| Revision as of 23:55, 31 January 2011 editMojo Hand (talk | contribs)Administrators89,848 edits Add hatnote to distinguish saccharine, as this seems to be ongoing point of confusion← Previous edit |
Latest revision as of 03:53, 26 December 2024 edit undoEsperfulmo (talk | contribs)Extended confirmed users19,188 edits →Safety and health effects: deleted a fabricated claim with a low quality reference that didn't even mention saccharin as a potential allerginTags: Mobile edit Mobile web edit Advanced mobile edit |
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|Reference=<ref>''Merck Index'', 11th Edition, '''8282'''.</ref> |
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| Reference = <ref name="pubchem">{{Cite web|date=13 June 2023|title=Saccharin|url=https://pubchem.ncbi.nlm.nih.gov/compound/5143|access-date=15 June 2023|publisher=PubChem, US National Library of Medicine}}</ref><ref name="Merck Millipore">{{Cite web |title=Saccharin (CAS: 81-07-2)|url=https://www.merckmillipore.com/IN/en/product/Saccharin,MDA_CHEM-820128|date=2023|access-date=August 22, 2022|publisher=]}}</ref> |
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|ImageFile=Saccharin-2D-skeletal.png |
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| ImageFile = Saccharin.svg |
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| ImageSize = 170px |
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|ImageFile1=Saccharin-from-xtal-3D-balls.png |
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| ImageClass = skin-invert |
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| ImageFile1 = Saccharin-from-xtal-3D-balls.png |
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|IUPACName=1,1-Dioxo-1,2-benzothiazol-3-one |
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| ImageSize1 = 170px |
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|OtherNames= Benzoic sulfimide<br> |
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| PIN = 1''H''-1λ<sup>6</sup>,2-Benzothiazole-1,1,3(2''H'')-trione |
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Ortho sulphobenzamide<br> |
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| OtherNames = {{Unbulleted list|ortho-benzoic sulfimide|ortho sulphobenzimide}}<ref>{{cite book | title = NCERT Chemistry Part II Textbook for Class XII | publisher = ] | date = 2021 | location = Delhi | page = 449 | isbn = 978-81-7450-716-7}}</ref> |
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|Section1= {{Chembox Identifiers |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| IUPHAR_ligand = 5432 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 4959 |
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| ChemSpiderID = 4959 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| StdInChIKey = CVHZOJJKTDOEJC-UHFFFAOYSA-N |
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| StdInChIKey = CVHZOJJKTDOEJC-UHFFFAOYSA-N |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| CASNo=81-07-2 |
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| CASNo =81-07-2 |
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| PubChem=5143 |
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| PubChem =5143 |
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| ChEBI_Ref = {{ebicite|changed|EBI}} |
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| SMILES = O=C2c1ccccc1S(=O)(=O)N2 |
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| ChEBI = 32111 |
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| SMILES = O=C2c1ccccc1S(=O)(=O)N2 |
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| C = 7 | H = 5 | N = 1 | O = 3 | S = 1 |
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| C=7 | H=5 | N=1 | O=3 | S=1 |
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| Appearance =White crystalline solid |
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| MolarMass=183.1845 |
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| Density =0.828 g/cm<sup>3</sup> |
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| Appearance=White crystalline solid |
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| MeltingPtC = 228.8 to 229.7 |
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| Density=0.828 g/cm<sup>3</sup> |
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| MeltingPt=228.8-229.7 °C |
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| Solubility=1 g per 290 mL |
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| Solubility =1 g per 290 mL |
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| pKa = 1.6<ref name="BellHigginson"/> |
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|Section3= {{Chembox Hazards |
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'''Saccharin''', also called '''saccharine''', '''benzosulfimide''', or '''E954''', or used in saccharin sodium or saccharin calcium forms, is a non-nutritive ].<ref name="pubchem" /><ref name="drugs">{{cite web|url=https://www.drugs.com/inactive/saccharin-172.html|title = Saccharin |website=Drugs.com |date=16 August 2022|accessdate=15 June 2023}}</ref> Saccharin is a ] that is about 500 times sweeter than ], but has a bitter or metallic ], especially at high concentrations.<ref name="pubchem" /> It is used to sweeten products, such as ]s, ], ]s, ] products, ]s, and for masking the bitter taste of some ]s.<ref name="pubchem" /><ref name="drugs" /> It appears as white crystals and is odorless.<ref name="pubchem" /> |
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'''Saccharin'''<ref>The word '''saccharin''' (as above) has no final "e". The word '''saccharine''', with a final "e", is much older and is an adjective meaning "sugary" – its connection with sugar means the term is used ]ically, often in a derogative sense, to describe something "unpleasantly over-polite" or "overly sweet". Both words are derived from the ] word ''σάκχαρον'' (''sakcharon'', German "ch" sound), which ultimately derives from ] for ], ''sharkara'' (शर्करा), which literally means "gravel" </ref> is an ]. The basic substance, benzoic ], has effectively no ] and is much sweeter than ], but has an unpleasant bitter or metallic ], especially at high concentrations. It is used to sweeten products such as drinks, candies, biscuits, medicines, and toothpaste. |
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==Etymology== |
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Saccharin derives its name from the word "saccharine", meaning "sugary". The word saccharine is used figuratively, often in a derogative sense, to describe something "unpleasantly over-polite" or "overly sweet".<ref>{{cite web |url=https://dictionary.reference.com/browse/saccharine |title=Saccharine |website=Reference.com |url-status=live |archive-url=https://web.archive.org/web/20070303203138/https://dictionary.reference.com/browse/saccharine |archive-date=2007-03-03 }}</ref> Both words are derived from the ] word {{lang|grc|σάκχαρον}} (''sakkharon'') meaning "gravel".<ref>{{cite web | url = https://www.etymonline.com/index.php?term=saccharine | title = Saccharine |website= etymonline.com | url-status=live | archive-url = https://web.archive.org/web/20060323232123/https://www.etymonline.com/index.php?term=saccharine | archive-date = 2006-03-23 }}</ref> Similarly, saccharose is an obsolete name for ] (table sugar). |
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==Properties== |
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==Properties== |
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] |
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Saccharin is unstable when heated but it does not react chemically with other food ingredients. As such, it stores well. Blends of saccharin with other sweeteners are often used to compensate for each sweetener's weaknesses and faults. A 10:1 ]:saccharin blend is common in countries where both these sweeteners are legal; in this blend, each sweetener masks the other's off-taste. Saccharin is often used together with ] in diet soda, so that some sweetness remains should the fountain syrup be stored beyond aspartame's relatively short shelf life. Saccharin is believed to be an important discovery, especially for ], as it goes directly through the human ] without being digested. Although saccharin has no ], it can trigger the release of ] in humans and rats, apparently as a result of its taste,<ref>{{cite journal |
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| unused_data=DUPLICATE DATA: pmid = 18556090 |
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Saccharin is heat-stable.<ref>{{cite web |url=https://projects.ncsu.edu/project/sweeteners/sweetener_comparisons.html |title=Sweetener Comparisons |publisher=NCSU |website=Food Ingredient Series |date=2006 |archive-url=https://web.archive.org/web/20190120000626/https://projects.ncsu.edu/project/sweeteners/sweetener_comparisons.html |archive-date=2019-01-20}}</ref> It does not react chemically with other food ingredients; as such, it stores well. Blends of saccharin with other sweeteners are often used to compensate for each sweetener's weaknesses and faults. A 10:1 ]–saccharin blend is common in countries where both these sweeteners are legal; in this blend, each sweetener masks the other's offtaste. Saccharin is often used with ] in diet ], so some sweetness remains should the fountain syrup be stored beyond aspartame's relatively short shelf life. |
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| pmid=18556090 |
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| title= Cephalic phase insulin release in healthy humans after taste stimulation? |
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| author = Just T, Pau HW, Engel U, Hummel T |
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| journal = Appetite |
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| volume = 238 |
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| date = November 10, 2008 |
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| pages = 622–7 |
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| issue = 4 |
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| doi = 10.1016/j.appet.2008.04.271 |
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}}</ref><ref>{{cite journal |
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| title= Taste-induced changes in plasma insulin and glucose turnover in lean and genetically obese rats |
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| doi= 10.2337/diabetes.37.6.773 |
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| author= E Ionescu, F Rohner-Jeanrenaud, J Proietto, RW Rivest and B Jeanrenaud |
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| journal=Diabetes |
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| volume=37 |
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| year= 1988 |
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| pmid = 3289998 |
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| pages = 773–9 |
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| issue= 6 |
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}}</ref><ref>{{cite journal |
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| url = http://ajpendo.physiology.org/cgi/content/abstract/238/4/E336 |
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| title= Cephalic-phase insulin secretion in normal and pancreatic islet-transplanted rats |
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| author = H. R. Berthoud, E. R. Trimble, E. G. Siegel, D. A. Bereiter and B. Jeanrenaud |
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| journal = American Journal of Physiology-Endocrinology and Metabolism |
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| volume = 238 |
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| date = April 1, 1980 | pmid = 6769337 |
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| pages = E336–40 |
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| issue = 4 |
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}}</ref> as can other sweeteners like aspartame.<ref>{{cite journal |author=Ferland A, Brassard P, Poirier P |title=Is aspartame really safer in reducing the risk of hypoglycemia during exercise in patients with type 2 diabetes? |journal=Diabetes Care |volume=30 |issue=7 |pages=e59 |year=2007 |month=July |pmid=17596482 |doi=10.2337/dc06-1888 |url=http://care.diabetesjournals.org/content/30/7/e59.long }}</ref> |
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In its acid form, saccharin is not water-soluble. The form used as an artificial sweetener is usually its ] ]. The ] salt is also sometimes used, especially by people restricting their dietary sodium intake. Both salts are highly water-soluble: 0.67 grams per milliliter water at room temperature.<ref>{{cite journal | author = Remsen, I. and Fahlberg, C., | title =Über die Oxydation des Orthotoluolsulfamids| journal = Chemische Berichte | year = 1879| volume = 12| pages= 469–473|url = http://gallica.bnf.fr/ark:/12148/bpt6k90688q/f519.chemindefer }}</ref><ref>{{cite journal |author = P. M. Priebem, G. B. Kauffman | title =Making governmental policy under conditions of scientific uncertainty: A century of controversy about saccharin in congress and the laboratory | journal = Minerva| volume = 18| issue = 4 |pages = 556–574| year = 1980 | doi = 10.1007/BF01096124 |pmid = 11611011}}</ref> |
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In its acid form, saccharin is not water-soluble. The form used as an artificial sweetener is usually its ] ].<ref>{{cite journal | vauthors = Chattopadhyay S, Raychaudhuri U, Chakraborty R | title = Artificial sweeteners - a review | journal = Journal of Food Science and Technology | volume = 51 | issue = 4 | pages = 611–21 | date = April 2014 | pmid = 24741154 | pmc = 3982014 | doi = 10.1007/s13197-011-0571-1 }}</ref> The ] salt is also sometimes used, especially by people restricting their ] intake. Both salts are highly water-soluble: 0.67 g/ml in water at room temperature.<ref name="Fahlberg">{{cite journal| vauthors = Fahlberg C, Remsen I | title = Über die Oxydation des Orthotoluolsulfamids |trans-title=On the oxidation of orthotoluenesulphamide| journal = Berichte der Deutschen Chemischen Gesellschaft zu Berlin|date= 1879| volume = 12| pages = 469–473| url = https://gallica.bnf.fr/ark:/12148/bpt6k90688q/f519.chemindefer| doi = 10.1002/cber.187901201135| url-status=live| archive-url = https://web.archive.org/web/20130513081829/https://gallica.bnf.fr/ark:/12148/bpt6k90688q/f519.chemindefer| archive-date = 2013-05-13}}</ref><ref name = "Priebem">{{cite journal | vauthors = Priebe PM, Kauffman GB | title = Making governmental policy under conditions of scientific uncertainty: a century of controversy about saccharin in Congress and the laboratory | journal = Minerva | volume = 18 | issue = 4 | pages = 556–74 |date= 1980 | pmid = 11611011 | doi = 10.1007/BF01096124 | s2cid = 40526005 }}</ref> |
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==Safety and health effects== |
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In the 1970s, studies performed on laboratory rats found an association between consumption of high doses of saccharin and the development of ].<ref name=NCI>{{cite web | url = https://www.cancer.gov/about-cancer/causes-prevention/risk/diet/artificial-sweeteners-fact-sheet | title = Artificial Sweeteners and Cancer | publisher = ] | url-status=live | archive-url = https://web.archive.org/web/20151208135059/https://www.cancer.gov/about-cancer/causes-prevention/risk/diet/artificial-sweeteners-fact-sheet | archive-date = 2015-12-08 | date = 2005-08-18 }}</ref> However, further study determined that this effect was due to a mechanism that is not relevant to humans (deposition of crystals; see {{Section link|#History}} section).<ref name=NCI/> ] studies have shown no evidence that saccharin is associated with bladder cancer in humans.<ref name=NCI/><ref>{{cite journal | vauthors = Weihrauch MR, Diehl V | title = Artificial sweeteners--do they bear a carcinogenic risk? | journal = Annals of Oncology | volume = 15 | issue = 10 | pages = 1460–5 | date = October 2004 | pmid = 15367404 | doi = 10.1093/annonc/mdh256 | doi-access = free }}</ref> The ] (IARC) originally classified saccharin in ] ("possibly carcinogenic to humans") based on the rat studies, but downgraded it to ] ("not classifiable as to the carcinogenicity to humans") upon review of the subsequent research.<ref>{{cite web | url = https://enhs.umn.edu/current/saccharin/fda.html | title = Saccharin: FDA Agencies | publisher = ], Environmental Health Sciences | url-status=live | archive-url = https://web.archive.org/web/20160227162124/https://enhs.umn.edu/current/saccharin/fda.html | archive-date = 2016-02-27 }}</ref> |
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Saccharin has no ] and no nutritional value.<ref>{{cite web | url = https://www.diabetes.org/diabetes-basics/common-terms/common-terms-s-z.html | title = Common Terms: S–Z | publisher = ] | url-status=live | archive-url = https://web.archive.org/web/20151128211136/https://www.diabetes.org/diabetes-basics/common-terms/common-terms-s-z.html | archive-date = 2015-11-28 }}</ref> It is safe to consume for individuals with ] or ].<ref>{{cite web | url = https://journal.diabetes.org/diabetesspectrum/99v12n4/pg250.asp | title = Low-Calorie Sweeteners: What's News, What's New | publisher = ] | url-status=live | archive-url = https://web.archive.org/web/20160304043724/https://journal.diabetes.org/diabetesspectrum/99v12n4/pg250.asp | archive-date = 2016-03-04 }}</ref><ref>{{cite web | url = https://health.clevelandclinic.org/2015/06/are-artificial-sweeteners-safe-for-people-with-diabetes/ | title = Are Artificial Sweeteners Safe for People With Diabetes? | publisher = ] | url-status=live | archive-url = https://web.archive.org/web/20161002053142/https://health.clevelandclinic.org/2015/06/are-artificial-sweeteners-safe-for-people-with-diabetes/ | archive-date = 2016-10-02 | date = 2015-06-29 }}</ref> |
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People with sulfonamide allergies can experience allergic reactions to saccharin, although it has been suggested that this may be due to a general predisposition to allergic reactions rather than a specific cross-reaction between antimicrobial sulfonamides and non-antimicrobial ones (like saccharin).<ref>{{cite journal|doi=10.1056/nejmoa022963 |title=Absence of Cross-Reactivity between Sulfonamide Antibiotics and Sulfonamide Nonantibiotics |date=2003 |last1=Strom |first1=Brian L. |last2=Schinnar |first2=Rita |last3=Apter |first3=Andrea J. |last4=Margolis |first4=David J. |last5=Lautenbach |first5=Ebbing |last6=Hennessy |first6=Sean |last7=Bilker |first7=Warren B. |last8=Pettitt |first8=Dan |journal=New England Journal of Medicine |volume=349 |issue=17 |pages=1628–1635 |pmid=14573734 |doi-access=free }}</ref><ref>{{cite journal|doi=10.3390/pharmacy7030132 |doi-access=free |title=Sulfonamide Allergies |date=2019 |last1=Giles |first1=Amber |last2=Foushee |first2=Jaime |last3=Lantz |first3=Evan |last4=Gumina |first4=Giuseppe |journal=Pharmacy |volume=7 |issue=3 |page=132 |pmid=31514363 |pmc=6789825 }}</ref> |
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==History== |
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==History== |
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Saccharin was first produced in 1878 by ], a chemist working on coal tar derivatives in ]'s laboratory at the ]. The sweet taste of saccharin was discovered when Fahlberg noticed a sweet taste on his hand one evening, and connected this with the compound which he had been working on that day<ref name="isbn0-313-33758-6">{{cite book |author=Myers, Rusty L.; Myers, Richard L. |title=The 100 most important chemical compounds: a reference guide |publisher=Greenwood Press |location=Westport, Conn |year=2007 |pages=241 |isbn=0-313-33758-6 |oclc= |doi= |accessdate=}}</ref>. Fahlberg and Remsen published articles on benzoic sulfimide in 1879 and 1880. In 1884, now working on his own in New York City, Fahlberg applied for patents in several countries describing methods of producing this substance that he named saccharin. Fahlberg would soon grow wealthy, while Remsen merely grew irate, believing that he deserved credit for substances produced in his laboratory. On the matter, Remsen commented, "Fahlberg is a scoundrel. It nauseates me to hear my name mentioned in the same breath with him." |
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Saccharin was produced first in 1879, by ], a chemist working on ] derivatives in ]'s laboratory at ].<ref>(As discussed below, the relative contributions of Fahlberg and Remsen to the discovery were later contested, with no final resolution in sight; the 1879 paper announcing the discovery lists both names as authors, with Fahlberg's name first.)</ref> Fahlberg noticed a ] on his hand one evening, and connected this with the compound benzoic sulfimide on which he had been working that day.<ref>Fahlberg's account of how he discovered the sweetness of saccharin appears in: {{cite journal|author=Anon. |date=July 17, 1886 |url=https://books.google.com/books?id=f4I9AQAAIAAJ&pg=PA36 |title=The inventor of saccharine |archive-url=https://web.archive.org/web/20170314015912/https://books.google.com/books?id=f4I9AQAAIAAJ&pg=PA36 |archive-date=2017-03-14 |journal=Scientific American |series=new series |volume=60 |issue=3 |page=36}}</ref><ref name="isbn0-313-33758-6">{{cite book | vauthors = Myers RL, Myers RL |title=The 100 Most Important Chemical Compounds: A Reference Guide |publisher=Greenwood Press |location=Westport, Connecticut |date=2007 |pages=241 |isbn=978-0-313-33758-1 }}</ref> Fahlberg and Remsen published articles on benzoic sulfimide in 1879 and 1880.<ref name = "Fahlberg"/><ref>{{cite journal | vauthors = Remsen I, Fahlberg C | date = February 1880 | title = On the Oxidation of Substitution Products of Aromatic Hydrocarbons. IV. – On the oxidation of orthotoluenesulphamide | url = https://babel.hathitrust.org/cgi/pt?id=uiug.30112000116845;view=1up;seq=434 | journal = American Chemical Journal | volume = 1 | issue = 6 | pages = 426–439 | access-date = 2022-02-24 | archive-date = 2021-02-24 | archive-url = https://web.archive.org/web/20210224042450/https://babel.hathitrust.org/cgi/pt?id=uiug.30112000116845;view=1up;seq=434 | url-status = live }} From pages 430–431: |
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Although saccharin was commercialized not long after its discovery, it was not until sugar shortages during ] that its use became widespread. Its popularity further increased during the 1960s and 1970s among dieters, since saccharin is a ]-free sweetener. In the United States saccharin is often found in restaurants in ] packets; the most popular brand is "]". |
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: "It possesses a 'very marked sweet taste, being much sweeter than cane-sugar'. The taste is perfectly pure. The minutest quantity of the substance, a bit of its powder scarcely visible, if placed upon the tip of the tongue, causes a sensation of pleasant sweetness throughout the entire cavity of the mouth. As stated above, the substance is soluble to only a slight extent in cold water, but if a few drops of the cold aqueous solution be placed in an ordinary goblet full of water, the latter then tastes like the sweetest syrup. Its presence can hence easily be detected in the dilutest solutions by the taste."</ref> In 1884, then working on his own in ], Fahlberg applied for patents in several countries, describing methods of producing this substance that he named saccharin.<ref>{{cite patent|inventor=Fahlberg, C. |inventor2=List, A. |title=Manufacture of saccharine compounds |country=US |number=319082 |fdate=August 7, 1884}}</ref> Two years later, he began production of the substance in a factory in a suburb of ] in Germany. Fahlberg would soon grow wealthy, while Remsen merely grew irritated, believing he deserved credit for substances produced in his laboratory. On the matter, Remsen commented, "Fahlberg is a scoundrel. It nauseates me to hear my name mentioned in the same breath with him."<ref>{{Cite book |publisher=Journal of Chemical Education |location=Easton, Pennsylvania |title=The Life of Ira Remsen | vauthors=Getman FH |date=1940 |page=66 |oclc=2640159 |ol=6411359M }}</ref> |
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Although saccharin was commercialized not long after its discovery, until sugar shortages during ], its use had not become widespread. Its popularity further increased during the 1960s and 1970s among dieters, since saccharin is a ]-free sweetener. In the United States, saccharin is often found in restaurants in ] packets; the most popular brand is "]". |
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Saccharin was delisted by the Office of Environmental Health Hazard Assessment (OEHHA) of the ] from the list of chemicals known to the state to cause cancer on April 6, 2001.<ref>http://oehha.ca.gov/prop65/prop65_list/files/P65single121809.pdf</ref> It had been added to the list in 1989. |
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Due to the difficulty of importing sugar from the ] during ], the ] was founded in 1917 to produce saccharin at its Paragon Works near ], ]. Production was licensed and controlled by the ] in London. Production continued on the site until 1926. |
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== Chemistry == |
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Saccharin has the chemical formula C<sub>7</sub>H<sub>5</sub>NO<sub>3</sub>S and it can be produced in various ways.<ref> |
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{{cite journal |
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| author = David J. Ager, David P. Pantaleone, Scott A. Henderson, ], Indra Prakash, D. Eric Walters |
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| title = Commercial, Synthetic Nonnutritive Sweeteners |
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| journal = ] |
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| year = 1998 |
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| volume = 37 |
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| issue = 13-24 |
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| pages = 1802–17 |
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| doi = 10.1002/(SICI)1521-3773(19980803)37:13/14<1802::AID-ANIE1802>3.0.CO;2-9}}</ref> The original route starts with ], but yields from this starting point are low. In 1950, an improved synthesis was developed at the ] of ]. In this synthesis, ] successively reacts with ], ], ], and then ] to yield saccharin. Another route begins with o-]. It is also known as ortho sulfobenzoic acid.<ref>Bungard, 1967</ref> |
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===Government regulation=== |
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Saccharin is an acid with a ] of about 2 (the acidic hydrogen being that attached to the nitrogen).<ref></ref><ref></ref> |
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{{Globalize|section|USA|2name=the United States|date=October 2015}} |
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Starting in 1907, the ] began investigating saccharin as a result of the ]. ], then the director of the bureau of chemistry for the FDA, viewed it as an illegal substitution of a valuable ingredient, sugar, by a less valuable ingredient. In a clash that had career consequences, Wiley told President ], "Everyone who ate that sweet corn was deceived. He thought he was eating sugar, when in point of fact he was eating a coal tar product totally devoid of food value and extremely injurious to health." But Roosevelt himself was a consumer of saccharin, and, in a heated exchange, Roosevelt angrily answered Wiley by stating, "Anybody who says saccharin is injurious to health is an idiot." The episode proved the undoing of Wiley's career.<ref>{{cite web |url=https://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/SelectionsFromFDLIUpdateSeriesonFDAHistory/ucm091680.htm |title=Sugar: A Cautionary Tale |website=FDA.gov |access-date=2010-06-20 |url-status=live |archive-url=https://web.archive.org/web/20100428052615/https://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/SelectionsFromFDLIUpdateSeriesonFDAHistory/ucm091680.htm |archive-date=2010-04-28 }}</ref> |
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Saccharin can be used to prepare exclusively disubstituted ]s from ] via a ].<ref>{{cite journal |author=Sugasawa, S.; Abe, K. |journal=J. Pharm. Soc. Jpn. |volume=72 |pages=270 |year=1952 }}<br/>{{cite journal |journal=Chem Abstr |volume=47 |pages=1626c |year=1953 }}</ref> |
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In 1911, Food Inspection Decision 135 stated that foods containing saccharin were ].<ref name="Dunn1913">{{cite book | vauthors = Dunn CW |title=Federal, State, and Territorial Reference Manual of Pure Food and Drug Law: Dunn's Pure Food and Drug Legal Manual|url=https://books.google.com/books?id=P34sAQAAMAAJ&pg=PA1327|date=1913|page=1327|url-status=live|archive-url=https://web.archive.org/web/20170313213259/https://books.google.com/books?id=P34sAQAAMAAJ&pg=PA1327|archive-date=2017-03-13}}</ref> However, in 1912, Food Inspection Decision 142 stated that saccharin was not harmful.<ref name="Health1921">{{cite news |publisher=California State Board of Health |title=Monthly Bulletin |url=https://books.google.com/books?id=swBFAQAAMAAJ&pg=PA21 |date=1921 |page=21 |url-status=live |archive-url=https://web.archive.org/web/20170314015938/https://books.google.com/books?id=swBFAQAAMAAJ&pg=PA21 |archive-date=2017-03-14 }}</ref> |
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==Government regulation== |
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More controversy was stirred in 1969 with the discovery of files from the FDA's investigations of 1948 and 1949. These investigations, which had originally argued against saccharin use, were shown to prove little about saccharin being harmful to human health.{{citation needed|date=August 2014}} In 1977, the FDA made an attempt to completely ban the substance,<ref name=Priebem/><ref name=Conis/> following studies showing that the substance caused ] in rats. The attempted ban was unsuccessful due to public opposition that was encouraged by industry advertisements,<ref name=Conis/> and instead the following label was mandated: "Use of this product may be hazardous to your health. This product contains saccharin which has been determined to cause cancer in laboratory animals". That requirement was dropped in 2000 following new research that concluded humans reacted differently than rats and were not at risk of cancer at typical intake levels.<ref name=Conis/> (See also: {{Section link|#Warning label addition and removal}} below.) The sweetener has continued to be widely used in the United States and is now the third-most popular artificial sweetener behind ] and ]. |
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Starting in 1907, the ] began investigating saccharin as a direct result of the ]. ], then the director of the bureau of chemistry for the USDA, viewed it as an illegal substitution of a valuable ingredient (sugar) by a less valuable ingredient. In a clash that had career consequences, Wiley told then President ] that "Everyone who ate that sweet corn was deceived. He thought he was eating sugar, when in point of fact he was eating a coal tar product totally devoid of food value and extremely injurious to health." But Roosevelt himself was a consumer of saccharin, and in a heated exchange, Roosevelt angrily answered Wiley by stating, "Anybody who says saccharin is injurious to health is an idiot."<ref>{{cite web |url=http://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/SelectionsFromFDLIUpdateSeriesonFDAHistory/ucm091680.htm |title=Sugar: A Cautionary Tale |publisher=www.fda.gov |accessdate=2010-06-20 }}</ref> The episode proved the undoing of Wiley's career. |
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In the ], saccharin is also known by the ] (additive code) E954.<ref name=":0">{{Cite web |title=Approved additives and E numbers {{!}} Food Standards Agency |url=https://www.food.gov.uk/business-guidance/approved-additives-and-e-numbers |access-date=2024-05-02 |website=www.food.gov.uk |language=en}}</ref> |
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In 1911, the Food Inspection Decision 135 stated that foods containing saccharin were adulterated. However in 1912, Food Inspection Decision 142 stated that saccharin was not harmful. |
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The current status of saccharin is that it is allowed in most countries, and countries such as Canada have lifted their previous ban of it as a food additive.<ref>{{cite web |url=https://www.agcanada.com/daily/saccharin-cleared-for-use-in-foods-in-canada |title=Saccharin cleared for use in foods in Canada |publisher=] |website=AgCanada.com |access-date=2022-02-24 |archive-date=2021-05-15 |archive-url=https://web.archive.org/web/20210515023008/https://www.agcanada.com/daily/saccharin-cleared-for-use-in-foods-in-canada |url-status=live }}</ref> The claims that it is associated with bladder cancer were shown to be unfounded in experiments on primates.<ref name="Takayama-1998">{{cite journal | vauthors = Takayama S, Sieber SM, Adamson RH, Thorgeirsson UP, Dalgard DW, Arnold LL, Cano M, Eklund S, Cohen SM | display-authors = 6 | title = Long-term feeding of sodium saccharin to nonhuman primates: implications for urinary tract cancer | journal = Journal of the National Cancer Institute | volume = 90 | issue = 1 | pages = 19–25 | date = January 1998 | pmid = 9428778 | doi = 10.1093/jnci/90.1.19 | doi-access = free }}</ref> (It is, however, prohibited to mail saccharin tablets or packets to France.)<ref>{{cite web |url=https://pe.usps.com/text/imm/fh_005.htm |title=USPS Mailing Conditions|access-date=2013-04-07 |url-status=live |archive-url=https://web.archive.org/web/20130404124454/https://pe.usps.com/text/Imm/fh_005.htm |archive-date=2013-04-04 }}</ref> |
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More controversy was stirred in 1969 with the discovery of files from the FDA's investigations of 1948 and 1949. These investigations, which had originally argued against saccharin use, were shown to prove little about saccharin being harmful to human health. In 1972 the USDA made an attempt to completely ban the substance.<ref>Preibe and Kauffman, 2,3,4,6,7</ref> However, this attempt was also unsuccessful and the sweetener is widely used in the United States; it is the third-most popular after ] and ]. |
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Saccharin was formerly on California's list of chemicals known to the state to cause cancer for the purposes of ], but it was delisted in 2001.<ref>{{cite web| url= https://www.oehha.ca.gov/prop65/CRNR_notices/chemicals_reconsideration/fdelistsacc.html |title=Saccharin Delisted Effective April 6, 2001 as Known to the State to Cause Cancer | vauthors = Sun M |date=28 December 2015 |website=CA.gov|url-status=live |archive-url= https://web.archive.org/web/20110310010350/https://oehha.ca.gov/prop65/CRNR_notices/chemicals_reconsideration/fdelistsacc.html |archive-date=10 March 2011}}</ref> |
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In the European Union saccharin is also known by the ] (additive code) '''E954'''. |
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====Warning label addition and removal==== |
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The current status of saccharin is that it is allowed in most countries, and countries like Canada are considering lifting their previous ban of it as a food additive.<ref>http://www.hc-sc.gc.ca/fn-an/securit/addit/sweeten-edulcor/saccharin_qa-qr-eng.php</ref> The concerns that it is associated with bladder cancer were proved to be without foundation in experiments on primates.<ref name="Takayama-1998">{{Cite journal | last1 = Takayama | first1 = S. | last2 = Sieber | first2 = SM. | last3 = Adamson | first3 = RH. | last4 = Thorgeirsson | first4 = UP. | last5 = Dalgard | first5 = DW. | last6 = Arnold | first6 = LL. | last7 = Cano | first7 = M. | last8 = Eklund | first8 = S. | last9 = Cohen | first9 = SM. | title = Long-term feeding of sodium saccharin to nonhuman primates: implications for urinary tract cancer. | journal = J Natl Cancer Inst | volume = 90 | issue = 1 | pages = 19–25 | month = Jan | year = 1998 | doi = 10.1093/jnci/90.1.19| pmid = 9428778 }}</ref> |
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In 1958, the United States Congress amended the ] with the ] to mandate that the ] not approve substances that "induce cancer in man, or, after tests, found to induce cancer in animals." Studies in laboratory rats during the early 1970s linked saccharin with the development of bladder cancer in rodents. As a consequence, all food containing saccharin was labeled with a warning meeting the requirement of the ].<ref>{{cite news | date=1973-05-22 | access-date=2011-06-09 | url=https://news.google.com/newspapers?id=moBFAAAAIBAJ&pg=6480,3710197&dq=saccharin+warning&hl=en | title=Saccharin warning | publisher=Associated Press via Telegraph-Herald | archive-date=2021-12-23 | archive-url=https://web.archive.org/web/20211223100811/https://news.google.com/newspapers?id=moBFAAAAIBAJ&pg=6480,3710197&dq=saccharin+warning&hl=en | url-status=live }}</ref> |
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However, in 2000, the warning labels were removed because scientists learned that rodents, unlike humans, have a unique combination of high pH, high ], and high protein levels in their urine.<ref name="Whysner-1996">{{cite journal | vauthors = Whysner J, Williams GM | title = Saccharin mechanistic data and risk assessment: urine composition, enhanced cell proliferation, and tumor promotion | journal = Pharmacology & Therapeutics | volume = 71 | issue = 1–2 | pages = 225–52 |date= 1996 | pmid = 8910956 | doi = 10.1016/0163-7258(96)00069-1 }}</ref><ref name="Dybing-2002">{{cite journal | vauthors = Dybing E | title = Development and implementation of the IPCS conceptual framework for evaluating mode of action of chemical carcinogens | journal = Toxicology | volume = 181-182 | pages = 121–5 | date = December 2002 | pmid = 12505296 | doi = 10.1016/S0300-483X(02)00266-4 | bibcode = 2002Toxgy.181..121D }}</ref> One or more of the proteins that are more prevalent in male rats combine with calcium phosphate and saccharin to produce microcrystals that damage the lining of the bladder. Over time, the rat's bladder responds to this damage by overproducing cells to repair the damage, which leads to tumor formation. Since this does not occur in humans, there is no elevated risk of bladder cancer.<ref>{{cite web|publisher=National Toxicology Program |url=https://ntp.niehs.nih.gov/ntp/roc/content/appendix_b.pdf |title=Report on Carcinogens, Thirteenth Edition, Appendix B |archive-url=https://web.archive.org/web/20160520211549/https://ntp.niehs.nih.gov/ntp/roc/content/appendix_b.pdf |archive-date=2016-05-20 |pages= 2–4}}<br/>Linked from {{cite web|url=https://ntp.niehs.nih.gov/pubhealth/roc/listings/archive/index.html?substance=Saccharin |title=Saccharin index page |archive-url=https://web.archive.org/web/20160307065735/https://ntp.niehs.nih.gov/pubhealth/roc/listings/s/saccharin/summary/index.html |archive-date=2016-03-07 |publisher=National Toxicology Program |date=November 18, 2014 |access-date= 2016-02-29}}</ref> |
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== Warning label removal == |
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Studies in laboratory rats during the early 1970s linked saccharin with the development of bladder cancer in rodents, resulting in the United States Congress mandating that all food containing saccharin bear a warning label. |
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The delisting of saccharin led to legislation repealing the warning label requirement for products containing saccharin.<ref>{{cite web|publisher=National Cancer Institute |url=https://www.cancer.gov/about-cancer/causes-prevention/risk/diet/artificial-sweeteners-fact-sheet |title=Artificial Sweeteners and Cancer |archive-url=https://web.archive.org/web/20151208135059/https://www.cancer.gov/about-cancer/causes-prevention/risk/diet/artificial-sweeteners-fact-sheet |archive-date=2015-12-08 |date=August 5, 2009 |access-date= 2016-02-29}}</ref> In 2001, the U.S. Food and Drug Administration and the state of California reversed their positions on saccharin, declaring it safe for consumption.<ref name="Conis">{{cite news| vauthors = Conis E |url= https://www.latimes.com/health/la-he-nutrition-lab-saccharin-20101227,0,4550768.story |title=Saccharin's mostly sweet following |archive-url=https://web.archive.org/web/20110217231323/https://www.latimes.com/health/la-he-nutrition-lab-saccharin-20101227,0,4550768.story |archive-date=2011-02-17 |newspaper=Los Angeles Times |date=December 27, 2010 |access-date=2011-01-14}}</ref> The FDA's decision followed a 2000 determination by the U.S. ]' ] to remove saccharin from its list of carcinogens. |
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However, in 2000, the warning labels were removed because scientists learned that rodents, unlike humans, have a unique combination of high pH, high calcium phosphate, and high protein levels in their urine.<ref name="Whysner-1996">{{Cite journal | last1 = Whysner | first1 = J. | last2 = Williams | first2 = GM. | title = Saccharin mechanistic data and risk assessment: urine composition, enhanced cell proliferation, and tumor promotion. | journal = Pharmacol Ther | volume = 71 | issue = 1-2 | pages = 225–52 | month = | year = 1996 | doi = 10.1016/0163-7258(96)00069-1| pmid = 8910956 }}</ref><ref name="Dybing-2002">{{Cite journal | last1 = Dybing | first1 = E. | title = Development and implementation of the IPCS conceptual framework for evaluating mode of action of chemical carcinogens. | journal = Toxicology | volume = 181-182 | issue = | pages = 121–5 | month = Dec | year = 2002 | doi = 10.1016/S0300-483X(02)00266-4| pmid = 12505296 }}</ref> One or more of the proteins that is more prevalent in male rats combines with calcium phosphate and saccharin to produce microcrystals that damage the lining of the bladder. Over time, the rat's bladder responds to this damage by over-producing cells to repair the damage, and this leads to tumor formation. As this does not occur in humans, there is no elevated bladder cancer risk. |
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The ] has officially removed saccharin and its salts from their list of hazardous constituents and commercial chemical products. In a release in December 2010, the EPA stated that saccharin is no longer considered a potential hazard to human health.<ref>{{cite news|url=https://yosemite.epa.gov/opa/admpress.nsf/d0cf6618525a9efb85257359003fb69d/ea895a11ea50a56d852577f9005e2690!OpenDocument |title=EPA Removes Saccharin from Hazardous Substances Listing |archive-url=https://web.archive.org/web/20101224101552/https://yosemite.epa.gov/opa/admpress.nsf/d0cf6618525a9efb85257359003fb69d/ea895a11ea50a56d852577f9005e2690!OpenDocument |archive-date=2010-12-24 |date=December 14, 2010 |access-date= 2011-01-14}}</ref> |
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The delisting of saccharin led to legislation, which was signed into law on December 21, 2000, repealing the warning label requirement for products containing saccharin. In 2001 the U.S. ] and the state of ] reversed their positions on saccharin, declaring it safe for consumption.<ref>Conis, Elena. ''Los Angeles Times''. December 27, 2010, accessed January 14, 2011.</ref> The FDA’s decision followed a 2000 determination by the U.S. Department of Health and Human Services' National Toxicology Program to remove saccharin from its list of carcinogens. |
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==Chemistry== |
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The EPA has officially removed saccharin and its salts from their list of hazardous constituents and commercial chemical products. In a December 14, 2010 release, the EPA stated that saccharin is no longer considered a potential hazard to human health.<ref> December 14, 2010, accessed January 14, 2011.</ref> |
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===Preparation=== |
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Saccharin can be produced in various ways.<ref>{{cite journal | vauthors = Ager DJ, Pantaleone DP, Henderson SA, Katritzky AR, Prakash I, Walters DE | author-link4 = Alan R. Katritzky | title=Commercial, Synthetic Nonnutritive Sweeteners | journal = ] |date=1998 |volume=37 |issue=13–24 |pages=1802–1823 | doi = 10.1002/(SICI)1521-3773(19980803)37:13/14<1802::AID-ANIE1802>3.0.CO;2-9 }}</ref> The original route by Remsen and Fahlberg starts with ]; another route begins with ].<ref>{{cite journal| vauthors = Bungard G |date=1967 |title=Die Süßstoffe |trans-title=Sweeteners |journal=Der Deutscher Apotheker |volume=19 |page=150}}</ref> Sulfonation of toluene by ] gives the ''ortho'' and ''para'' substituted ]s. The ''ortho'' isomer is separated and converted to the ] with ]. Oxidation of the methyl substituent gives the carboxylic acid, which cyclicizes to give saccharin free acid:<ref name = ullmann>{{Ullmann's | doi = 10.1002/14356007.a26_023 | title = Sweeteners | vauthors = Lipinski GW }}</ref> |
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In 1950, an improved synthesis was developed at the ] of ]. In this synthesis, the ] successively reacts with ] (from ] and ]), ], ], and then ] to yield saccharin:<ref name="ullmann" /> |
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===Properties and reactions=== |
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The free acid of saccharin has a low ] of 1.6 (the acidic hydrogen being that attached to the nitrogen).<ref name="BellHigginson">{{cite journal | vauthors = Bell RP, Higginson WC |title=The Catalyzed Dehydration of Acetaldehyde Hydrate, and the Effect of Structure on the Velocity of Protolytic Reactions| journal=] |volume=197 |issue=1049 |date=1949 |pages=141–159 |doi=10.1098/rspa.1949.0055|bibcode=1949RSPSA.197..141B |doi-access=free }}</ref> Saccharin can be used to prepare exclusively disubstituted ]s from ] via a nucleophilic substitution,<ref>{{cite journal | vauthors = Jaroentomeechai T, Yingsukkamol PK, Phurat C, Somsook E, Osotchan T, Ervithayasuporn V | title = Synthesis and reactivity of nitrogen nucleophiles-induced cage-rearrangement silsesquioxanes | journal = Inorganic Chemistry | volume = 51 | issue = 22 | pages = 12266–72 | date = November 2012 | pmid = 23134535 | doi = 10.1021/ic3015145 }}</ref> followed by a ].<ref>{{cite journal | vauthors = Ragnarsson U, Grehn L |title=Novel Gabriel reagents |journal=Accounts of Chemical Research |date=May 2002 |volume=24 |issue=10 |pages=285–289 |doi=10.1021/ar00010a001 }}</ref><ref>{{cite journal |vauthors=Sugasawa S, Abe K |title=A New Method for the Preparation of Secondary Amines. I. Synthesis of Aliphatic Secondary Amines |journal=Yakugaku Zasshi |date=1952 |volume=72 |issue=2 |pages=270–273 |doi=10.1248/yakushi1947.72.2_270|url=https://www.jstage.jst.go.jp/article/yakushi1947/72/2/72_2_270/_pdf |url-status=live |archive-url=https://web.archive.org/web/20171003224615/https://www.jstage.jst.go.jp/article/yakushi1947/72/2/72_2_270/_pdf |archive-date=2017-10-03 |doi-access=free }}</ref> |
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== See also == |
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== See also == |
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== References == |
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{{Reflist}} |
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== External links == |
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==Notes and references== |
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* {{Commons category-inline}} |
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{{Reflist|2}} |
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{{Consumer Food Safety}} |
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{{Consumer Food Safety}} |
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{{Food Substitutes}} |
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{{E number infobox 950-969}} |
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{{E number infobox 950-969}} |
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