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Arsenic trioxide

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Arsenic trioxide is an inorganic compound with the formula As
2O
3.[5] As an industrial chemical, its major uses include the manufacture of wood preservatives, pesticides, and glass.[6] It is sold under the brand name Trisenox among others[2][3] when used as a medication to treat a type of cancer known as acute promyelocytic leukemia.[7] For this use it is given by injection into a vein.[7]

Arsenic trioxide
Arsenic trioxide   As   O
Clinical data
PronunciationAR se nik tri OKS id
Trade namesTrisenox, others
Other namesArsenic(III) oxide,
Arsenic sesquioxide,
Arseneous oxide,
Ratsbane,
Arseneous anhydride,
White arsenic,
Aqua Tofani[1]
AHFS/Drugs.comMonograph
MedlinePlusa608017
License data
Pregnancy
category
  • AU: X (High risk)
Routes of
administration		Intravenous
Drug classAntineoplastic agent
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding75%
ExcretionUrine
Identifiers
  • Diarsenic trioxide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.014.075 Edit this at Wikidata
Chemical and physical data
FormulaAs2O3
Molar mass197.840 g·mol−1
3D model (JSmol)
Density3.74 g/cm3
Melting point312.2 °C (594.0 °F)
Boiling point465 °C (869 °F)
Solubility in water20 g/L (25 °C)
(see text)
  • O1[As]3O[As]2O[As](O3)O[As]1O2
  • InChI=1S/As2O3/c3-1-4-2(3)5-1
     checkY
  • Key:GOLCXWYRSKYTSP-UHFFFAOYSA-N
Arsenic trioxide
Identifiers
ECHA InfoCard 100.014.075 Edit this at Wikidata
EC Number
  • 215-481-4
Hazards
GHS labelling:[4]
GHS05: Corrosive GHS06: Toxic GHS08: Health hazard GHS09: Environmental hazard
Danger
H300, H314, H350, H410
P201, P202, P260, P264, P270, P273, P280, P301+P330+P331, P303+P361+P353, P304+P340+P310, P305+P351+P338+P310, P308+P313, P363, P391, P405, P501
Safety data sheet (SDS) american elements SDS
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Common side effects include vomiting, diarrhea, swelling, shortness of breath, and headaches.[7] Severe side effects may include APL differentiation syndrome and heart problems.[7] Use during pregnancy or breastfeeding may harm the baby.[8][9] Its mechanism in treating cancer is not entirely clear.[7]

Arsenic trioxide was approved for medical use in the United States in 2000.[7] It is on the World Health Organization's List of Essential Medicines.[10] Approximately 50,000 tonnes are produced a year.[11] Due to its toxicity, a number of countries have regulations around its manufacture and sale.[12]

Uses

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Medical

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Main article: Medical use of arsenic trioxide

Arsenic trioxide is indicated in combination with tretinoin for treatment of adults with newly-diagnosed low-risk acute promyelocytic leukemia whose acute promyelocytic leukemia is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression; and for induction of remission and consolidation in patients with acute promyelocytic leukemia who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose acute promyelocytic leukemia is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.[2][3][13]

Arsenic trioxide is used to treat a type of cancer known as acute promyelocytic leukemia (APL).[7] It may be used both in cases that are unresponsive to other agents, such as all-trans retinoic acid (ATRA) or as part of the initial treatment of newly diagnosed cases.[7] This initial treatment may include combination therapy of arsenic trioxide with all-trans retinoic acid (ATRA).[14]

Effectiveness appears similar to Realgar/Indigo naturalis, which can be taken by mouth and is less expensive but is less available.[15] It works by encouraging the proteosome breakdown of retinoic acid receptor alpha, by moving the protein on to the nuclear matrix and increasing ubiquitination.[16]

In the 1970s, Chinese researcher Zhang Tingdong and colleagues discovered this use.[17] It was approved for leukemia treatment in the United States in 2000.[18] University of Hong Kong developed a liquid form of arsenic trioxide that can be given by mouth.[19] Organoarsenic compounds, such as feed additives (roxarsone) and medication (neosalvarsan), are derived from arsenic trioxide.[citation needed]

Manufacturing

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Industrial uses include usage as a precursor to forestry products, in colorless glass production, and in electronics.[11] Being the main compound of arsenic, the trioxide is the precursor to elemental arsenic, arsenic alloys, and arsenide semiconductors. Bulk arsenic-based compounds sodium arsenite and sodium cacodylate are derived from the trioxide.[citation needed]

A variety of applications exploit arsenic's toxicity, including the use of the oxide as a wood preservative. Copper arsenates, which are derived from arsenic trioxide, are used on a large scale as a wood preservative in the U.S. and Malaysia, but such materials are banned in many parts of the world. This practice remains controversial.[11] In combination with copper(II) acetate, arsenic trioxide gives the vibrant pigment known as Paris green used in paints and as a rodenticide. This application has been discontinued.[citation needed]

Alternative medicine

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Despite the well known toxicity of arsenic, arsenic trioxide was used in traditional Chinese medicine, where it is known as pi-shuang (Chinese: 砒霜; pinyin: pīshuāng; lit. 'arsenic frost'). In homeopathy, it is called arsenicum album. Some discredited patent medicines, e.g., Fowler's solution, contained derivatives of arsenic oxide.[20]

Toxicology

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See also: Arsenic poisoning

As with other inorganic arsenic compounds, arsenic trioxide is toxic to living organisms. Arsenic trioxide is readily absorbed by the digestive system. Ingestion of as little as 0.1 grams can be fatal.[11]

Chronic arsenic poisoning is known as arsenicosis. This disorder affects workers in smelters, in populations whose drinking water contains high levels of arsenic (0.3–0.4 ppm), and in patients treated for long periods with arsenic-based pharmaceuticals. Long-term ingestion of arsenic trioxide either in drinking water or as a medical treatment can lead to skin cancer. Reproductive problems (high incidences of miscarriage, low birth weight, congenital deformations) have also been indicated in one study of women exposed to arsenic trioxide dust as employees or neighbours of a copper foundry.

In the U.S., the OSHA 1910.1018 occupational permissible exposure limit for inorganic arsenic compounds in breathing zone air is 0.010 mg/m3.

Production and occurrence

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Historic arsenic mine Sankt Blasen, Austria

Arsenic trioxide can be generated via routine processing of arsenic compounds including the oxidation (combustion) of arsenic and arsenic-containing minerals in air. Illustrative is the roasting of orpiment, a typical arsenic sulfide ore.

2 As
2S
3 + 9 O
2 → 2 As
2O
3 + 6 SO
2

Most arsenic oxide is, however, obtained as a volatile by-product of the processing of other ores. For example, arsenopyrite, a common impurity in gold- and copper-containing ores, liberates arsenic trioxide upon heating in air. The processing of such minerals has led to numerous cases of poisonings,[21] and after the mine is closed, the leftover trioxide waste will present environmental hazard (as was the case with the Giant Mine, for example). Only in China are arsenic ores intentionally mined.[11]

In the laboratory, it is prepared by hydrolysis of arsenic trichloride:[22]

2 AsCl3 + 3 H2O → As2O3 + 6 HCl

As
2O
3 occurs naturally as two minerals, arsenolite (cubic) and claudetite (monoclinic). Both are relatively rare secondary minerals found in oxidation zones of As-rich ore deposits.

Properties and reactions

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Arsenic trioxide is an amphoteric oxide, and its aqueous solutions are weakly acidic. Thus, it dissolves readily in alkaline solutions to give arsenites. It is less soluble in acids, although it will dissolve in hydrochloric acid.[23]

With anhydrous HF and HCl, it gives AsF3 and the trichloride:[22]

As2O3 + 6 HX → 2 AsX3 + 3 H2O (X = F, Cl)

Only with strong oxidizing agents such as ozone, hydrogen peroxide, and nitric acid does it yield arsenic pentoxide, As
2O
5 or its corresponding acid:[22]

2 HNO3 + As2O3 + 2 H2O → 2 H3AsO4 + N2O3

In terms of its resistance to oxidation, arsenic trioxide differs from phosphorus trioxide, which readily combusts to phosphorus pentoxide.

Reduction gives elemental arsenic or arsine (AsH
3) depending on conditions:[22]

As2O3 + 6 Zn + 12 HNO3 → 2 AsH3 + 6 Zn(NO3)2 + 3 H2O

This reaction is used in the Marsh test.

Structure

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In the liquid and gas phase below 800 °C, arsenic trioxide has the formula As
4O
6 and is isostructural with P
4O
6. Above 800 °C As
4O
6 significantly dissociates into molecular As
2O
3, which adopts the same structure as N
2O
3. Three forms (polymorphs) are known in the solid state: a high temperature ( > 110 °C) cubic As
4O
6, containing molecular As
4O
6, and two related polymeric forms.[24] The polymers, which both crystallize as monoclinic crystals, feature sheets of pyramidal AsO
3 units that share O atoms.[25]

     
arsenolite
(cubic)
claudetite I
(monoclinic)
claudetite II
(monoclinic)

Society and culture

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Environmental effects

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Smelting and related ore processing often generate arsenic trioxide, which poses a risk to the environment. For example, the Giant Mine in Canada processed substantial amounts of arsenopyrite-contaminated gold ores.

Arsenic poisoning in literature and society

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Main article: Arsenic poisoning

The poisonous properties of arsenic are the subject of an extensive literature.[26][27][28]

In Austria, there lived the so-called "arsenic eaters of Styria", who ingested doses far beyond the lethal dose of arsenic trioxide without any apparent harm. Arsenic is thought to enable strenuous work at high altitudes, e.g. in the Alps.[29][30][31][32]

References

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  1. ^ Shakhashiri BZ. "Chemical of the Week: Arsenic". University of Wisconsin-Madison Chemistry Dept. Archived from the original on 2 August 2008. Retrieved 3 August 2008.
  2. ^ a b c "Trisenox- arsenic trioxide injection, solution". DailyMed. 30 June 2022. Archived from the original on 3 February 2024. Retrieved 3 February 2024.
  3. ^ a b c "Trisenox EPAR". European Medicines Agency. 10 August 2010. Archived from the original on 16 August 2023. Retrieved 3 February 2024.
  4. ^ "Safety Data Sheet". American Elements. 2021. Archived from the original on 4 January 2022. Retrieved 4 January 2022.
  5. ^ Sun H (2010). Biological Chemistry of Arsenic, Antimony and Bismuth. John Wiley & Sons. p. 295. ISBN 9780470976227. Archived from the original on 14 April 2023. Retrieved 18 March 2023.
  6. ^ Landner L (2012). Chemicals in the Aquatic Environment: Advanced Hazard Assessment. Springer Science & Business Media. p. 259. ISBN 9783642613340. Archived from the original on 14 April 2023. Retrieved 18 March 2023.
  7. ^ a b c d e f g h "Arsenic Trioxide Monograph for Professionals". Drugs.com. Archived from the original on 15 November 2019. Retrieved 15 November 2019.
  8. ^ British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 907. ISBN 9780857113382.
  9. ^ "Arsenic trioxide (Trisenox) Use During Pregnancy". Drugs.com. Archived from the original on 15 November 2019. Retrieved 16 November 2019.
  10. ^ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
  11. ^ a b c d e Grund SC, Hanusch K, Wolf HU. "Arsenic and Arsenic Compounds". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a03_113.pub2. ISBN 978-3527306732.
  12. ^ Consolidated List of Products Whose Consumption And/or Sale Have Been Banned, Withdrawn, Severely Restricted Or Not Approved by Governments: Chemicals (PDF). United Nations Publications. 2009. p. 24. ISBN 9789211302196.
  13. ^ "Drug Approval Package: Trisenox (Arsenic Trioxide) NDA #21-248". U.S. Food and Drug Administration (FDA). 12 July 2001. Archived from the original on 3 February 2024. Retrieved 3 February 2024.
  14. ^ Zhu J, Chen Z, Lallemand-Breitenbach V, de Thé H (September 2002). "How acute promyelocytic leukaemia revived arsenic". Nature Reviews. Cancer. 2 (9): 705–713. doi:10.1038/nrc887. PMID 12209159. S2CID 2815389.
  15. ^ Howard SC. "Proposal for the inclusion of arsenic therapies in the WHO Model List of Essential Medicines for the treatment of acute promyelocytic leukemia" (PDF). WHO. Archived from the original (PDF) on 9 March 2022. Retrieved 15 November 2019.
  16. ^ Zhu J, Koken MH, Quignon F, Chelbi-Alix MK, Degos L, Wang ZY, et al. (April 1997). "Arsenic-induced PML targeting onto nuclear bodies: implications for the treatment of acute promyelocytic leukemia". Proceedings of the National Academy of Sciences of the United States of America. 94 (8): 3978–3983. Bibcode:1997PNAS...94.3978Z. doi:10.1073/pnas.94.8.3978. PMC 20553. PMID 9108090.
  17. ^ Rao Y, Li R, Zhang D (June 2013). "A drug from poison: how the therapeutic effect of arsenic trioxide on acute promyelocytic leukemia was discovered". Science China Life Sciences. 56 (6): 495–502. doi:10.1007/s11427-013-4487-z. PMID 23645104.
  18. ^ Bian Z, Chen S, Cheng C, Wang J, Xiao H, Qin H (2012). "Developing new drugs from annals of Chinese medicine". Acta Pharmaceutica Sinica B. 2: 1–7. doi:10.1016/j.apsb.2011.12.007.
  19. ^ Au WY, Kumana CR, Kou M, Mak R, Chan GC, Lam CW, et al. (July 2003). "Oral arsenic trioxide in the treatment of relapsed acute promyelocytic leukemia". Blood. 102 (1): 407–408. doi:10.1182/blood-2003-01-0298. PMID 12814916.
  20. ^ Gibaud S, Jaouen G (2010). "Arsenic-Based Drugs: From Fowler's Solution to Modern Anticancer Chemotherapy". Medicinal Organometallic Chemistry. Topics in Organometallic Chemistry. Vol. 32. pp. 1–20. Bibcode:2010moc..book....1G. doi:10.1007/978-3-642-13185-1_1. ISBN 978-3-642-13184-4.
  21. ^ "Giant Mine – Northwest Territories Region – Indian and Northern Affairs Canada". Archived from the original on 27 June 2006. Retrieved 28 August 2007.
  22. ^ a b c d Handbook of Preparative Inorganic Chemistry, 2nd Ed. Edited by G. Brauer, Academic Press, 1963, NY.
  23. ^ Greenwood, N. N.; & Earnshaw, A. (1997). Chemistry of the Elements (2nd Edn.), Oxford:Butterworth-Heinemann. ISBN 0-7506-3365-4.
  24. ^ Wells A.F. Structural Inorganic Chemistry. 5th. London, England: Oxford University Press, 1984. Print. ISBN 0-19-855370-6
  25. ^ Holleman AF, Wiberg E (2001). Inorganic Chemistry. San Diego: Academic Press. ISBN 0-12-352651-5.
  26. ^ "Stanton v Benzler 9716830". U.S. 9th Circuit Court of Appeals. 17 June 1998. Archived from the original on 21 October 2012. Retrieved 9 June 2008. (...) convicted by a jury of first degree murder for poisoning her ex-husband. Her ex-husband's body was found with traces of arsenic trioxide in it.
  27. ^ Emsley J (2006). "Arsenic". The Elements of Murder: A History of Poison. Oxford University Press. pp. 93–197. ISBN 978-0-19-280600-0.
  28. ^ Flaubert G (1856). Madame Bovary.
  29. ^ "Arsenic Eaters". The New York Times. 26 July 1885. Archived from the original on 27 July 2018. Retrieved 27 July 2018.
  30. ^ Allesch RM (1959). Arsenik. Seine Geschichte in Österreich. Archiv für vaterländische Geschichte und Topographie. Vol. 54. Klagenfurt: Kleinmayr.
  31. ^ Przygoda G, Feldmann J, Cullen WR (2001). "The arsenic eaters of Styria: a different picture of people who were chronically exposed to arsenic". Applied Organometallic Chemistry. 15 (6): 457–462. doi:10.1002/aoc.126.
  32. ^ Whorton JC (2010). The Arsenic Century. Oxford University Press. pp. 270–273. ISBN 978-0-19-960599-6.
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