Chemistry:Denatonium

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Denatonium, usually available as denatonium benzoate (under trade names such as Denatrol, BITTERANT-b, BITTER+PLUS, Bitrex, Bitrix, and Aversion) and as denatonium saccharinate (BITTERANT-s), is the bitterest chemical compound known, with bitterness thresholds of 0.05 ppm for the benzoate and 0.01 ppm for the saccharinate.[1] It was discovered in 1958 during research on local anesthetics by T. & H. Smith of Edinburgh, Scotland, and registered under the trademark Bitrex.[2][3]

Dilutions of as little as 10 ppm are unbearably bitter to most people. Denatonium salts are usually colorless and odorless solids, but are often traded as solutions. They are used as aversive agents (bitterants) to prevent inappropriate ingestion. Denatonium is used in denatured alcohol,[4] antifreeze, preventive nail biting preparations, respirator mask fit-testing, animal repellents, liquid soaps, shampoos, and Nintendo Switch game cards to prevent accidental swallowing or choking by children. It is not known to pose any long-term health risks.[1]

The name denatonium reflects the substance's primary use as a denaturant and its chemical nature as a cation, hence -onium as a Neo-Latin suffix.

Structure, synthesis, and physical properties

Denatonium is a quaternary ammonium cation. It is composed as a salt with any of several anions, such as benzoate or saccharinate. It can be obtained by the quaternization of lidocaine, a popular anesthetic, with benzyl chloride or a similar reagent.[5] To obtain other salts, like the benzoate, the formed denatonium chloride is subjected to an anion exchange reaction with sodium benzoate, or first sodium hydroxide to make denatonium hydroxide followed by neutralization with benzoic acid.[5] Other similar compounds are procaine and benzocaine.[6]

Biochemistry

Denatonium in humans is recognized by eight distinct bitter taste receptors: TAS2R4, TAS2R8, TAS2R10, TAS2R39, TAS2R43, TAS2R16, TAS2R46, and TAS2R47, being by far the most sensitive[clarification needed] to the compound.[7][8]

Denatonium can act as a bronchodilator by activating bitter taste receptors in the airway smooth muscle.[9]

Applications

The bitterness of the compound guides most applications of denatonium. Denatonium benzoate is used to denature ethanol so that it is not treated as an alcoholic beverage with respect to taxation and sales restrictions. One designation in particular, SD-40B, indicates that ethanol has been denatured using denatonium benzoate.

Denatonium is commonly included in placebos used in clinical trials to mimic the bitter taste of certain medications.[1]

Denatonium benzoate is an ingredient in certain nail polishes and varnishes designed to discourage nail biting, as the bitter denatonium serves as an aversive.[10]


In 1995, the U.S. state of Oregon required that denatonium benzoate be added to products containing sweet-tasting ethylene glycol and methanol such as antifreeze and windshield washer fluid to prevent poisonings of children and animals.[11] In December 2012, U.S. manufacturers voluntarily agreed to add denatonium benzoate to antifreeze sold nationwide.[12]

Animals are known to have different sensitivities to the effects of denatonium. It is used in some animal repellents (especially for such large mammals as deer). It has been used to safeguard rat poisons from human consumption,[13] as humans are able to detect denatonium at much lower concentrations than rodents.[14]

Nintendo Switch and Nintendo Switch 2 game cartridges are coated in denatonium benzoate to prevent young children from consuming them, intentionally or not.[15][16]

Lithium button cells, which can cause severe internal injuries if swallowed, are sometimes coated with denatonium benzoate to discourage small children from swallowing them.

The reverse side of a Duracell 2025 coin cell 2-pack, showing the Bitrex logo and an indicator of its "repulsive taste". The small graphic shows a cartoon of a baby's face with eyes screwed up and tongue poking out in obvious disgust.
The reverse side of a Duracell 2025 coin cell 2-pack sold in the United Kingdom, showing the Bitrex logo and an indicator of its "repulsive taste". The graphic is at the upper left side of the card.

See also

References

  1. ↑ 1.0 1.1 1.2 "Final Report Study of Aversive Agents". Consumer Product Safety Commission United States of America. 18 November 1992. http://www.cpsc.gov/LIBRARY/FOIA/foia99/os/aversive.pdf. Retrieved 15 November 2010. 
  2. ↑ "Bitrex(R) — Branded Denatonium Benzoate". Macfarlan Smith. http://www.macsmith.com/index.php?page=bitrex. 
  3. ↑ "Denatonium Benzoate". https://www.encyclopedia.com/science/academic-and-educational-journals/denatonium-benzoate. 
  4. ↑ "Ethanol Denaturants". The Online Distillery Network. 1993-11-22. http://www.distill.com/specs/EU2.html. 
  5. ↑ 5.0 5.1 Stachowiak, Witold; Wysocki, Marcin; Niemczak, Michał (2022-04-12). ""Bitter" Results: Toward Sustainable Synthesis of the Most Bitter Substances, Denatonium Saccharinate and Denatonium Benzoate, Starting from a Popular Anesthetic, Lidocaine" (in en). Journal of Chemical Education 99 (4): 1604–1611. doi:10.1021/acs.jchemed.1c00995. ISSN 0021-9584. Bibcode: 2022JChEd..99.1604S. 
  6. ↑ Holvoet, Jean-Patrick. "Denatonium". Sentinalco. http://www.sentinalco.com/page/denatonium/f1.html. 
  7. ↑ Meyerhof, W.; Batram, C.; Kuhn, C.; Brockhoff, A.; Chudoba, E.; Bufe, B.; Appendino, G.; Behrens, M. (2009). "The Molecular Receptive Ranges of Human TAS2R Bitter Taste Receptors". Chemical Senses 35 (2): 157–170. doi:10.1093/chemse/bjp092. PMID 20022913. 
  8. ↑ "BitterDB - Denatonium benzoate". Hebrew University of Jerusalem. http://bitterdb.agri.huji.ac.il/bitterdb/compound.php?id=94. 
  9. ↑ Deshpande, D. A.; Wang, W. C. H.; McIlmoyle, E. L.; Robinett, K. S.; Schillinger, R. M.; An, S. S.; Sham, J. S. K.; Liggett, S. B. (2010). "Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction". Nature Medicine 16 (11): 1299–1304. doi:10.1038/nm.2237. PMID 20972434. 
  10. ↑ Allen KW (March 1996). "Chronic nailbiting: a controlled comparison of competing response and mild aversion treatments". Behav Res Ther 34 (3): 269–72. doi:10.1016/0005-7967(95)00078-X. PMID 8881096. 
  11. ↑ "Was it necessary to add Bitrex (denatonium benzoate) to automotive products?". Veterinary and Human Toxicology 46 (3): 150–2. June 2004. ISSN 0145-6296. PMID 15171494. 
  12. ↑ "Antifreeze and Engine Coolant Being Bittered Nationwide". Consumer Specialty Products Association. 13 December 2012. http://www.cspa.org/category/news-releases/2012/12/antifreeze-and-engine-coolant-being-bittered-nationwide/. 
  13. ↑ "Rats - Rat Poison & Rat Bait Stations". Pestcontrolshop.co.uk. http://www.pestcontrolshop.co.uk/acatalog/rats.html. 
  14. ↑ Frank ME, Bouverat BP, MacKinnon BI, Hettinger TP. The distinctiveness of ionic and nonionic bitter stimuli. Physiol Behav. 2004 Jan;80(4):421-31. doi:10.1016/j.physbeh.2003.09.009
  15. ↑ Dornbush, Johnathon (2 March 2017). "Nintendo Switch Cartridges Taste Terrible". http://www.ign.com/articles/2017/03/02/nintendo-switch-cartridges-taste-terrible. 
  16. ↑ "Switch 2 Carts Still Taste Bad, Designed Purposefully To Be Spat Out" (in en-US). https://www.gamespot.com/articles/switch-2-carts-still-taste-bad-designed-purposefully-to-be-spat-out/1100-6530649/. 



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