Coumarin

Not to be confused with coumadin or dicoumarol.
This article is about the sweet-smelling plant substance called coumarin. For the anticoagulant rodenticide poisons often called "coumarins" or "coumadins", see 4-hydroxycoumarins.
Coumarin
Names
IUPAC name
2H-chromen-2-one
Other names
1-benzopyran-2-one
Identifiers
91-64-5 YesY
3D model (Jmol) Interactive image
ChEBI CHEBI:28794 YesY
ChEMBL ChEMBL6466 YesY
ChemSpider 13848793 YesY
DrugBank DB04665 YesY
ECHA InfoCard 100.001.897
EC Number 202-086-7
KEGG D07751 YesY
PubChem 323
RTECS number GN4200000
UNII A4VZ22K1WT YesY
Properties
C9H6O2
Molar mass 146.15 g·mol−1
Appearance colorless to white crystals
Odor pleasant, like vanillabeans
Density 0.935 g/cm3 (20 °C (68 °F))
Melting point 71 °C (160 °F; 344 K)
Boiling point 301.71 °C (575.08 °F; 574.86 K)
0.17 g/100 mL
Solubility very soluble in ether, diethyl ether, chloroform, oil, pyridine
soluble in ethanol
log P 1.39
Vapor pressure 1.3 hPa (106 °C (223 °F))
Structure
orthorhombic
Hazards
Safety data sheet Sigma-Aldrich
NFPA 704
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g., canola oil Health code 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g., chloroform Reactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogen Special hazards (white): no codeNFPA 704 four-colored diamond
1
2
0
Flash point 150 °C (302 °F; 423 K)
Lethal dose or concentration (LD, LC):
293 mg/kg (rat, oral)
Related compounds
Related compounds
 Chromone
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
YesY verify (what is YesYN ?)
Infobox references

Coumarin (/ˈkuːmərɪn/; 2H-chromen-2-one) is a fragrant organic chemical compound in the benzopyrone chemical class, which is a colorless crystalline substance in its standard state. It is a natural substance found in many plants.

The name comes from a French term for the tonka bean, coumarou, one of the sources from which coumarin was first isolated as a natural product in 1820. It has a sweet odor, readily recognised as the scent of new-mown hay, and has been used in perfumes since 1882. Sweet woodruff, Meadowsweet, sweet grass and sweet-clover in particular are named for their sweet (i.e., pleasant) smell, which in turn is due to their high coumarin content. When it occurs in high concentrations in forage plants, coumarin is a somewhat bitter-tasting appetite suppressant, and is presumed to be produced by plants as a defense chemical to discourage predation.

Coumarin is used in certain perfumes and fabric conditioners. Coumarin has been used as an aroma enhancer in pipe tobaccos and certain alcoholic drinks, although in general it is banned as a flavorant food additive, due to concerns regarding its hepatotoxicity in animal models.

Coumarin was first synthesized in 1868. It is used in the pharmaceutical industry as a precursor reagent in the synthesis of a number of synthetic anticoagulant pharmaceuticals similar to dicoumarol, the notable ones being warfarin (brand name Coumadin) and some even more potent rodenticides that work by the same anticoagulant mechanism. 4-hydroxycoumarins are a type of vitamin K antagonist. Pharmaceutical (modified) coumarins were all developed from the study of sweet clover disease; see warfarin for this history. However, unmodified coumarin itself, as it occurs in plants, has no effect on the vitamin K coagulation system, or on the action of warfarin-type drugs.

Coumarin has clinical medical value by itself, as an edema modifier. Coumarin and other benzopyrones, such as 5,6-benzopyrone, 1,2-benzopyrone, diosmin, and others, are known to stimulate macrophages to degrade extracellular albumin, allowing faster resorption of edematous fluids.[1][2] Other biological activities that may lead to other medical uses have been suggested, with varying degrees of evidence.

Coumarin is also used as a gain medium in some dye lasers,[3][4][5] and as a sensitizer in older photovoltaic technologies.[6]

History

The word "Tonka" for tonka beans is taken from the Galibi (Carib) tongue spoken by natives of French Guiana (one source for the plant); it also appears in Tupi, another language of the same region, as the name of the tree. The old genus name, Coumarouna, was formed from another Tupi name for tree, kumarú. The French word for Tonka bean, coumarou, is from this name.

Coumarin, named for coumarou was first isolated from Tonka beans and sweet clover in 1820 by A. Vogel of Munich, who initially mistook it for benzoic acid.[7] Also in 1820, Nicholas Jean Baptiste Gaston Guibourt (1790-1867) of France independently isolated coumarin, but he realized that it was not benzoic acid.[8] In a subsequent essay he presented to the pharmacy section of l'Académie royale de Médecine, Guibourt named the new substance "coumarine".[9] In 1835, the French pharmacist A. Guillemette proved that Vogel and Guibourt had isolated the same substance.[10] Coumarin was first synthesized in 1868 by the English chemist William Henry Perkin.[11]

Synthesis

Coumarin can be prepared by a number of name reactions with the Perkin reaction between salicylaldehyde and acetic anhydride being a popular example. The Pechmann condensation provides another route to coumarin and its derivatives; as does the Kostanecki acylation which can also be used to produce chromones.

Natural occurrences

Coumarin is found naturally in many plants, notably in high concentration in the tonka bean (Dipteryx odorata), vanilla grass (Anthoxanthum odoratum), sweet woodruff (Galium odoratum), mullein (Verbascum spp.), sweet grass (Hierochloe odorata), cassia cinnamon (Cinnamomum cassia) not to be confused with true cinnamon ("Ceylon cinnamon", Cinnamomum zeylanicum which contains little coumarin),[12] sweet-clover (Melilotus ssp.), deertongue (Dichanthelium clandestinum), and the leaves of many cherry blossom tree varieties (of the Prunus genus). Coumarin is also found in extracts of Justicia pectoralis.[13][14]

Related compounds are found in some but not all specimens of licorice.[15]

Metabolism

The biosynthesis of coumarin in plants is via hydroxylation, glycolysis, and cyclization of cinnamic acid.

Metabolism in humans

The enzyme encoded by the gene UGT1A8 has glucuronidase activity with many substrates including coumarins.[16]

Biological function

Coumarin has appetite-suppressing properties, which may discourage animals from eating plants which contain it. Though the compound has a pleasant sweet odor, it has a bitter taste, and animals tend to avoid it.[17]

Derivatives

Coumarin and its derivatives are all considered phenylpropanoids.

Some naturally occurring coumarin derivatives include umbelliferone (7-hydroxycoumarin), aesculetin (6,7-dihydroxycoumarin), herniarin (7-methoxycoumarin), psoralen and imperatorin.

4-Phenylcoumarin is the backbone of the neoflavones, a type of neoflavonoids.

Medical use

Coumarins have shown some evidence of biological activity, but they are approved for few medical uses as pharmaceuticals. It is used in the treatment of asthma[18] and lymphedema.[19] Coumarin therapy is found to increase the plasma anti-thrombin levels. Both Coumarin and indandione derivatives produce a uricosuric effect, by interfering with the renal tubular reabsorption of urate.

Laser applications

Coumarin dyes are extensively used as gain media in blue-green tunable organic dye lasers.[3][4][5] Among the various coumarin laser dyes are the coumarin 480, 490, 504, 521, 504T, and 521T.[5] Coumarin tetramethyl laser dyes offer wide tunability and high laser gain,[20][21] and they are also used as active medium in coherent OLED emitters.[22]

Toxicity and use in foods, beverages, cosmetics, and tobacco

Coumarin is moderately toxic to the liver and kidneys, with a median lethal dose (LD50) of 275 mg/kg, a low toxicity compared to related compounds. Though it is only somewhat dangerous to humans, coumarin is hepatotoxic in rats, but less so in mice. Rodents metabolize it mostly to 3,4-coumarin epoxide, a toxic, unstable compound that on further differential metabolism may cause liver cancer in rats and lung tumors in mice.[23][24] Humans metabolize it mainly to 7-hydroxycoumarin, a compound of lower toxicity. The German Federal Institute for Risk Assessment has established a tolerable daily intake (TDI) of 0.1 mg coumarin per kg body weight, but also advises that higher intake for a short time is not dangerous.[25] The Occupational Safety and Health Administration (OSHA) of the United States does not classify coumarin as a carcinogen for humans.[26]

European health agencies have warned against consuming high amounts of cassia bark, one of the four main species of cinnamon, because of its coumarin content.[27][28] According to the German Federal Institute for Risk Assessment (BFR), 1 kg of (cassia) cinnamon powder contains about 2.1 to 4.4 g of coumarin.[29] Powdered cassia cinnamon weighs 0.56 g/cm3,[30] so a kilogram of cassia cinnamon powder equals 362.29 teaspoons. One teaspoon of cassia cinnamon powder therefore contains 5.8 to 12.1 mg of coumarin, which may be above the tolerable daily intake value for smaller individuals.[29] However, the BFR only cautions against high daily intake of foods containing coumarin. Its report[29] specifically states that Ceylon cinnamon (Cinnamomum verum) contains "hardly any" coumarin.

The European Regulation (EC) No 1334/2008 describes the following maximum limits for coumarin: 50 mg/kg in traditional and/or seasonal bakery ware containing a reference to cinnamon in the labeling, 20 mg/kg in breakfast cereals including muesli, 15 mg/kg in fine bakery ware, with the exception of traditional and/or seasonal bakery ware containing a reference to cinnamon in the labeling, and 5 mg/kg in desserts. An investigation from the Danish Veterinary and Food Administration in 2013 shows that bakery goods characterized as fine bakery ware exceeds the European limit (15 mg/kg) in almost 50% of the cases.[31] The paper also mentions tea as an additional important contributor to the overall coumarin intake, especially for children with a sweet habit.

Coumarin is found naturally in many edible plants such as strawberries, black currants, apricots, and cherries.[32]

Coumarin is often found in artificial vanilla substitutes, despite having been banned as a food additive in numerous countries since the mid-20th century. Coumarin was banned as a food additive in the United States in 1954, largely because of the hepatotoxicity results in rodents.[33] Coumarin is currently listed by the Food and Drug Administration (FDA) of the United States among "Substances Generally Prohibited From Direct Addition or Use as Human Food", according to 21 CFR 189.130,[34][35] but some natural additives containing coumarin, such as the flavorant sweet woodruff are allowed "in alcoholic beverages only" (21 CFR 172.510).[36] In Europe, popular examples of such beverages are Maiwein (white wine with woodruff) and Żubrówka (vodka flavoured with bison grass).

Coumarin is subject to restrictions on its use in perfumery,[37] as some people may become sensitized to it, however the evidence that coumarin can cause an allergic reaction in humans is disputed.[38]

Minor neurological dysfunction was found in children exposed to coumarin during pregnancy. 306 children were tested at ages 7–15 years to determine subtle neurological effects from coumarin exposure. Results showed a dose response relationship between coumarin exposure and minor neurological dysfunction. Overall, a 1.9 (90%) increase in minor neurological dysfunction was observed for children exposed to coumarin. In conclusion, researchers stated, "The results suggest that coumarins have an influence on the development of the brain which can lead to mild neurologic dysfunctions in children of school age."[39]

Coumarin is still used as a legal flavorant in the tobacco industry, particularly for sweet pipe tobacco. Its presence in cigarette tobacco led former Brown & Williamson executive[40] Jeffrey Wigand to contact CBS's news show 60 Minutes in 1995, charging a “form of rat poison” was in the tobacco. He held that from a chemist’s point of view, coumarin is an “immediate precursor” to the rodenticide coumadin. Dr. Wigand later stated that coumarin itself is dangerous, pointing out that the FDA had banned its addition to human food in 1954.[41] Under his later testimony he would repeatedly classify coumarin as a "lung-specific carcinogen".[42] In Germany, coumarin is banned as additive in tobacco.

Alcoholic beverages sold in the European Union are limited to a maximum of 10 mg/l coumarin by law.[43] Cinnamon flavor is generally cassia bark steam-distilled to concentrate the cinnamaldehyde, for example, to about 93%. Clear cinnamon-flavored alcoholic beverages generally test negative for coumarin, but if whole cassia bark is used to make mulled wine, then coumarin shows up in significant levels.

Related compounds and derivatives

Main article: 4-Hydroxycoumarins

Compounds derived from coumarin are also called coumarins or coumarinoids; this family includes:

Although coumarin itself has no anticoagulant properties, it is transformed into the natural anticoagulant dicoumarol by a number of species of fungi. This occurs as the result of the production of 4-hydroxycoumarin, then further (in the presence of naturally occurring formaldehyde) into the actual anticoagulant dicoumarol, a fermentation product and mycotoxin. Dicoumarol substance was responsible for the bleeding disease known historically as "sweet clover disease" in cattle eating moldy sweet clover silage.[50] Coumarin has anti-tumor activity[51] and anti-fungal properties.[52]

Use as pesticides

Many of the above-stated compounds (to be specific, the 4-hydroxycoumarins, sometimes loosely called coumarins) are used as anticoagulant drugs and/or as rodenticides, which work by the anticoagulant mechanism. They block the regeneration and recycling of vitamin K. These chemicals are sometimes also incorrectly referred to as "coumadins" rather than 4-hydroxycoumarins. Coumadin is a brand name for the drug warfarin.

Some of the 4-hydroxycoumarin anticoagulant class of chemicals are designed to have very high potency and long residence times in the body, and these are used specifically as poison rodenticides. Death occurs after a period of several days to two weeks, usually from internal hemorrhaging.

Vitamin K is a true antidote for poisoning by these antirodenticide 4-hydroxycoumarins such as bromadiolone. Treatment usually comprises a large dose of vitamin K given intravenously immediately, followed by doses in pill form for a period of at least two weeks, though usually three to four, afterwards. Treatment may even continue for several months. If caught early, the prognosis is good, even when large amounts are ingested. In the short term, transfusion with fresh frozen plasma to provide clotting factors, provides time for vitamin K to reverse enzyme poisoning in the liver, and allow new clotting factors to be synthesized there.

References

  1. ↑ Casley-Smith, J. R.; et al. (1993). "Treatment of lymphedema of the arms and legs with 5,6-benzo-(alpha)-pyrone". NEJM. 329 (16): 1158–63. doi:10.1056/nejm199310143291604.
  2. ↑ Review of benzypyrone drugs and edema. Lymphoedema.org
  3. 1 2 Schäfer, F. P. (Ed.). Dye Lasers, 3rd Ed. Berlin, Springer-Verlag. 1990.
  4. 1 2 Duarte, F. J. and L. W. Hillman (Eds.). Dye Laser Principles. New York, Academic. 1990.
  5. 1 2 3 Duarte, F. J. Tunable Laser Optics. New York, Elsevier-Academic. 2003. Appendix of Laser Dyes.
  6. ↑ U.S. Pat. No. 4175982 to Loutfy et al., issued Nov 27 1978 to Xerox Corp.
  7. ↑ See:
    • Vogel, A (1820). "Darstellung von Benzoesäure aus der Tonka-Bohne und aus den Meliloten - oder Steinklee - Blumen (Preparation of benzoic acid from tonka beans and from the flowers of melilot or sweet clover)". Annalen der Physik. 64 (2): 161–66. doi:10.1002/andp.18200640205.
    • Vogel, A. (1820). De l'existence de l'acide bezoïque dans la feve de tonka et dans les fleurs de mélilot (On the existence of benzoic acid in the tonka bean and in the flowers of melilot). Journal de Pharmacie 6 305-09. pages 307-08.
  8. ↑ Guibourt, N. J. B. G. Histoire Abrégée des Droques Simples (Abridged History of Simple Drugs). Volume 2. Paris, L. Colas. 1820. pages 160-161.
  9. ↑ See:
    • Journal de Chimie Médicale, de Pharmacie et de Toxicologie, 1 : 303 (1825): "… plus récemment, dans un essai de nomenclature chimique, lu à la section of Pharmacie de l'Académie royale de Médecine, il l'a désignée sous le nom de coumarine, tiré du nom du végétal coumarouna odorata …" (… more recently, in an essay on chemical nomenclature, [which was] read to the pharmacy section of the Royal Academy of Medicine, he [Guibourt] designated it by the name "coumarine", derived from the name of the vegetable Coumarouna odorata …).
    • Guibourt, N. J. B. G. Histoire Naturelle des Drogues Simples, ... , 6th ed. Paris, J. B. Baillière et fils. 1869. bottom of page 377: "… la matière cristalline de la fève tonka (matière que j'ai nommée coumarine) …" (… the crystaline matter of the tonka bean (matter that I named coumarine …).
  10. ↑ Guillemette, A (1835). "Recherches sur la matière cristalline du mélilot" [Research into the crystalline material of melilot]. Journal de Pharmacie. 21: 172–78.
  11. ↑ Perkin, W. H. (1868). "On the artificial production of coumarin and formation of its homologues". Journal of the Chemical Society. 21: 53–63. doi:10.1039/js8682100053.
  12. ↑ What is the difference between cinnamon and cassia? http://www.whfoods.com/genpage.php?tname=newtip&dbid=31
  13. ↑ Leal, L. K. A. M.; A. A. G. Ferreira; G. A. Bezerra; F. J. A. Matos; G. S. B. Viana (May 2000). "Antinociceptive, anti-inflammatory and bronchodilator activities of Brazilian medicinal plants containing coumarin: a comparative study". Journal of Ethnopharmacology. 70 (2): 151–159. doi:10.1016/S0378-8741(99)00165-8. ISSN 0378-8741. PMID 10771205. Retrieved 2010-06-26.
  14. ↑ Lino, C. S.; M. L. Taveira; G. S. B. Viana; F. J. A. Matos (1997). "Analgesic and antiinflammatory activities of Justicia pectoralis Jacq and its main constituents: coumarin and umbelliferone". Phytotherapy Research. 11 (3): 211–215. doi:10.1002/(SICI)1099-1573(199705)11:3<211::AID-PTR72>3.0.CO;2-W. Retrieved 2010-06-26.
  15. ↑ Hatano T; et al. (1991). "[Phenolic constituents of licorice. IV. Correlation of phenolic constituents and licorice specimens from various sources, and inhibitory effects of... - PubMed - NCBI". Yakugaku Zasshi. 111: 311–21. PMID 1941536.
  16. ↑ Ritter, J. K.; et al. (Mar 1992). "A novel complex locus UGT1 encodes human bilirubin, phenol, and other UDP-glucuronosyltransferase isozymes with identical carboxyl termini". J Biol Chem. 267 (5): 3257–61. PMID 1339448.
  17. ↑ Link, K. P. (1 January 1959). "The discovery of dicumarol and its sequels". Circulation. 19 (1): 97–107. doi:10.1161/01.CIR.19.1.97. PMID 13619027.
  18. ↑ Liu, H. Extraction and Isolation of Compounds from Herbal Medicines. In: Willow, J. and H. Liu (Eds.) Traditional Herbal Medicine Research Methods. John Wiley and Sons, Inc. 2011.
  19. ↑ Farinola, N.; Piller, N. (June 1, 2005). "Pharmacogenomics: Its role in re-establishing coumarin as treatment for lymphedema". Lymphatic Research and Biology. 3 (2): 81–86. doi:10.1089/lrb.2005.3.81. PMID 16000056.
  20. ↑ Chen, C. H., Fox, J. L., Duarte, F. J., Lasing characteristics of new-coumarin-analog dyes: broadband and narrow-linewidth performance, Appl. Opt. 27, 443-445 (1988).
  21. ↑ Duarte, F. J., Liao, L. S., Vaeth, K. M., and Miller, A. M., Widely tunable laser emission using the coumarin 545 tetramethyl dye as gain medium, J. Opt. A: Pure Appl. Opt. 8, 172-174 (2006).
  22. ↑ Duarte, F. J., Liao, L. S., and Vaeth, K. M., Coherence characteristics of electrically excited tandem organic light-emitting diodes, Opt. Lett. 30, 3072–3074 (2005).
  23. ↑ Vassallo, J. D.; et al. (2004). "Metabolic detoxification determines species differences in coumarin-induced hepatotoxicity". Toxicological Sciences. 80 (2): 249–57. doi:10.1093/toxsci/kfh162. PMID 15141102.
  24. ↑ Born, S. L.; et al. (2003). "Comparative metabolism and kinetics of coumarin in mice and rats". Food and chemical toxicology. 41 (2): 247–58. doi:10.1016/s0278-6915(02)00227-2. PMID 12480300.
  25. ↑ "Frequently Asked Questions about coumarin in cinnamon and other foods" (PDF). The German Federal Institute for Risk Assessment. 30 October 2006.
  26. ↑ "Chemical Sampling Information - Coumarin". Retrieved 30 December 2015.
  27. ↑ "Cassia cinnamon with high coumarin contents to be consumed in moderation - BfR". Retrieved 30 December 2015.
  28. ↑ "German Christmas Cookies Pose Health Danger". NPR.org. 25 December 2006. Retrieved 30 December 2015.
  29. 1 2 3 High daily intakes of cinnamon: Health risk cannot be ruled out. BfR Health Assessment No. 044/2006, 18 August 2006
  30. ↑ Engineering Resources - Bulk Density Chart
  31. ↑ Ballin, Nicolai Z.; Ann T. Sørensen. "Coumarin content in cinnamon containing food products on the Danish market". Food Control. 38 (2014): 198–203. doi:10.1016/j.foodcont.2013.10.014.
  32. ↑ Pubchem. "coumarin". Retrieved 30 December 2015.
  33. ↑ Marles, R. J.; et al. (1986). "Coumarin in vanilla extracts: Its detection and significance". Economic Botany. 41 (1): 41–47. doi:10.1007/BF02859345.
  34. ↑ "Food and Drugs". Retrieved 30 December 2015.
  35. ↑ http://www.cfsan.fda.gov/~dms/eafus.html
  36. ↑ "Food and Drugs". Retrieved 30 December 2015.
  37. ↑ http://www.ifraorg.org/en-us/standards_restricted/s3/p3
  38. ↑ http://www.leffingwell.com/Cropwatch%20Claims%20Victory%20Over%2026%20Allergens.pdf
  39. ↑ Wessling, J (2001). "Neurological outcome in school-age children after in utero exposure to coumarins". Early Human Development. 63 (2): 83–95. doi:10.1016/S0378-3782(01)00140-2.
  40. ↑ "Jeffrey Wigand : Jeffrey Wigand on 60 Minutes". Retrieved 30 December 2015.
  41. ↑ "Tobacco On Trial". Retrieved 30 December 2015.
  42. ↑ http://legacy.library.ucsf.edu/tid/tnt32e00
  43. ↑ "Thieme E-Journals - Planta Medica / Abstract". Retrieved 30 December 2015.
  44. ↑ International Programme on Chemical Safety. "Brodifacoum (pesticide data sheet)". Archived from the original on 2006-12-09. Retrieved 2006-12-14.
  45. ↑ Laposata M, Van Cott EM, Lev MH (2007). "Case 1-2007—A 40-Year-Old Woman with Epistaxis, Hematemesis, and Altered Mental Status". 356 (2): 174–82.
  46. ↑ International Programme on Chemical Safety. "Bromadiolone (pesticide data sheet)". Archived from the original on 2006-12-21. Retrieved 2006-12-14.
  47. ↑ Compendium of Pesticide Common Names. "Coumafuryl data sheet". Retrieved 2007-08-17.
  48. ↑ International Programme on Chemical Safety. "Difenacoum (health and safety guide)". Retrieved 2006-12-14.
  49. ↑ Syah, Y. M.; et al. (2009). "A modified oligostilbenoid, diptoindonesin C, from Shorea pinanga Scheff". Natural Product Research. 23 (7): 591–4. doi:10.1080/14786410600761235. PMID 19401910.
  50. ↑ Bye, A.; King, H. K. (1970). "The biosynthesis of 4-hydroxycoumarin and dicoumarol by Aspergillus fumigatus Fresenius". Biochemical Journal. 117: 237–45. doi:10.1042/bj1170237.
  51. ↑ Weber, U. S.; Steffen, B; Siegers, C. P. (1998). "Antitumor-activities of coumarin, 7-hydroxy-coumarin and its glucuronide in several human tumor cell lines". Research communications in molecular pathology and pharmacology. 99 (2): 193–206. PMID 9583093.
  52. ↑ Montagner, C; De Souza, S. M.; Groposoa, C; Delle Monache, F; Smânia, E. F.; Smânia Jr, A (2008). "Antifungal activity of coumarins". Zeitschrift für Naturforschung C. 63 (1-2): 21–8. doi:10.1515/znc-2008-1-205. PMID 18386483.

External links

This article is issued from Wikipedia - version of the 12/1/2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.