assoc. 101 (19): 1472–1475. doi:10.1001/jama.1933.02740440032009]} This effect occurs via DNP acting as a proton ionophore. After only its first year on the market, Tainter estimated that at least 100,000 people had been treated with DNP in the United States, in addition to many others abroad.^{[Tainter ML, Cutting WC, Stockton AB (1934). “Use of Dinitrophenol in Nutritional Disorders: A Critical Survey of Clinical Results”. Am J Public Health. 24 (10): 1045–1053. doi:10.2105/AJPH.24.10.1045. PMC 1558869. PMID 18014064]}
    • In light of the adverse effects and fatal hyperthermia caused by DNP when it was used clinically, the dose was slowly titrated according to personal tolerance, which varies greatly.^{[Simkins, S. (1937). “Dinitrophenol and desiccated thyroid in the treatment of obesity: a comprehensive clinical and laboratory study”. J Am Med Assoc. 108: 2110–2117. doi:10.1001/jama.1937.02780250024006]} Concerns about dangerous side-effects and rapidly developing cataracts^{[Horner, WD (1941). “A Study of Dinitrophenol and Its Relation to Cataract Formation”. Trans Am Ophthalmol Soc. 39: 405–37. PMC 1315023. PMID 16693262]} resulted in DNP being discontinued in the United States by the end of 1938.^{[Colman, Eric (July 2007). “Dinitrophenol and obesity: an early twentieth-century regulatory dilemma”. Regulatory Toxicology and Pharmacology. 48 (2): 115–117. doi:10.1016/j.yrtph.2007.03.006. ISSN 0273-2300. PMID 17475379]} In 1938, the FDA included DNP in a list of drugs potentially so toxic that they should not be used even under a physician’s supervision.^{[ FDA Consumer. U.S. Department of Health, Education, and Welfare, Public Health Service, Food and Drug Administration. 1987.]}
      • “In studies of intermediate-duration oral exposure to 2,4-DNP, cases of death from agranulocytosis (described in the discussion of Hematological Effects) have been attributed to 2,4-DNP. These cases occurred during the usual dosing regimens for weight loss, employing increasing doses in one case from 2.9 to 4.3 mg/kg/day of 2,4-DNP for 6 weeks (Dameshek and Gargill 1934); a dose of 1.03 mg/kg/day 2,4-DNP for 46 days in another case (Goldman and Haber 1936); and in another, from 0.62 to 3.8 mg/kg/day 2,4-DNP as sodium 2,4-DNP for 41 days (Silver 1934). In all cases, the patients were under medical supervision.“^{[“ATSDR Toxicological Profile for Dinitrophenols, 2. HEALTH EFFECTS” (PDF). www.atsdr.cdc.gov.]}
        •  Agranulocytosis is a serious condition that occurs when there is an extremely low number of granulocytes (a type of white blood cell) in the blood. Granulocytes are an important part of the immune system and help the body fight infection. [Definition of agranulocytosis – NCI Dictionary of Cancer Terms]
• 2,4,6-Trinitrophenol is better known as picric acid, which has a well-developed chemistry.
  • The name “picric” comes from Greek: πικρός (pikros), meaning “bitter”, due to its bitter taste. It is one of the most acidic phenols. Like other strongly nitrated organic compounds, picric acid is an explosive, which is its primary use. It has also been used as medicine (antiseptic, burn treatments) and as a dye.
  • Picric acid was probably first mentioned in the alchemical writings of Johann Rudolf Glauber.
  • Initially, it was made by nitrating substances such as animal horn, silk, indigo, and natural resin, the synthesis from indigo first being performed by Peter Woulfe during 1771.^{[Peter Woulfe (1771) “Experiments to shew the nature of aurum mosaicum,” Philosophical Transactions of the Royal Society of London, 61: 114–130. See pages 127–130: “A method of dying wool and silk, of a yellow colour, with indigo; and also with several other blue and red colouring substances.” and “Receipt for making the yellow dye.” — where Woulfe treats indigo with nitric acid (“acid of nitre”).]} 
  • The German chemist Justus von Liebig had named picric acid Kohlenstickstoffsäure (rendered in French as acide carboazotique).
  • Picric acid was given that name by the French chemist Jean-Baptiste Dumas in 1841.^{[Dumas, J. (1841). “Quatrième mémoire sur les types chimiques” [Fourth memoir on chemical types]. Annales de Chimie et de Physique. 3rd series (in French). 2: 204–232. From p. 228: “C’est sous ce nom que j’ai désigné l’acide carboazotique, …” (It is by this name [i.e., picric acid] that I designated carboazotic acid, … )]} 
  • Its synthesis from phenol, and the correct determination of its formula, were accomplished during 1841.^{[Auguste Laurent (1841) “Sur le phényle et ses dérivés” (On phenol and its derivatives), Annales de Chimie et de Physique, series 3, 3: 195–228; see especially pages 221–228.]} 
  • In 1799, French chemist Jean-Joseph Welter (1763–1852) produced picric acid by treating silk with nitric acid; he found that potassium picrate could explode.^{[Welter (1799). “Sur quelques matières particulières, trouvées dans les substances animals, traitées par l’acide nitrique” [On some particular materials, found in animal substances, treated with nitric acid]. Annales de Chimie et de Physique. 1st series (in French). 29: 301–305. From p. 303: “Le lendemain je trouvai la capsule tapisée de cristaux dorés qui avoient la finesse de la soie, qui détonoient comme la poudre à canon, et qui, à mon avis, en auroient produit l’effet dans une arme à feu.” (The next day, I found the crucible covered with golden crystals which had the fineness of silk, which detonated like gun powder, and which, in my opinion, would produce the same effect in a firearm.) Welter named picric acid amer (bitter): from p. 304: ” … je nommerai amer.” ( … I will name it “bitter”.)]} 
  • Not until 1830 did chemists think to use picric acid as an explosive. Before then, chemists assumed that only the salts of picric acid were explosive, not the acid itself.
    • A theory to explain why picrate salts detonated whereas picric acid itself didn’t, was proposed by the French chemists Antoine Fourcroy and Louis Vauquelin in 1806 and reiterated by the French chemist Michel Chevreul in 1809. Picric acid evidently contained enough oxygen within itself — i.e., it was “super-oxygenated” (suroxigéné) (Fourcroy and Vauquelin, 1806), p. 543; (Chevreul, 1809), p. 129) — to combust completely even in the absence of air (because even in the absence of air, heat could transform it completely into gases, leaving no carbon).((Fourcroy and Vauquelin, 1806), pp. 542–543); (Chevreul, 1809), pp. 127–128) However, when picric acid was burned, the heat that was generated, caused some of the acid to evaporate, dissipating so much heat that only burning, not detonation, occurred. By contrast, picrate salts were solids that did not sublimate, so they did not dissipate heat; hence they did detonate.((Fourcroy and Vauquelin, 1806), p. 542); (Chevreul, 1809), pp. 129–130) See:
      • Fourcroy; Vauquelin (1806). “Mémoire sur la découverte d’une nouvelle matière inflammable et détonnante, formée par l’action de l’acide nitrique sur l’indigo et les matières animales” [Memoir on the discovery of a new flammable and explosive substance, formed by the action of nitric acid on indigo and animal substances]. Mémoires de l’Institute des Sciences et Arts (in French). 6: 531–543.
      • Chevreul (1809). “Extrait d’un mémoire sur les substances amères formées par la réaction de l’acide nitrique sur l’indigo” [Extract from a memoir on the bitter substances formed by the reaction of nitric acid with indigo]. Annales de Chimie et de Physique (in French). 72: 113–142.
  • In 1871 Hermann Sprengel proved it could be detonated^[Note] and afterwards most military powers used picric acid as their main high explosive material.
    • Note: In March 1871, Sprengel detonated picric acid at the gunpowder works of John Hall & Sons in Faversham in Kent, England.
      • Sprengel filed patents in Britain for “safety explosives” (i.e., stable explosives) on April 6, 1871 (no. 921), and on October 5, 1871 (no. 2642); in the latter patent, Sprengel proposed using picric acid dissolved in nitric acid as an explosive.
      • Hermann Sprengel (1873) “On a new class of explosives which are non-explosive during their manufacture, storage, and transport”, Journal of the Chemical Society, 26 : 796–808 doi:10.1039/js8732600796.
      • Hermann Sprengel, The Discovery of Picric Acid (Melinite, Lyddite) “As a Powerful Explosive” …, 2nd ed. (London: Eyre & Spottiswoode, 1903). This pamphlet is a collection of (splenetic) letters in which Sprengel defends his priority in the use of picric acid as a high explosive.
  • Picric acid was the first strongly explosive nitrated organic compound widely considered suitable to withstand the shock of firing in conventional artillery. Nitroglycerine and nitrocellulose (guncotton) were available earlier but shock sensitivity sometimes caused detonation in an artillery barrel at the time of firing. In 1885, based on research of Hermann Sprengel, French chemist Eugène Turpin patented the use of pressed and cast picric acid in blasting charges and artillery shells. In 1887 the French government adopted a mixture of picric acid and guncotton with the name Melinite. In 1888, Britain started manufacturing a very similar mixture in Lydd, Kent, with the name Lyddite. Japan followed with an alternative stabilization approach known as Shimose powder which, instead of attempting to stabilize the material itself, instead removed its contact with metal by coating the inside of the shells with layers of ceramic and wax.^{[Koike, Shigeki (2006). “The Russo-Japanese War and the system of SHIMOSE gunpowder” (PDF). Bulletin of Papers (in Japanese). Takasaki City University of Economics. 1 (49).]} In 1889, a mixture of ammonium cresylate with trinitrocresol, or an ammonium salt of trinitrocresol, started to be manufactured with the name Ecrasite in Austria-Hungary. By 1894 Russia was manufacturing artillery shells filled with picric acid. Ammonium picrate (known as Dunnite or explosive D) was used by the United States beginning in 1906. However, shells filled with picric acid become unstable if the compound reacts with metal shell or fuze casings to form metal picrates which are more sensitive than the parent phenol. The sensitivity of picric acid was demonstrated by the Halifax Explosion.
  • Picric acid was used in the Battle of Omdurman,^{[Brown, G.I. (1998). The big bang: a history of explosives. Stroud, UK: Sutton Pub. p. 151–163. ISBN 0-7509-1878-0. OCLC 40348081]} the Second Boer War,^{[Wisser, John Philip (1901). The second Boer War, 1899–1900. Hudson-Kimberly. p. 243. Retrieved 2009-07-22.]} the Russo-Japanese War,^{[Dunnite Smashes Strongest Armor, The New York Times, August 18, 1907]} and World War I.^{[Marc Ferro. The Great War. London and New York: Routeladge Classics, p. 98.]} Germany began filling artillery shells with Trinitrotoluene (TNT) in 1902. Toluene was less readily available than phenol, and TNT is less powerful than picric acid, but improved safety of munitions manufacturing and storage caused the replacement of picric acid by TNT for most military purposes between the World Wars.^{[Brown, G.I. (1998), The Big Bang: a History of Explosives, Sutton Publishing ISBN 0-7509-1878-0 pp.151–163]}
  • Efforts to control the availability of phenol, the precursor to picric acid, emphasize its importance in World War I. Germans are reported to have bought US supplies of phenol and converted it to acetylsalicylic acid, i.e., aspirin, to keep it from the Allies. (See Great Phenol Plot.) At the time, phenol was obtained from coal as a co-product of coke ovens and the manufacture of gas for gas lighting. Laclede Gas reports being asked to expand production of phenol (and toluene) to assist the war effort.^{[Beck, Bill (2007) Laclede Gas and St. Louis: 150 Years Working Together, 1857–2007, Laclede Gas Company, ISBN 978-0-9710910-1-6 p. 64]} 
  • Both Monsanto^{[Forrestal, Dan J. (1977), Faith, Hope & $5000: The Story of Monsanto, Simon & Schuster, ISBN 0-671-22784-X[2] p. 24]} and Dow Chemical^{[ Brandt, E.N. (1997), Growth Company: Dow Chemical’s First Century, Michigan State University, ISBN 0-87013-426-4 p. 77, 97 and 244]} began manufacturing synthetic phenol in 1915, with Dow being the main producer. Dow describes picric acid as “the main battlefield explosive used by the French. Large amounts [of phenol] also went to Japan, where it was made into picric acid sold to the Russians.”^{[Brandt, E.N. (1997), Growth Company: Dow Chemical’s First Century, Michigan State University, ISBN 0-87013-426-4 p. 97]}
  • Thomas Edison needed phenol to manufacture phonograph records. He responded by undertaking production of phenol at his Silver Lake, NJ, facility using processes developed by his chemists.^{[Conot, Robert (1979), A Streak of Luck: The Life & Legend of Thomas Alva Edison, Seaview Books, NY, p 413-4]} He built two plants with a capacity of six tons of phenol per day. Production began the first week of September, one month after hostilities began in Europe. He built two plants to produce raw material benzene at Johnstown, PA, and Bessemer, AL, replacing supplies previously from Germany. Edison also manufactured aniline dyes, which had previously been supplied by the German dye trust. Other wartime products include xylene, p-phenylenediamine, shellac, and pyrax. Wartime shortages made these ventures profitable. In 1915, his production capacity was fully committed by midyear.
  • The aromatic ring of phenol is activated towards electrophilic substitution reactions, and attempted nitration of phenol, even with dilute nitric acid, results in the formation of high molecular weight tars. In order to minimize these side reactions, anhydrous phenol is sulfonated with fuming sulfuric acid, and the resulting p-hydroxyphenylsulfonic acid is then nitrated with concentrated nitric acid. During this reaction, nitro groups are introduced, and the sulfonic acid group is displaced. The reaction is highly exothermic, and careful temperature control is required. Another method of picric acid synthesis is direct nitration of 2,4-Dinitrophenol with nitric acid.^{[Agrawal, Jai Prakash; Hodgson, Robert (2007-01-11). Organic Chemistry of Explosives. John Wiley & Sons. ISBN 9780470059357][Green, Arthur George (1919-04-01). “Manufacture of picric acid. US Patent US1299171A”. patents.google.com. Retrieved 2018-08-26.]} It crystallizes in the orthorhombic space group Pca2₁ with a = 9.13 Å, b = 18.69 Å, c = 9.79 Å and α = β = γ = 90°.^{[V. Bertolasi, P. Gilli, G. Gilli: Hydrogen Bonding and Electron Donor-Acceptor (EDA) Interactions Controlling the Crystal Packing of Picric Acid and Its Adducts with Nitrogen Bases. Their Rationalization in Terms of the pK_a Equalization and Electron-Pair Saturation Concepts. In: Cryst. Growth Des. 2011, 11, 2724–2735, doi:10.1021/cg101007a.]}
  • By far the greatest use has been in munitions and explosives. Explosive D, also known as Dunnite, is the ammonium salt of picric acid. Dunnite is more powerful but less stable than the more common explosive TNT (which is produced in a similar process to picric acid but with toluene as the feedstock). Picramide, formed by aminating picric acid (typically beginning with Dunnite), can be further aminated to produce the very stable explosive TATB.
  • It has found some use in organic chemistry for the preparation of crystalline salts of organic bases (picrates) for the purpose of identification and characterization.
  • In metallurgy, a 4% picric acid in ethanol etch termed “picral” has been commonly used in optical metallography to reveal prior austenite grain boundaries in ferritic steels. The hazards associated with picric acid have meant it has largely been replaced with other chemical etchants. However, it is still used to etch magnesium alloys, such as AZ31.
  • Bouin solution is a common picric-acid-containing fixative solution used for histology specimens.^{[Carson, Freida L.; Hladik, Christa (2009). Histotechnology: A Self-Instructional Text (3 ed.). Hong Kong: American Society for Clinical Pathology Press. p. 19. ISBN 978-0-89189-581-7]} 
  • It improves the staining of acid dyes, but it can also result in hydrolysis of any DNA in the sample.^{[Llewellyn, Brian D (February 2009). “Picric Acid”. StainsFile. Archived from the original on 31 May 2015. Retrieved 28 September 2012.]}
  • Clinical chemistry laboratory testing utilizes picric acid for the Jaffe reaction to test for creatinine. It forms a colored complex that can be measured using spectroscopy.^{[ Creatinine Direct Procedure, on CimaScientific]}
  • Picric acid forms red isopurpurate with hydrogen cyanide (HCN). By photometric measurement of the resulting dye picric acid can be used to quantify hydrogen cyanide.^{[Quantification of total cyanide content in stone fruit kernels. Archived 2019-04-30 at the Wayback Machine pdf, Pg.33]}
  • During the early 20th century, picric acid was used to measure blood glucose levels. When glucose, picric acid and sodium carbonate are combined and heated, a characteristic red color forms. With a calibrating glucose solution, the red color can be used to measure the glucose levels added. This is known as the Lewis and Benedict method of measuring glucose.^{[“Measuring blood glucose levels in the 1920s”. Tacomed.com. Archived from the original on 16 December 2018. Retrieved 13 June 2017.]}
  • Much less commonly, wet picric acid has been used as a skin dye, or temporary branding agent. It reacts with proteins in the skin to give a dark brown color that may last as long as a month.
  • During the early 20th century, picric acid was stocked in pharmacies as an antiseptic and as a treatment for burns, malaria, herpes, and smallpox. Picric acid-soaked gauze was also commonly stocked in first aid kits from that period as a burn treatment. It was notably used for the treatment of burns suffered by victims of the Hindenburg disaster in 1937. Picric acid was also used as a treatment for trench foot suffered by soldiers stationed on the Western Front during World War I.^{[(1922) [1] History of the Great War – Surgery of the War, Vol. 1, Pg. 175.]}
  • Picric acid has been used for many years by fly tyers to dye mole skins and feathers a dark olive green for use as fishing lures. Its popularity has been tempered by its toxic nature.
  • Modern safety precautions recommend storing picric acid wet, to minimize the danger of explosion. Dry picric acid is relatively sensitive to shock and friction, so laboratories that use it store it in bottles under a layer of water, rendering it safe. Glass or plastic bottles are required, as picric acid can easily form metal picrate salts that are even more sensitive and hazardous than the acid itself. Industrially, picric acid is especially hazardous because it is volatile and slowly sublimes even at room temperature. Over time, the buildup of picrates on exposed metal surfaces can constitute an explosion hazard.^{[“Picric Acid, Wet”. HAZARD.com Web Site. 21 April 1998. Retrieved 13 April 2021]}
  • Picric acid gauze, if found in antique first aid kits, presents a safety hazard because picric acid of that vintage (60–90 years old) will have become crystallized and unstable,^{[Harding, Evan; Searle, Jamie (7 July 2021). “Potentially explosive substance was in Catlins museum for decades”. Stuff. Retrieved 20 July 2021.]} and may have formed metal picrates from long storage in a metal first aid case.
  • Bomb disposal units are often called to dispose of picric acid if it has dried out.^{[Bomb squad called to Dublin lab”. irishtimes.com. Irish Times. 1 October 2010. Retrieved 22 July 2011][Unstable chemicals made safe by army”. rte.ie. RTÉ News. 3 November 2010. Retrieved 22 July 2011]} In the United States there was an effort to remove dried picric acid containers from high school laboratories during the 1980s.
  • Munitions containing picric acid may be found in sunken warships. The buildup of metal picrates over time renders them shock-sensitive and extremely hazardous. It is recommended that shipwrecks that contain such munitions not be disturbed in any way. The hazard may subside when the shells become corroded enough to admit seawater as these materials are water-soluble.^{[Albright, p.78]} 
  • Currently there are various fluorescent probes to sense and detect picric acid in very minute quantity.^{[Arunkumar, Chellaiah; Sujatha, Subramaniam (26 Oct 2015). “Protonation and axial ligation intervened fluorescence turn-off sensing of picric acid in freebase and tin(iv) porphyrins”. RSC Advances. 5 (113): 93243. Bibcode:2015RSCAd…593243S. doi:10.1039/C5RA18310C]}
  • See Also Shellite (explosive), an explosive containing Picric acid, formerly used in naval shells, Table of explosive detonation velocities and RE factor and Verhoeff’s stain and Styphnic acid

Safety

Nitrophenols are poisonous. Occasionally, nitrophenols contaminate the soil near former explosives or fabric factories and military plants, and current research is aimed at remediation.^{[Fact sheet at atsdr.cdc.gov]}

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