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{{chembox
{{chembox
| Verifiedfields = changed
| Watchedfields = changed
| Watchedfields = changed
| verifiedrevid = 573678824
| verifiedrevid = 457481039
| Name = Thiomersal
| Name = Xylitol
| Reference = <ref>[[Material safety data sheet]] for [http://ehsrms.uaa.alaska.edu/CMS/Laboratory/MSDS/MSDS%20by%20Vendor/Fisher/Xylitol.pdf xylitol] from [[Fisher Scientific]]. {{Retrieved|accessdate=2014-11-02}}</ref>
| ImageFile = Thiomersal-Skeletal-Structure-SVG.svg
| ImageFile = Xylitol-2D-structure.svg
| ImageSize =
| ImageSize =
| ImageName = Thiomersal
| ImageName = Xylitol
| ImageFile1 = Xylitol crystals.jpg
| ImageFile2 = Thiomersal-from-xtal-3D-vdW.png
| ImageSize2 =
| ImageSize1 = 250px
| ImageCaption1 = Xylitol crystals
| IUPACName = Ethyl(2-mercaptobenzoato-(2-)-''O'',''S'') mercurate(1-) sodium
| IUPACName = (2''R'',4''S'')-Pentane-1,2,3,4,5-pentol
| OtherNames = Mercury((o-carboxyphenyl)thio)ethyl sodium salt
| OtherNames = 1,2,3,4,5-Pentahydroxypentane; <br>Xylite
|Section1={{Chembox Identifiers
|Section1={{Chembox Identifiers
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 10772045
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 508338
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 2225PI3MOV
| InChI = 1/C7H6O2S.C2H5.Hg.Na/c8-7(9)5-3-1-2-4-6(5)10;1-2;;/h1-4,10H,(H,8,9);1H2,2H3;;/q;;2*+1/p-2/rC9H10HgO2S.Na/c1-2-10-13-8-6-4-3-5-7(8)9(11)12;/h3-6H,2H2,1H3,(H,11,12);/q;+1/p-1
| InChIKey = RTKIYNMVFMVABJ-TYXNQWANAP
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 9546
| SMILES = [Na+].[O-]C(=O)c1ccccc1S[Hg]CC
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C7H6O2S.C2H5.Hg.Na/c8-7(9)5-3-1-2-4-6(5)10;1-2;;/h1-4,10H,(H,8,9);1H2,2H3;;/q;;2*+1/p-2
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = RTKIYNMVFMVABJ-UHFFFAOYSA-L
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 54-64-8
| CASNo = 87-99-0
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| PubChem = 16684434
| UNII_Ref = {{fdacite|correct|FDA}}
| RTECS = OV8400000
| EINECS = 200-210-4
| UNII = VCQ006KQ1E
| ATCCode_prefix = D08
| ChEMBL = 96783
| ATCCode_suffix = AK06
| PubChem = 6912
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
}}
| ChemSpiderID = 6646
| SMILES = O[C@H](CO)[C@H](O)[C@@H](O)CO
| InChI = 1/C5H12O5/c6-1-3(8)5(10)4(9)2-7/h3-10H,1-2H2/t3-,4+,5+
| InChIKey = HEBKCHPVOIAQTA-SCDXWVJYBA
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 1S/C5H12O5/c6-1-3(8)5(10)4(9)2-7/h3-10H,1-2H2/t3-,4+,5+
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = HEBKCHPVOIAQTA-SCDXWVJYSA-N
}}
|Section2={{Chembox Properties
|Section2={{Chembox Properties
| C=5 | H=12 | O=5
| Formula = [[carbon|C]]<sub>9</sub>[[hydrogen|H]]<sub>9</sub>[[Mercury (element)|Hg]][[sodium|Na]][[Oxygen|O]]<sub>2</sub>[[sulfur|S]]
| Density = 1.52&nbsp;g/cm<sup>3</sup>
| MolarMass = 404.81 g/mol
| MeltingPtC = 92 to 96
| Appearance = White or slightly yellow powder
| MeltingPt_notes =
| Density = 2.508 g/cm<sup>3</sup><ref name=molstruct/>
| BoilingPtC = 345.39
| Solubility = 1000 g/l (20&nbsp;°C)
| BoilingPt_notes = Predicted value using Adapted Stein & Brown method<ref>{{cite web|title=Xylitol|url=http://www.chemspider.com/Chemical-Structure.6646.html|website=Chemspider|accessdate=13 May 2015}}</ref>
| MeltingPtC = 232 to 233
| Solubility = ~ 0.1 g/mL
| MeltingP_notes = (decomposition)
}}
| BoilingPt =
|Section3={{Chembox Hazards
| pKa =
| NFPA-H = 1
}}
|Section4={{Chembox Thermochemistry
| DeltaHf =
}}
|Section7={{Chembox Hazards
| EUClass = Very toxic ('''T+''')<br/>Dangerous for the environment ('''N''')<br/> Repr. Cat. 1
| NFPA-H = 3
| NFPA-F = 1
| NFPA-F = 1
| NFPA-R = 1
| NFPA-R = 0
| RPhrases = {{R26/27/28}} {{R33}} {{R40}} {{R50/53}} {{R60}} {{R61}}
| SPhrases = {{S13}} {{S28}} {{S36}} {{S45}} {{S53}} {{S60}} {{S61}}
| FlashPtC = 250
| LD50 = 75 mg/kg (oral, rat)<ref>http://chem.sis.nlm.nih.gov/chemidplus/rn/54-64-8</ref>
| ExternalMSDS = [http://www.conncoll.edu/offices/envhealth/MSDS/neuroscience/thimerosal.pdf External MSDS]
}}
}}
}}
|Section8={{Chembox Related
| OtherFunction_label = [[alkane]]s
| OtherFunction = [[Pentane]]
}}
}}

'''Xylitol''' {{IPAc-en|ˈ|z|aɪ|l|ɪ|t|ɒ|l}} is a [[sugar alcohol]] used as a sweetener. The name derives from {{lang-el|ξύλον}}, ''xyl[on],'' "wood" + suffix -''itol'', used to denote [[sugar alcohols]]. Xylitol is categorized as a polyalcohol or sugar alcohol (alditol). It has the formula CH<sub>2</sub>OH(CHOH)<sub>3</sub>CH<sub>2</sub>OH and is an [[Chirality (chemistry)|achiral]]<ref>{{cite book|last=Wrolstad|first=Ronald E.|title=Food Carbohydrate Chemistry|year=2012|publisher=John Wiley & Sons|isbn=9780813826653|url=http://books.google.ca/books?id=gVB8l8ukYPYC&pg=PA176|accessdate=October 20, 2012|page=176|quote=Xylitol contains asymmetric carbon atoms, but it is not [[Chirality (chemistry)|chiral]] because the molecule as a whole is symmetrical.}}</ref> [[isomer]] of pentane-1,2,3,4,5-pentol. Xylitol is roughly as sweet as [[sucrose]] (table sugar), with 33% fewer calories. Unlike other natural or synthetic sweeteners, xylitol is actively beneficial for dental health by reducing [[dental caries|caries]] (cavities) to a third in regular use and helpful to remineralization.<ref>{{cite journal|last=Steinberg|first=LM|author2=Odusola, F|author3= Mandel, ID|title=Remineralizing potential, antiplaque and antigingivitis effects of xylitol and sorbitol sweetened chewing gum.|journal=Clinical preventive dentistry|date=Sep–Oct 1992|volume=14|issue=5|pages=31–4|pmid=1291185|url=http://www.ncbi.nlm.nih.gov/pubmed/1291185|accessdate=13 November 2013}}</ref> Multiple studies utilizing electron microscopy have indicated that xylitol is effective in inducing remineralization of deeper layers of demineralized [[Tooth enamel|enamel]].<ref>{{cite web|url=http://www.ncbi.nlm.nih.gov/pubmed/14700079|title=Remineralization effects of xylitol on demineralized enamel.|author=Miake Y , et al.|work=nih.gov|accessdate=12 July 2015}}</ref><ref>http://www.drellie.com/pdfs/The-Remineralization-effects-of-XYLITOL.pdf</ref> Fair evidence was found that xylitol (as chewing gum, lozenges, nasal spray, etc.) reduced the incidence of acute [[otitis media|middle ear infection]] in healthy children.<ref name=":21">{{cite pmid |22071833 }}</ref>

Xylitol is naturally found in low concentrations in the [[fiber]]s of many [[fruit]]s and [[vegetable]]s, and can be extracted from various [[berry|berries]], [[oat]]s, and [[mushroom]]s, as well as fibrous material such as [[corn husk]]s and [[sugar cane]] [[bagasse]],<ref>{{cite book |last=Gare |first=Fran |title=The Sweet Miracle of Xylitol |url=http://books.google.com/?id=5tgZG6Sb2aAC |date=February 1, 2003 |publisher=Basic Health Publications, Inc. |isbn=1-59120-038-5 }}</ref><ref>{{cite journal | doi = 10.1016/j.biortech.2005.08.015 | author = Rao, R. Sreenivas; Jyothi, Ch. Pavana; Prakasham, RS; Sharma, PN; Rao, L. Venkateswar | year = 2006 | title = Other material suggests that there is no xylitol in any fruit and vegtables. | pmid=16242318 | volume=97 | journal=Bioresour. Technol. | pages=1974–8}}{{Verification needed|date=June 2015}}</ref><ref>{{cite journal | title=Xylitol production from corn fiber and sugarcane bagasse hydrolysates by Candida tropicalis | url = http://www.aseanbiotechnology.info/Abstract/21019424.pdf | journal = Bioresource Technology | volume = 97 | issue = 15| pages = 1974–1978 | pmid = 16242318 |accessdate= March 14, 2012 | doi=10.1016/j.biortech.2005.08.015 | date=October 2006}}</ref> and birch.<ref name="xylitol canada">{{cite web |title=FAQ |url=http://www.xylitolcanada.com/faq/|publisher=Xylitol Canada|accessdate=March 14, 2012}}</ref> However, industrial production starts from [[xylan]] (a [[hemicellulose]]) extracted from hardwoods<ref>{{cite journal | url=http://www.dichep.unige.it/old_site/Italiano/ricerca/pub_biotec_av/1999/1999_12.pdf | title=Xylitol Production from Hardwood Hemicellulose Hydrosylates | author=Converti, Atillio; Parego, Patrizia; Dominguez, Jose Manuel | journal=Applied Biochemistry and Biotechnology | year=1999 | volume=82 | pages=141–151 | doi=10.1385/abab:82:2:141}}</ref>
or corncobs, which is hydrolyzed into [[xylose]] and catalytically hydrogenated into xylitol. A study in [[Laboratory rat|rats]] found that xylitol had reduced or nonexistent side effects compared to other artificial sweeteners, and lower caloric value and [[cariogenicity]] than sucrose.<ref>{{Cite doi|10.1159/000338440}}</ref>


==Production==
'''Thiomersal''' ([[International Nonproprietary Name|INN]]), commonly known in the U.S. as '''thimerosal''', is an [[organomercury]] compound. This compound is a well established [[antiseptic]] and [[antifungal agent]].
Xylitol was discovered almost simultaneously by [[Germany|German]] and [[France|French]] chemists in the late 19th century,<ref name=xlear.com>{{cite web|title=Xylitol FAQ's|url=http://xlear.com/xylitol-faq.aspx|publisher=Xlear|accessdate=March 14, 2012}}</ref> and was first popularized in [[Europe]] as a safe sweetener that would not affect [[insulin]] levels of people with [[diabetes]].
Xylitol is produced by [[hydrogenation]] of [[xylose]], which converts the sugar (an [[aldehyde]]) into a primary alcohol. It can also be extracted from natural sources, and is often harvested by tapping birch trees to produce [[birch sap]].
Another method of producing xylitol is through microbial processes, including fermentative and biocatalytic processes in bacteria, fungi, and yeast cells, that take advantage of the xylose-intermediate fermentations to produce high yield of xylitol.<ref>{{cite journal|last=Nigam|first=Poonam|author2=Singh, D.|title=Processes for Fermentative Production of Xylitol--a Sugar Substitute|journal=Process Biochemistry|year=1995|volume=30|pages=117–124|doi=10.1016/0032-9592(95)80001-8}}</ref> Common yeast cells used in effectly fermenting and producing xylitol are ''[[Candida tropicalis]]'' and ''[[Candida guilliermondii]]''.<ref>{{cite journal|last=Barbosa,|first=M.F.S.|author2=de Medeiros, M.B.|author3= de Manchilha, I.M.|author4= Schneider, H.|author5= Lee, H.|title=Screening of yeasts for production of xylitol from D-xylose and some factors which affect xylitol yield in Candida guillermondii|journal=J. Indust. Microbiol.|year=1988|volume=3|pages=241–251|doi=10.1007/bf01569582}}</ref>
Its dental significance was researched in [[Finland]] in the early 1970s. There, scientists at [[University of Turku]] demonstrated dental benefits in what became known as the "Turku sugar studies".<ref name="xlear.com"/>


==Properties==
The pharmaceutical corporation [[Eli Lilly and Company]] gave thiomersal the trade name '''Merthiolate'''. It has been used as a [[preservative]] in [[vaccine]]s, [[immunoglobulin]] preparations, [[Allergy#Diagnosis|skin test antigens]], [[antivenin]]s, [[ophthalmology|ophthalmic]] and nasal products, and [[tattoo]] inks.<ref>{{cite doi|10.1155/2012/373678}}</ref> Its use as a vaccine preservative [[Thiomersal controversy|was controversial]], and it was phased out from routine childhood vaccines in the [[European Union]], and a few other countries in response to popular fears.<ref name=drugsaf/> The current scientific consensus is that no convincing scientific evidence supports these fears.<ref>{{cite book|last=Immunization Safety Review Committee, Board on Health Promotion and Disease Prevention, Institute of Medicine|title=Immunization Safety Review: Vaccines and Autism.|year=2004|publisher=The National Academies Press.|location=Washington, DC|isbn=0-309-09237-X}}</ref><ref>{{cite journal |last=Doja |first=Asif |last2=Roberts |first2=Wendy |title=Immunizations and autism: a review of the literature |journal=[[Canadian Journal of Neurological Sciences|Can J Neurol Sci]] |date=November 2006 |volume=33 |issue=4 |pages=341–6| pmid=17168158 |doi=10.1017/s031716710000528x}}</ref>
One gram of xylitol contains 2.4 [[calories|kilocalories]] (kcal),<ref>{{cite web|last=Walters|first=D. Eric|title=Xylitol|url=http://www.sweetenerbook.com/xylitol.html|work=All About Sweeteners |accessdate= March 14, 2012}}</ref> as compared to one gram of [[sugar]], which has 3.87&nbsp;kcal.<ref>{{cite web|title=Sugars, granulated (sucrose)|url=http://nutritiondata.self.com/facts/sweets/5592/2 |publisher= Self Nutrition Data|accessdate=March 14, 2012}} With a serving size of 100 grams, there are 387 calories.</ref> Xylitol has virtually no [[aftertaste]], and is advertised as "safe for [[diabetics]] and individuals with [[hyperglycemia]]." This tolerance is attributed to the lower effect of xylitol on a person's [[blood sugar]], compared to that of regular [[sugars]] as it has an extremely low [[glycemic index]] of 7 (glucose has a GI of 100).<ref>[http://www.ajcn.org/content/76/1/5/T1.expansion.html The American Journal of Clinical Nutrition, January 1, 2002: ''International table of glycemic index and glycemic load values''] Retrieved 2012-08-26</ref> Xylitol has no known toxicity or carcinogenicity, and is considered safe by the U.S. FDA<ref>{{cite web|url=http://www.tomsofmaine.com/ingredients/overlay/xylitol-flavor|title=Tom's of Maine|work=tomsofmaine.com|accessdate=12 July 2015}}</ref>


==Health benefits==
In the U.S., Thiomersal has been removed from or reduced to trace amounts in all vaccines routinely recommended for children 6 years of age and younger with the exception of inactivated influenza vaccine. Vaccines with trace amounts of thiomersal contain 1 microgram or less of mercury per dose, less than 2.5% of the intake of mercury considered tolerable per day by the [[World Health Organization|WHO]].<ref>http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/VaccineSafety/UCM096228</ref><ref>{{cite web|last1=Bose-O'Reilly et al.|title=Mercury Exposure and Children’s Health|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3096006/|website=Curr Probl Pediatr Adolesc Health Care.|accessdate=4 July 2015}}</ref>


== Structure ==
===Dental care===
Xylitol is a "[[tooth-friendly]]", [[fermentation|nonfermentable]] sugar alcohol.<ref>{{cite journal |last=Edwardsson|first=Stig|author2=Birkhed, Dowen|author3= Mejàre, Bertil|title=Acid production from Lycasin, maltitol, sorbitol and xylitol by oral streptococci and lactobacilli|journal=Acta Odontologica Scandinavica|year=1977|volume=35|issue=5|pages=257–263|pmid=21508|doi=10.3109/00016357709019801}}</ref><ref>{{cite journal|last=Drucker|first=D.B.|author2=Verran, J.|title=Comparative effects of the substance-sweeteners glucose, sorbitol, sucrose, xylitol and trichlorosucrose on lowering of pH by two oral Streptococcus mutans strains in vitro|journal=Archives of Oral Biology |year=1979 |volume=24 |issue=12 |pages=965–970|doi=10.1016/0003-9969(79)90224-3|pmid=44996}}</ref> It appears to have more dental health benefits than other [[polyol|polyalcohols]].<ref>{{cite journal | last = Maguire | first = A |author2=Rugg-Gunn, A J|title=Xylitol and caries prevention — is it a magic bullet? |journal=British Dental Journal |year=2003 |volume=194 |issue=8 |pages=429–436 |doi= 10.1038/sj.bdj.4810022 |url=http://www.nature.com/bdj/journal/v194/n8/abs/4810022a.html |accessdate= March 14, 2012|pmid=12778091}}</ref> The structure of xylitol contains a [[tridentate|tridentate ligand]], (H-C-OH)<sub>3</sub> that can rearrange with polyvalent cations like Ca<sup>2+</sup>. This interaction allows Ca<sup>2+</sup> to be transported through the gut wall barrier and through saliva may remineralize enamel before dental cavities form.<ref name=ReferenceA>{{cite book |title= Functional foods, ageing and degenerative disease|year=2004|publisher=Woodhead Publishing |location= Cambridge, England |isbn=978-1-85573-725-9|url=http://books.google.ca/books?id=E32UlBYUZhcC&lpg=PP1&pg=PA202#v=onepage&q&f=false|author=Reusens, B.|editor=Remacle, Claude; Reusens, Brigitte |accessdate= March 14, 2012 |page=202}}</ref>


Early studies from Finland in the 1970s found compared to chewing sucrose-flavored gum, xylitol resulted in nearly two fewer cavities or missing teeth.<ref name=aapd>{{cite journal|title=Policy on the Use of Xylitol in Caries Prevention|journal=Reference Manual|year=2010 | volume = 33 | issue = 6 | pages = 42–44 | url = http://www.aapd.org/media/Policies_Guidelines/P_Xylitol.pdf|accessdate=March 14, 2012|publisher=American Academy of Pediatric Dentistry}}</ref> Cavity-causing [[bacteria]] prefer [[Hexose|six-carbon sugars]] or [[disaccharide]]s, while xylitol is non-[[fermentation|fermentable]] and cannot be used as an energy source - while still being taken up into the cell (due to similar shape) and leaving no room for the six-carbon sugars, interfering with bacterial growth and reproduction. The harmful micro-organisms are starved in the presence of xylitol, allowing the mouth to remineralize damaged teeth with less interruption. This same property renders it unsuitable for making [[bread]] as it interferes with the ability of [[yeast]] to digest sugars.<ref name=ReferenceA/> At least six&nbsp;grams of xylitol per day is thought to be needed for dental efficacy.<ref name=ReferenceA/>
Thiomersal features [[Mercury (element)|mercury]](II) with a coordination number 2, ''i.e.'' two [[ligands]] are attached to Hg, the [[thiolate]] and the ethyl group. The [[carboxylate]] group is not coordinated, but confers solubility in water. Like other two-coordinate Hg(II) compounds, the coordination geometry of Hg is linear, with a 180° S-Hg-C angle. Typically, organomercury thiolate compounds are prepared from organomercury chlorides.<ref name="molstruct">{{ cite journal | first1 = J. G. | last1 = Melnick | first2 = K. | last2 = Yurkerwich | first3 = D. | last3 = Buccella | first4 = W. | last4 = Sattler | first5 = G. | last5 = Parkin | title = Molecular Structures of Thimerosal (Merthiolate) and Other Arylthiolate Mercury Alkyl Compounds | journal = [[Inorganic Chemistry (journal)|Inorg. Chem.]] | year = 2008 | volume = 47 | issue = 14 | pmid = 18533648 | pages = 6421–6426 | doi = 10.1021/ic8005426 }}</ref>


Xylitol also inhibits the growth of ''[[Streptococcus pneumoniae]]'', as well as the attachment of ''[[Haemophilus influenzae]]'' on the [[nasopharyngeal]] cells.<ref name="ReferenceA"/>
== Use ==


The perception of sweetness obtained from consuming xylitol causes the secretion of saliva which acts as a buffer against the acidic environment created by the microorganisms in dental plaque. Increase in salivation can raise the falling pH to a neutral range within few minutes of xylitol consumption.<ref>{{cite journal|last=Scheinin|first=Arje|title=Dental Caries, Sugars and Xylitol|journal=Ann Med|year=1993|volume=25|pages=519–521}}</ref>
Thiomersal's main use is as an antiseptic and antifungal agent. In multidose injectable drug delivery systems, it prevents serious adverse effects such as the ''[[Staphylococcus]]'' infection that, in one 1928 incident, killed 12 of 21 children [[vaccinate]]d with a [[diphtheria]] vaccine that lacked a preservative.<ref name=T-in-vaccines/> Unlike other vaccine preservatives used at the time, thiomersal does not reduce the potency of the vaccines that it protects.<ref name=Baker>{{cite journal |journal= Am J Public Health |year=2008 |title= Mercury, Vaccines, and Autism: One Controversy, Three Histories |author= Baker JP |doi=10.2105/AJPH.2007.113159 |pmid=18172138 |volume=98 |issue=2 |pages=244–53 |pmc= 2376879}}</ref> [[Bacteriostatic]]s like thiomersal are not needed in single-dose injectables.<ref>{{cite web | url = http://www.fda.gov/cber/vaccine/thimfaq.htm | title = Thimerosal in Vaccines: Frequently Asked Questions | publisher = [[Food and Drug Administration (United States)|Food and Drug Administration]] | accessdate = 2008-03-09 }}</ref>


However, despite these promising conjectures two systematic reviews of clinical trials could not find conclusive evidence that xylitol was indeed superior to other polyols such as [[sorbitol]]<ref>{{Cite journal | doi = 10.1111/j.1875-595X.2011.00113.x | title = Effect of xylitol versus sorbitol: A quantitative systematic review of clinical trials | year = 2012 | last1 = Mickenautsch | first1 = Steffen | last2 = Yengopal | first2 = Veerasamy | journal = International Dental Journal | volume = 62 | issue = 4 | pages = 175–88 | pmid = 23016999}}</ref> or equal to that of topical [[fluoride]] in its anti-caries effect.<ref>{{Cite journal | doi = 10.1111/j.1875-595X.2011.00086.x | title = Anticariogenic effect of xylitol versus fluoride - a quantitative systematic review of clinical trials | year = 2012 | last1 = Mickenautsch | first1 = Steffen | last2 = Yengopal | first2 = Veerasamy | journal = International Dental Journal | volume = 62 | pages = 6–20 | pmid = 22251032 | issue = 1}}</ref>
In the United States, countries in the European Union and a few other affluent countries, thiomersal is no longer used as a preservative in routine childhood [[vaccination schedule]]s.<ref name="drugsaf">{{cite journal |journal= Drug Saf |year=2005 |volume=28 |issue=2 |pages=89–101 |title= Thiomersal in vaccines: balancing the risk of adverse effects with the risk of vaccine-preventable disease |author= Bigham M, Copes R |pmid=15691220 |doi= 10.2165/00002018-200528020-00001}}</ref> In the U.S., the only exceptions among vaccines routinely recommended for children are some formulations of the inactivated influenza vaccine for children older than two years.<ref>{{cite web |title= Thimerosal in seasonal influenza vaccine |url=http://cdc.gov/FLU/ABOUT/QA/thimerosal.htm |date=2007-10-26 |accessdate=2008-04-02 |author= Coordinating Center for Infectious Diseases |publisher= Centers for Disease Control and Prevention |archiveurl = http://web.archive.org/web/20080411133237/http://www.cdc.gov/FLU/ABOUT/QA/thimerosal.htm |archivedate = 2008-04-11}}</ref> Several vaccines that are not routinely recommended for young children do contain thiomersal, including DT ([[diphtheria]] and [[tetanus]]), Td (tetanus and diphtheria), and TT (tetanus toxoid); other vaccines may contain a trace of thiomersal from steps in manufacture.<ref name=T-in-vaccines>{{cite web |date=2008-06-03 |url=http://www.fda.gov/cber/vaccine/thimerosal.htm |accessdate=2008-07-25 |title= Thimerosal in vaccines |publisher= Center for Biologics Evaluation and Research, U.S. Food and Drug Administration}}</ref> Also, four rarely used treatments for pit viper, coral snake, and black widow venom still contain thiomersal.<ref>{{cite web |date=2004-09-09 |url=http://www.fda.gov/cber/blood/mercplasma.htm |accessdate=2007-10-01 |title= Mercury in plasma-derived products |publisher= U.S. Food and Drug Administration |archiveurl = http://web.archive.org/web/20070929122259/http://www.fda.gov/cber/blood/mercplasma.htm <!-- Bot retrieved archive --> |archivedate = 2007-09-29}}</ref> Outside North America and Europe, many vaccines contain thiomersal; the [[World Health Organization]] has concluded that there is no evidence of toxicity from thiomersal in vaccines and no reason on safety grounds to change to more expensive single-dose administration.<ref>{{cite web |title= Thiomersal and vaccines |author= Global Advisory Committee on Vaccine Safety |publisher= World Health Organization |url=http://www.who.int/vaccine_safety/topics/thiomersal/en/index.html |date=2006-07-14 |accessdate=2007-11-20}}</ref> The [[United Nations Environment Programme|United Nations Environment Program]] backed away from an earlier proposal of adding thiomersal in vaccines to the list of banned compounds in a treaty aimed at reducing exposure to mercury worldwide.<ref>{{cite web|url= http://www.npr.org/blogs/health/2012/12/17/167280941/experts-argue-against-proposed-ban-on-vaccine-preservative|title=Doctors Argue Against Proposed Ban on Vaccine Preservative|author=Hamilton, Jon|publisher=[[NPR]]|date=17 December 2012|accessdate=25 February 2013}}</ref> Citing medical and scientific consensus that thiomersal in vaccines posed no safety issues, but that eliminating the preservative in multi-dose vaccines, primarily used in developing countries, will lead to high cost and a requirement for refrigeration which the developing countries can ill afford, the UN’s final decision is to exclude thiomersal from the treaty.<ref>{{cite web|url=http://www.fiercevaccines.com/story/un-excludes-vaccine-preservative-mercury-treaty/2013-01-24|title=U.N. excludes vaccine preservative from mercury treaty|author=Bryant, Alison|publisher=fiercevaccine.com|date=24 January 2013|accessdate=25 February 2013}}</ref>


In the 33-month Xylitol for Adult Caries Trial, participants were given lozenges of either five grams of xylitol or a sucralose-sweetened placebo. While this study initially found no statistically significant reduction in 33-month caries increment among adults at an elevated risk of developing caries,<ref>{{cite journal | url=http://jada.ada.org/content/144/1/21.abstract | title=Results from the Xylitol for Adult Caries Trial (X-ACT) | author=Bader, James D., et al. | journal=The Journal of the American Dental Association |date=Jan 2013 | volume=144 | issue=1 | pages=21–30 | doi=10.14219/jada.archive.2013.0010}}</ref> a further examination of data from this study revealed a significant reduction in the incidence of root caries in the group that received xylitol.<ref>{{cite journal | title=Tooth-surface-specific Effects of Xylitol: Randomized Trial Results | author=Ritter, AV, Bader, JD, Leo, MC, Preisser, JS, Shugars, DA, Vollmer, WM, Amaechi, BT, Holland, JC | journal=Journal of Dental Research |date=June 2013 | volume=92 | issue=6 | pages=512–517 | doi=10.1177/0022034513487211}}</ref>
== Toxicology ==


Xylitol is categorized by the [[Food and Drug Administration|U.S. Food and Drug Administration]] as a food additive.<ref>{{cite web | url=http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=172.395| title=CITE: 21CFR172.395 | publisher=United States Food and Drug Administration | work=Code of Federal Regulations Title 21 | date=2012-04-01}}</ref>
Thiomersal is very toxic by inhalation, ingestion, and in contact with skin (EC [[hazard symbol]] T+), with a danger of cumulative effects. It is also very toxic to aquatic organisms and may cause long-term adverse effects in aquatic environments (EC hazard symbol N).<ref>{{cite web |url=http://www.merck-chemicals.com/documents/sds/emd/int/en/8170/817043.pdf |format=PDF |date=2005-06-12 |accessdate=2010-01-01 |publisher=Merck |title=Safety data sheet, Thiomersal Ph Eur, BP, USP }}</ref> In the body, it is metabolized or degraded to [[ethylmercury]] (C<sub>2</sub>H<sub>5</sub>Hg<sup>+</sup>) and [[thiosalicylate]].<ref name=T-in-vaccines/>
Like other sugar alcohol-sweetened products, xylitol-sweetened products are allowed to be labeled with the claim that they do not promote dental cavities.


===Diabetes===
Cases have been reported of severe [[Mercury poisoning|poisoning]] by accidental exposure or attempted suicide, with some fatalities.<ref>{{cite journal |journal=Environ Health Perspect |year=2002 |volume=110 |issue=S1 |pages=11–23 |title=The three modern faces of mercury |author=Clarkson TW |pmid=11834460 |pmc=1241144 |url=http://www.ehponline.org/members/2002/suppl-1/11-23clarkson/clarkson-full.html |doi=10.1289/ehp.02110s111 }}</ref> Animal experiments suggest that thiomersal rapidly dissociates to release ethylmercury after injection; that the disposition patterns of mercury are similar to those after exposure to equivalent doses of ethylmercury chloride; and that the central nervous system and the kidneys are targets, with lack of motor coordination being a common sign. Similar signs and symptoms have been observed in accidental human poisonings. The mechanisms of toxic action are unknown. Fecal excretion accounts for most of the elimination from the body. Ethylmercury clears from blood with a [[half-life]] of about 18 days in adults. Ethylmercury is eliminated from the brain in about 14 days in infant monkeys.
Possessing approximately 33% fewer calories, xylitol is a lower-[[calorie]] alternative to table sugar. Absorbed more slowly than sugar, it does not contribute to high blood sugar levels or the resulting hyperglycemia caused by insufficient insulin response. This characteristic has also proven beneficial for people suffering from [[metabolic syndrome]], a common disorder that includes insulin resistance, hypertension, hypercholesterolemia, and an increased risk for blood clots.<ref>{{cite journal|last=Martí|first=N.|author2=Funes, L.L.|author3= Saura, D.|author4= Micol, V.|title=An update on alternative sweeteners|journal=International sugar journal |date=July 2008 |volume=110 |issue=1315 |pages=425–429 |issn=0020-8841}}</ref> Xylitol is used as a sweetener in medicines, [[chewing gum]] and [[pastille]]s.<ref>{{cite web|last=Savola|first=Päivikki|title=Xylitol combats cavities |url=http://virtual.finland.fi/netcomm/news/showarticle.asp?intNWSAID=43050#xyl|work=Advanced food development and functional foods from Finland|publisher=Finfood - Finnish Food Information |archiveurl= http://web.archive.org/web/20080411105055/http://virtual.finland.fi/netcomm/news/showarticle.asp?intNWSAID=43050#xyl |archivedate=April 18, 2008}}</ref>
Risk assessment for effects on the nervous system have been made by extrapolating from dose-response relationships for [[methylmercury]].<ref name=Clarkson/> Methylmercury and ethylmercury distribute to all body tissues, crossing the [[blood–brain barrier]] and the [[placental barrier]], and ethylmercury also moves freely throughout the body.<ref>{{cite journal |author=Clarkson TW, Vyas JB, Ballatori N |title=Mechanisms of mercury disposition in the body |journal= Am J Ind Med |volume=50 |issue=10 |pages=757–64 |year=2007 |pmid=17477364 |doi=10.1002/ajim.20476 }}</ref> Concerns based on extrapolations from methylmercury caused thiomersal to be removed from U.S. childhood vaccines, starting in 1999. Since then, it has been found that ethylmercury is eliminated from the body and the brain significantly faster than methylmercury, so the late-1990s risk assessments turned out to be overly conservative.<ref name=Clarkson/> Though inorganic mercury metabolized from ethylmercury has a much longer half-life in the brain, at least 120 days, it appears to be much less toxic than the inorganic mercury produced from mercury vapor, for reasons not yet understood.<ref name=Clarkson>{{cite journal |journal=Crit Rev Toxicol |year=2006 |volume=36 |issue=8 |pages=609–62 |title=The toxicology of mercury and its chemical compounds |author=Clarkson TW, Magos L |doi=10.1080/10408440600845619 |pmid=16973445 }}</ref> Thimerosal at concentrations relevant for infants' exposure (in vaccines) is toxic to cultured human-brain cells and to laboratory animals.<ref name=Dórea>{{cite journal |journal=Neurochem Res |year=2011 |volume=36 |issue=6 |pages=972–38 |title=Integrating experimental (in vitro and in vivo) neurotoxicity studies of low-dose thimerosal relevant to vaccines |author=Dórea JG |doi=10.1007/s11064-011-0427-0 |pmid=21350943 }}</ref>


=== Allergies ===
===Source of energy===


In the human gut xylitol is not absorbed as well as glucose or fructose; the unabsorbed xylitol acts as a dietary [[Dietary fiber|soluble fiber]] in helping to maintain certain aspects of gut function. Bacterial fermentation, mainly in the large gut, partly converts xylitol to [[short-chain fatty acid]]s that the gut can absorb as fuel for energy production in oxidative metabolic pathways. Xylitol also is useful in recovery after heavy exercise because the human body converts absorbed xylitol to [[glucose 6-phosphate]] and [[glycogen]]. The conversion is however slow, so that the xylitol amounts to a low-GI source of energy.<ref>{{cite journal|last=Vasilescu|first=Razvan|author2=Ionescu, A.M.|author3= Mihai, A.|author4= Carniciu, S.|author5= Ionescu-Tirgoviste, C.|title=Sweetners and metabolic diseases: Xylitol as a new player|journal=Proc. Rom. Acad.|year=2011|volume=2|series=B|pages=125–128}}</ref><ref>Xi Chen, Zi-Hua Jiang, Sanfeng Chen, and Wensheng Qin. Microbial and Bioconversion Production of D-xylitol and Its Detection and Application. Int J Biol Sci. 2010; 6(7): 834–844. Published online Dec 15, 2010. PMCID: PMC3005349
[[File:Epikutanni-test.jpg|thumb|180px |[[Patch test]]]]
</ref>
Thiomersal is used in [[patch test]]ing for people who have dermatitis, conjunctivitis, and other potentially allergic reactions. A 2007 study in Norway found that 1.9% of adults had a positive patch test reaction to thiomersal;<ref>{{cite journal |journal= Contact Dermatitis |year=2007 |volume=56 |issue=1 |pages=10–5 |title= Allergic contact sensitization in the general adult population: a population-based study from Northern Norway |author= Dotterud LK, Smith-Sivertsen T |doi=10.1111/j.1600-0536.2007.00980.x |pmid=17177703}}</ref> a higher prevalence of contact allergy (up to 6.6%) was observed in German populations.<ref name=Uter>{{cite journal |journal= J Clin Epidemiol |year=2004 |volume=57 |issue=6 |pages=627–32 |title= The prevalence of contact allergy differed between population-based and clinic-based data |author= Uter W, Ludwig A, Balda BR |doi=10.1016/j.jclinepi.2003.04.002 |pmid=15246132}}</ref> Thiomersal-sensitive individuals can receive [[Intramuscular injection|intramuscular]] rather than [[Subcutaneous injection|subcutaneous]] immunization,<ref>{{cite journal |journal= Contact Dermatitis |year=1991 |volume=24 |issue=1 |pages=6–10 |title= Vaccination despite thimerosal sensitivity |author= Aberer W |doi=10.1111/j.1600-0536.1991.tb01621.x |pmid=2044374}}</ref> though there have been no large sample sized studies regarding this matter to date. In real-world practice on vaccination of adult populations, contact allergy does not seem to elicit clinical reaction.<ref name=Uter/> Thiomersal allergy has decreased in Denmark, probably because of its exclusion from vaccines there.<ref>{{cite journal |journal= Contact Dermatitis |year=2007 |volume=57 |issue=5 |pages=287–99 |title= The epidemiology of contact allergy in the general population—prevalence and main findings |author= Thyssen JP, Linneberg A, Menné T, Johansen JD |doi=10.1111/j.1600-0536.2007.01220.x |pmid=17937743 |url=http://www.blackwell-synergy.com/doi/full/10.1111/j.1600-0536.2007.01220.x}}</ref> In a recent study of Polish children and adolescents with chronic/recurrent eczema, positive reactions to thiomersal were found in 11.7% of children (7–8 y.o.) and 37.6% of adolescents (16–17 y.o.). This difference in the sensitization rates can be explained by changing exposure patterns: The adolescents have received six thiomersal-preserved vaccines during their life course, with the last immunization taking place 2–3 years before the mentioned study, younger children received only four thiomersal-preserved vaccines, with the last one applied 5 years before the study, while further immunizations were performed with new thiomersal-free vaccines.<ref>{{cite journal |journal= Pediatr Allergy Immunol |year=2011 |volume=22 |issue=2 |pages=252–6 |title= The most important contact sensitizers in Polish children and adolescents with atopy and chronic recurrent eczema as detected with the extended European Baseline Series |author= Czarnobilska E, Obtulowicz K, Dyga W, Spiewak R |pmid=20969635 |doi=10.1111/j.1399-3038.2010.01075.x}}</ref>


=== Autism ===
===Ear infection===
Xylitol chewing gum appears to decrease rates of acute [[otitis media]] in children going to daycare by 25%.<ref>{{cite journal|last=Azarpazhooh|first=A|author2=Limeback, H |author3=Lawrence, HP |author4= Shah, PS |title=Xylitol for preventing acute otitis media in children up to 12 years of age.|journal=The Cochrane database of systematic reviews|date=Nov 9, 2011|issue=11|pages=CD007095|pmid=22071833|doi=10.1002/14651858.CD007095.pub2}}</ref>
Xylitol nasal sprays have also been shown to decrease incidence of acute otitis media as well as being a very effective way of both assisting and stimulating the body's own natural nasopharyngeal washing, and reducing both bacterial colonization and allergenic pollution, with their accompanying problems.<ref>{{cite journal|last=Jones|first=A|title=Intranasal Xylitol, Recurrent Otitis Media, and Asthma: Report of Three Cases.|journal=Clinical Practice of Alternative Medicine |date=Summer 2001|issue=2|pages=112–117}}</ref>


===Osteoporosis===
{{main|Thiomersal controversy}}
A feed containing Xylitol increased bone volume in rat studies conducted in 2001 and 2011, these results have generated interest in the sugar that would examine if it could be a human treatment for [[osteoporosis]].<ref>{{cite web|url=http://www.drugs.com/npp/xylitol.html|title=Xylitol|work=drugs.com|accessdate=12 July 2015}}</ref><ref>{{cite web|url=http://www.ncbi.nlm.nih.gov/pubmed/11721142|title=Increased bone volume and bone mineral content in xylitol-fed aged rats.|author=Mattila PT , et al.|work=nih.gov|accessdate=12 July 2015}}</ref><ref>{{cite web|url=http://www.ncbi.nlm.nih.gov/pubmed/21271323|title=The effects of oral xylitol administration on bone density in rat femur.|author=Sato H , et al.|work=nih.gov|accessdate=12 July 2015}}</ref>
Following a review of mercury-containing food and drugs mandated in 1999, the [[Centers for Disease Control]] (CDC) and the [[American Academy of Pediatrics]] asked vaccine manufacturers to remove thiomersal from vaccines as a purely precautionary measure, and it was rapidly phased out of most U.S. and European vaccines.<ref name="Baker"/><ref>{{cite web |url=http://www.fda.gov/cber/vaccine/thimfaq.htm |date=2007-06-07 |accessdate=2008-07-22 |title= Thimerosal in vaccines: frequently asked questions (FAQs) |publisher= Center for Biologics Evaluation and Research, U.S. Food and Drug Administration}}</ref> Many parents saw the action to remove thiomersal—in the setting of a perceived increasing rate of autism as well as increasing number of vaccines in the childhood vaccination schedule—as indicating that the preservative was the cause of autism.<ref name="Baker" /> The [[scientific consensus]] is that there is no scientific evidence supporting these claims, including the observation that the rate of autism continues to climb despite elimination of thiomersal from routine childhood vaccines.<ref name=DeStefano>{{cite journal |journal= Clin Pharmacol Ther |year=2007 |volume=82 |issue=6 |pages=756–9 |title= Vaccines and autism: evidence does not support a causal association |author= DeStefano F |doi=10.1038/sj.clpt.6100407 |pmid=17928818}}</ref><ref name=Doja>{{cite journal |journal= Can J Neurol Sci |year=2006 |volume=33 |issue=4 |pages=341–6 |title= Immunizations and autism: a review of the literature |author= Doja A, Roberts W |pmid=17168158 |doi=10.1017/s031716710000528x}}</ref><ref name=IOM2004/> Major scientific and medical bodies such as the [[Institute of Medicine]]<ref name=IOM2004>{{cite book |author= Immunization Safety Review Committee, Board on Health Promotion and Disease Prevention, [[Institute of Medicine]] |title= Immunization Safety Review: Vaccines and Autism |publisher= The National Academies Press |location= Washington, DC |year=2004 |isbn=0-309-09237-X |url=http://www.nap.edu/catalog/10997.html}}</ref> and [[World Health Organization]],<ref name=WHO>{{cite web |author= World Health Organization |year=2006 |url=http://who.int/vaccine_safety/topics/thiomersal/questions/en/ |title= Thiomersal and vaccines: questions and answers |accessdate=2009-05-19}}</ref> as well as governmental agencies such as the [[Food and Drug Administration]]<ref name=T-in-vaccines/> and the CDC<ref name=CDC>{{cite web |author= Centers for Disease Control |date=2008-02-08 |url=http://www.cdc.gov/vaccinesafety/updates/thimerosal.htm |title= Mercury and vaccines (thimerosal) |accessdate=2009-05-19}}</ref> reject any role for thiomersal in autism or other neurodevelopmental disorders.<ref name=Sugarman>{{cite journal |journal=N Engl J Med |year=2007 |volume=357 |issue=13 |pages=1275–7 |title=Cases in vaccine court—legal battles over vaccines and autism |author=Sugarman SD |pmid=17898095 |url=http://content.nejm.org/cgi/content/full/357/13/1275 |doi= 10.1056/NEJMp078168 }}</ref> This controversy has caused harm due to parents attempting to treat their autistic children with unproven and possibly dangerous treatments, discouraging parents from vaccinating their children due to fears about thiomersal toxicity,<ref name=Harris>{{cite news |work= New York Times |url=http://nytimes.com/2005/06/25/science/25autism.htm |date=2005-06-25 |title= On autism's cause, it's parents vs. research |author= Harris G, O'Connor A |accessdate=2010-07-02}}</ref> and diverting resources away from research into more promising areas for the [[cause of autism]].<ref name=Offit>{{cite journal |journal= N Engl J Med |year=2007 |volume=357 |issue=13 |pages=1278–9 |title= Thimerosal and vaccines—a cautionary tale |author= Offit PA |doi=10.1056/NEJMp078187 |pmid=17898096 |url=http://content.nejm.org/cgi/content/full/357/13/1278 |authorlink= Paul Offit}}</ref> Thousands of lawsuits have been filed in a [[vaccine court|U.S. federal court]] to seek damages from alleged toxicity from vaccines, including those purportedly caused by thiomersal.<ref>Autism cases in vaccine court:
*{{cite journal |journal= N Engl J Med |year=2007 |volume=357 |issue=13 |pages=1275–7 |title= Cases in vaccine court—legal battles over vaccines and autism |author= Sugarman SD |pmid=17898095 |url=http://content.nejm.org/cgi/content/full/357/13/1275 |doi= 10.1056/NEJMp078168}}
*{{cite web |author= [[U.S. Court of Federal Claims]] |date=2007-09-28 |url=http://www.uscfc.uscourts.gov/OSM/OSMAutism.htm |title= Vaccine Program/Office of Special Masters Omnibus Autism Proceeding |accessdate=2007-11-24 |archiveurl = http://web.archive.org/web/20071023235955/http://www.uscfc.uscourts.gov/OSM/OSMAutism.htm <!-- Bot retrieved archive --> |archivedate = 2007-10-23}}</ref>


== History ==
==Safety==
Xylitol has no known [[toxic]]ity in humans. In one study, the participants consumed a diet containing a monthly average of 1.5&nbsp;kg of xylitol with a maximum daily intake of 430&nbsp;g with no apparent ill effects.<ref name="Mäkinen_1976">{{cite journal |author=Mäkinen, KK |title=Long-term tolerance of healthy human subjects to high amounts of xylitol and fructose: general and biochemical findings |journal=Internationale Zeitschrift fur Vitamin und Ernahrungsforschung Beiheft |volume=15 |issue= |pages=92–104 |year=1976 |pmid=783060 |doi= 10.1002/14651858.CD010743|url=http://www.ncbi.nlm.nih.gov/pubmed/783060 }}</ref> Like most sugar alcohols, it has a [[laxative]] effect because sugar alcohols are not fully broken down during digestion; albeit one-tenth the strength of sorbitol.{{Clarify|date=June 2011}} The effect depends upon the individual. In one study of 13 children, four experienced diarrhea when consuming over 65&nbsp;grams per day.<ref name=Wang1981/> Studies have reported that adaptation occurs after several weeks of consumption.<ref name="Wang1981"/>


As with other sugar alcohols, with the exception of [[erythritol]], consumption in excess of one's laxation threshold (the amount of sweetener that can be consumed before abdominal discomfort sets in) can result in temporary gastrointestinal side effects, such as [[bloating]], [[flatulence]], and [[diarrhea]]. Adaptation, an increase of the laxation threshold, occurs with regular intake. Xylitol has a lower laxation threshold than some sugar alcohols, but is more easily tolerated than others such as [[mannitol]] and [[sorbitol]].<ref name=Wang1981>{{cite journal |author=Wang, Yeu-Ming; van Eys, Jan |title=Nutritional significance of fructose and sugar alcohols |journal=Annual Review of Nutrition |volume=1 |pages=437–75 |year=1981 |pmid=6821187 |doi=10.1146/annurev.nu.01.070181.002253 |url=}}</ref><ref>{{cite web|title=Sugar Alcohols|url=http://www.dm2nb.ca/pdf/patient_resources/diabetes/sugar_alcohols_cda.pdf|publisher=Canadian Diabetes Association|accessdate=March 14, 2012|date=May 2005}}</ref>
[[Morris Kharasch]], a [[chemist]] at the [[University of Maryland, College Park|University of Maryland]], filed a patent application for thiomersal in 1927;<ref>{{US patent|1672615}} "Alkyl mercuric sulphur compound and process of producing it".</ref> Eli Lilly later marketed the compound under the trade name Merthiolate.<ref name="Baker"/> [[In vitro]] tests conducted by Lilly investigators H. M. Powell and W. A. Jamieson found that it was forty to fifty times as effective as [[phenol]] against ''[[Staphylococcus aureus]]''.<ref name="Baker"/> It was used to kill bacteria and prevent contamination in antiseptic ointments, creams, jellies, and sprays used by consumers and in hospitals, including nasal sprays, eye drops, contact lens solutions, [[immunoglobulin]]s, and vaccines. Thiomersal was used as a preservative ([[bactericide]]) so that multidose vials of vaccines could be used instead of single-dose vials, which are more expensive. By 1938, Lilly's assistant director of research listed thiomersal as one of the five most important drugs ever developed by the company.<ref name="Baker"/>


== See also ==
===Xylitol toxicity in dogs===
Xylitol is well established as a life-threatening [[toxin]] to dogs. According to the [[ASPCA]] Animal Poison Control Center, the number of cases of xylitol toxicosis in dogs has significantly increased since the first reports in 2002. [[Dog]]s that have ingested foods containing xylitol (greater than 100&nbsp;milligrams of xylitol consumed per kilogram of bodyweight) have presented with low blood sugar ([[hypoglycemia]]), which can be life-threatening.<ref name=Dunayer_2006_acute>{{cite journal|last=Dunayer|first=Eric K.|author2=Gwaltney-Brant, Sharon M.|title=Acute hepatic failure and coagulopathy associated with xylitol ingestion in eight dogs|journal=[[Journal of the American Veterinary Medical Association]] |date=October 2006 |volume=229|issue=7|pages=1113–1117|doi=10.2460/javma.229.7.1113|pmid=17014359}}</ref> Low blood sugar can result in a loss of coordination, depression, collapse and seizures in as little as 30&nbsp;minutes.<ref name=Dunayer_2004>{{cite journal|last=Dunayer|first=Erik K.|title=Hypoglycemia following canine ingestion of xylitol-containing gum|journal=Veterinary and human toxicology |date=April 2004|volume=46|issue=2|pages=87–88|pmid=15080212}}</ref> Intake of doses of xylitol (greater than 500&nbsp;– 1000&nbsp;mg/kg bwt) has been implicated in liver failure in dogs, which can be fatal.<ref name=Dunayer_2006_new>{{cite journal|last=Dunayer|first=Erik K.|title=New findings on the effects of xylitol ingestion in dogs|journal=Veterinary Medicine|date=December 2006|volume=101|issue=12|pages=791–797|url=http://files.meetup.com/556343/xylitol%20in%20dogs.pdf|accessdate=March 14, 2012}}</ref> Possible cause of hypoglycemia experienced by dogs is the fact that the xylitol in gum is released more slowly and absorbed over longer period than when it is consumed as a pure form.<ref>{{cite journal|last=Dunayer|first=Eric K|title=Hypoglycemia Following Canine Ingestion of Xylitol-Containing Gum|journal=Vet. Human Toxicol.|year=2004|volume=46|issue=2|pages=87–88}}</ref>
===Xylitol toxicity in wild birds===
A vet examined the bodies of 30 Cape Sugarbirds that had died within 30 minutes of drinking a solution made with xylitol, from a feeder in a Hermanus garden.<ref>{{cite web|url=http://www.iol.co.za/scitech/science/environment/xylitol-could-kill-sugarbirds-and-pets-1.1847533#.VY7K6LyBQfo|title=Xylitol could kill sugarbirds - and pets|work=Independent Online|accessdate=12 July 2015}}</ref>


==See also==
* [[Argyrol]], a silver containing antimicrobial
{{Portal|Food|Dentistry}}
* [[Mercury (element)]]
* [[Aspartame]]
* [[Nitromersol]], a related antimicrobial
* [[L-xylulose reductase]]
* [[Sucralose]]
* [[Xylonic acid]]
* [[Birch sap]]


==Notes and references==
== References ==
{{reflist|colwidth=30em}}
{{reflist|colwidth=30em}}


{{E number infobox 950-969}}
{{Mercury compounds}}
{{vaccines}}
{{Sugar alcohols}}
{{Antiseptics and disinfectants}}


{{Authority control}}
[[Category:Thiolates]]
[[Category:Eli Lilly and Company]]
[[Category:Sweeteners]]
[[Category:Organomercury compounds]]
[[Category:Sugar alcohols]]
[[Category:Excipients]]
[[Category:Excipients]]
[[Category:Sodium compounds]]
[[Category:Benzoates]]

Revision as of 21:10, 14 July 2015

Xylitol[1]
Xylitol

Xylitol crystals
Names
IUPAC name
(2R,4S)-Pentane-1,2,3,4,5-pentol
Other names
1,2,3,4,5-Pentahydroxypentane;
Xylite
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.000.192 Edit this at Wikidata
UNII
  • InChI=1S/C5H12O5/c6-1-3(8)5(10)4(9)2-7/h3-10H,1-2H2/t3-,4+,5+ ☒N
    Key: HEBKCHPVOIAQTA-SCDXWVJYSA-N ☒N
  • InChI=1/C5H12O5/c6-1-3(8)5(10)4(9)2-7/h3-10H,1-2H2/t3-,4+,5+
    Key: HEBKCHPVOIAQTA-SCDXWVJYBA
  • O[C@H](CO)[C@H](O)[C@@H](O)CO
Properties
C5H12O5
Molar mass 152.146 g·mol−1
Density 1.52 g/cm3
Melting point 92 to 96 °C (198 to 205 °F; 365 to 369 K)
Boiling point 345.39 °C (653.70 °F; 618.54 K) Predicted value using Adapted Stein & Brown method[2]
~ 0.1 g/mL
Hazards
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth 1: Exposure would cause irritation but only minor residual injury. E.g. turpentineFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
1
1
0
Related compounds
Related alkanes
 Pentane
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Xylitol /ˈzaɪlɪtɒl/ is a sugar alcohol used as a sweetener. The name derives from Greek: ξύλον, xyl[on], "wood" + suffix -itol, used to denote sugar alcohols. Xylitol is categorized as a polyalcohol or sugar alcohol (alditol). It has the formula CH2OH(CHOH)3CH2OH and is an achiral[3] isomer of pentane-1,2,3,4,5-pentol. Xylitol is roughly as sweet as sucrose (table sugar), with 33% fewer calories. Unlike other natural or synthetic sweeteners, xylitol is actively beneficial for dental health by reducing caries (cavities) to a third in regular use and helpful to remineralization.[4] Multiple studies utilizing electron microscopy have indicated that xylitol is effective in inducing remineralization of deeper layers of demineralized enamel.[5][6] Fair evidence was found that xylitol (as chewing gum, lozenges, nasal spray, etc.) reduced the incidence of acute middle ear infection in healthy children.[7]

Xylitol is naturally found in low concentrations in the fibers of many fruits and vegetables, and can be extracted from various berries, oats, and mushrooms, as well as fibrous material such as corn husks and sugar cane bagasse,[8][9][10] and birch.[11] However, industrial production starts from xylan (a hemicellulose) extracted from hardwoods[12] or corncobs, which is hydrolyzed into xylose and catalytically hydrogenated into xylitol. A study in rats found that xylitol had reduced or nonexistent side effects compared to other artificial sweeteners, and lower caloric value and cariogenicity than sucrose.[13]

Production

Xylitol was discovered almost simultaneously by German and French chemists in the late 19th century,[14] and was first popularized in Europe as a safe sweetener that would not affect insulin levels of people with diabetes. Xylitol is produced by hydrogenation of xylose, which converts the sugar (an aldehyde) into a primary alcohol. It can also be extracted from natural sources, and is often harvested by tapping birch trees to produce birch sap. Another method of producing xylitol is through microbial processes, including fermentative and biocatalytic processes in bacteria, fungi, and yeast cells, that take advantage of the xylose-intermediate fermentations to produce high yield of xylitol.[15] Common yeast cells used in effectly fermenting and producing xylitol are Candida tropicalis and Candida guilliermondii.[16] Its dental significance was researched in Finland in the early 1970s. There, scientists at University of Turku demonstrated dental benefits in what became known as the "Turku sugar studies".[14]

Properties

One gram of xylitol contains 2.4 kilocalories (kcal),[17] as compared to one gram of sugar, which has 3.87 kcal.[18] Xylitol has virtually no aftertaste, and is advertised as "safe for diabetics and individuals with hyperglycemia." This tolerance is attributed to the lower effect of xylitol on a person's blood sugar, compared to that of regular sugars as it has an extremely low glycemic index of 7 (glucose has a GI of 100).[19] Xylitol has no known toxicity or carcinogenicity, and is considered safe by the U.S. FDA[20]

Health benefits

Dental care

Xylitol is a "tooth-friendly", nonfermentable sugar alcohol.[21][22] It appears to have more dental health benefits than other polyalcohols.[23] The structure of xylitol contains a tridentate ligand, (H-C-OH)3 that can rearrange with polyvalent cations like Ca2+. This interaction allows Ca2+ to be transported through the gut wall barrier and through saliva may remineralize enamel before dental cavities form.[24]

Early studies from Finland in the 1970s found compared to chewing sucrose-flavored gum, xylitol resulted in nearly two fewer cavities or missing teeth.[25] Cavity-causing bacteria prefer six-carbon sugars or disaccharides, while xylitol is non-fermentable and cannot be used as an energy source - while still being taken up into the cell (due to similar shape) and leaving no room for the six-carbon sugars, interfering with bacterial growth and reproduction. The harmful micro-organisms are starved in the presence of xylitol, allowing the mouth to remineralize damaged teeth with less interruption. This same property renders it unsuitable for making bread as it interferes with the ability of yeast to digest sugars.[24] At least six grams of xylitol per day is thought to be needed for dental efficacy.[24]

Xylitol also inhibits the growth of Streptococcus pneumoniae, as well as the attachment of Haemophilus influenzae on the nasopharyngeal cells.[24]

The perception of sweetness obtained from consuming xylitol causes the secretion of saliva which acts as a buffer against the acidic environment created by the microorganisms in dental plaque. Increase in salivation can raise the falling pH to a neutral range within few minutes of xylitol consumption.[26]

However, despite these promising conjectures two systematic reviews of clinical trials could not find conclusive evidence that xylitol was indeed superior to other polyols such as sorbitol[27] or equal to that of topical fluoride in its anti-caries effect.[28]

In the 33-month Xylitol for Adult Caries Trial, participants were given lozenges of either five grams of xylitol or a sucralose-sweetened placebo. While this study initially found no statistically significant reduction in 33-month caries increment among adults at an elevated risk of developing caries,[29] a further examination of data from this study revealed a significant reduction in the incidence of root caries in the group that received xylitol.[30]

Xylitol is categorized by the U.S. Food and Drug Administration as a food additive.[31] Like other sugar alcohol-sweetened products, xylitol-sweetened products are allowed to be labeled with the claim that they do not promote dental cavities.

Diabetes

Possessing approximately 33% fewer calories, xylitol is a lower-calorie alternative to table sugar. Absorbed more slowly than sugar, it does not contribute to high blood sugar levels or the resulting hyperglycemia caused by insufficient insulin response. This characteristic has also proven beneficial for people suffering from metabolic syndrome, a common disorder that includes insulin resistance, hypertension, hypercholesterolemia, and an increased risk for blood clots.[32] Xylitol is used as a sweetener in medicines, chewing gum and pastilles.[33]

Source of energy

In the human gut xylitol is not absorbed as well as glucose or fructose; the unabsorbed xylitol acts as a dietary soluble fiber in helping to maintain certain aspects of gut function. Bacterial fermentation, mainly in the large gut, partly converts xylitol to short-chain fatty acids that the gut can absorb as fuel for energy production in oxidative metabolic pathways. Xylitol also is useful in recovery after heavy exercise because the human body converts absorbed xylitol to glucose 6-phosphate and glycogen. The conversion is however slow, so that the xylitol amounts to a low-GI source of energy.[34][35]

Ear infection

Xylitol chewing gum appears to decrease rates of acute otitis media in children going to daycare by 25%.[36] Xylitol nasal sprays have also been shown to decrease incidence of acute otitis media as well as being a very effective way of both assisting and stimulating the body's own natural nasopharyngeal washing, and reducing both bacterial colonization and allergenic pollution, with their accompanying problems.[37]

Osteoporosis

A feed containing Xylitol increased bone volume in rat studies conducted in 2001 and 2011, these results have generated interest in the sugar that would examine if it could be a human treatment for osteoporosis.[38][39][40]

Safety

Xylitol has no known toxicity in humans. In one study, the participants consumed a diet containing a monthly average of 1.5 kg of xylitol with a maximum daily intake of 430 g with no apparent ill effects.[41] Like most sugar alcohols, it has a laxative effect because sugar alcohols are not fully broken down during digestion; albeit one-tenth the strength of sorbitol.[clarification needed] The effect depends upon the individual. In one study of 13 children, four experienced diarrhea when consuming over 65 grams per day.[42] Studies have reported that adaptation occurs after several weeks of consumption.[42]

As with other sugar alcohols, with the exception of erythritol, consumption in excess of one's laxation threshold (the amount of sweetener that can be consumed before abdominal discomfort sets in) can result in temporary gastrointestinal side effects, such as bloating, flatulence, and diarrhea. Adaptation, an increase of the laxation threshold, occurs with regular intake. Xylitol has a lower laxation threshold than some sugar alcohols, but is more easily tolerated than others such as mannitol and sorbitol.[42][43]

Xylitol toxicity in dogs

Xylitol is well established as a life-threatening toxin to dogs. According to the ASPCA Animal Poison Control Center, the number of cases of xylitol toxicosis in dogs has significantly increased since the first reports in 2002. Dogs that have ingested foods containing xylitol (greater than 100 milligrams of xylitol consumed per kilogram of bodyweight) have presented with low blood sugar (hypoglycemia), which can be life-threatening.[44] Low blood sugar can result in a loss of coordination, depression, collapse and seizures in as little as 30 minutes.[45] Intake of doses of xylitol (greater than 500 – 1000 mg/kg bwt) has been implicated in liver failure in dogs, which can be fatal.[46] Possible cause of hypoglycemia experienced by dogs is the fact that the xylitol in gum is released more slowly and absorbed over longer period than when it is consumed as a pure form.[47]

Xylitol toxicity in wild birds

A vet examined the bodies of 30 Cape Sugarbirds that had died within 30 minutes of drinking a solution made with xylitol, from a feeder in a Hermanus garden.[48]

See also

Notes and references

  1. ^ Material safety data sheet for xylitol from Fisher Scientific. Retrieved 2014-11-02.
  2. ^ "Xylitol". Chemspider. Retrieved 13 May 2015.
  3. ^ Wrolstad, Ronald E. (2012). Food Carbohydrate Chemistry. John Wiley & Sons. p. 176. ISBN 9780813826653. Retrieved October 20, 2012. Xylitol contains asymmetric carbon atoms, but it is not chiral because the molecule as a whole is symmetrical.
  4. ^ Steinberg, LM; Odusola, F; Mandel, ID (Sep–Oct 1992). "Remineralizing potential, antiplaque and antigingivitis effects of xylitol and sorbitol sweetened chewing gum". Clinical preventive dentistry. 14 (5): 31–4. PMID 1291185. Retrieved 13 November 2013.
  5. ^ Miake Y ; et al. "Remineralization effects of xylitol on demineralized enamel". nih.gov. Retrieved 12 July 2015. {{cite web}}: Explicit use of et al. in: |author= (help)
  6. ^ http://www.drellie.com/pdfs/The-Remineralization-effects-of-XYLITOL.pdf
  7. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 22071833 , please use {{cite journal}} with |pmid=22071833 instead.
  8. ^ Gare, Fran (February 1, 2003). The Sweet Miracle of Xylitol. Basic Health Publications, Inc. ISBN 1-59120-038-5.
  9. ^ Rao, R. Sreenivas; Jyothi, Ch. Pavana; Prakasham, RS; Sharma, PN; Rao, L. Venkateswar (2006). "Other material suggests that there is no xylitol in any fruit and vegtables". Bioresour. Technol. 97: 1974–8. doi:10.1016/j.biortech.2005.08.015. PMID 16242318.{{cite journal}}: CS1 maint: multiple names: authors list (link)[verification needed]
  10. ^ "Xylitol production from corn fiber and sugarcane bagasse hydrolysates by Candida tropicalis" (PDF). Bioresource Technology. 97 (15): 1974–1978. October 2006. doi:10.1016/j.biortech.2005.08.015. PMID 16242318. Retrieved March 14, 2012.
  11. ^ "FAQ". Xylitol Canada. Retrieved March 14, 2012.
  12. ^ Converti, Atillio; Parego, Patrizia; Dominguez, Jose Manuel (1999). "Xylitol Production from Hardwood Hemicellulose Hydrosylates" (PDF). Applied Biochemistry and Biotechnology. 82: 141–151. doi:10.1385/abab:82:2:141.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1159/000338440, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1159/000338440 instead.
  14. ^ a b "Xylitol FAQ's". Xlear. Retrieved March 14, 2012.
  15. ^ Nigam, Poonam; Singh, D. (1995). "Processes for Fermentative Production of Xylitol--a Sugar Substitute". Process Biochemistry. 30: 117–124. doi:10.1016/0032-9592(95)80001-8.
  16. ^ Barbosa,, M.F.S.; de Medeiros, M.B.; de Manchilha, I.M.; Schneider, H.; Lee, H. (1988). "Screening of yeasts for production of xylitol from D-xylose and some factors which affect xylitol yield in Candida guillermondii". J. Indust. Microbiol. 3: 241–251. doi:10.1007/bf01569582.{{cite journal}}: CS1 maint: extra punctuation (link)
  17. ^ Walters, D. Eric. "Xylitol". All About Sweeteners. Retrieved March 14, 2012.
  18. ^ "Sugars, granulated (sucrose)". Self Nutrition Data. Retrieved March 14, 2012. With a serving size of 100 grams, there are 387 calories.
  19. ^ The American Journal of Clinical Nutrition, January 1, 2002: International table of glycemic index and glycemic load values Retrieved 2012-08-26
  20. ^ "Tom's of Maine". tomsofmaine.com. Retrieved 12 July 2015.
  21. ^ Edwardsson, Stig; Birkhed, Dowen; Mejàre, Bertil (1977). "Acid production from Lycasin, maltitol, sorbitol and xylitol by oral streptococci and lactobacilli". Acta Odontologica Scandinavica. 35 (5): 257–263. doi:10.3109/00016357709019801. PMID 21508.
  22. ^ Drucker, D.B.; Verran, J. (1979). "Comparative effects of the substance-sweeteners glucose, sorbitol, sucrose, xylitol and trichlorosucrose on lowering of pH by two oral Streptococcus mutans strains in vitro". Archives of Oral Biology. 24 (12): 965–970. doi:10.1016/0003-9969(79)90224-3. PMID 44996.
  23. ^ Maguire, A; Rugg-Gunn, A J (2003). "Xylitol and caries prevention — is it a magic bullet?". British Dental Journal. 194 (8): 429–436. doi:10.1038/sj.bdj.4810022. PMID 12778091. Retrieved March 14, 2012.
  24. ^ a b c d Reusens, B. (2004). Remacle, Claude; Reusens, Brigitte (ed.). Functional foods, ageing and degenerative disease. Cambridge, England: Woodhead Publishing. p. 202. ISBN 978-1-85573-725-9. Retrieved March 14, 2012.{{cite book}}: CS1 maint: multiple names: editors list (link)
  25. ^ "Policy on the Use of Xylitol in Caries Prevention" (PDF). Reference Manual. 33 (6). American Academy of Pediatric Dentistry: 42–44. 2010. Retrieved March 14, 2012.
  26. ^ Scheinin, Arje (1993). "Dental Caries, Sugars and Xylitol". Ann Med. 25: 519–521.
  27. ^ Mickenautsch, Steffen; Yengopal, Veerasamy (2012). "Effect of xylitol versus sorbitol: A quantitative systematic review of clinical trials". International Dental Journal. 62 (4): 175–88. doi:10.1111/j.1875-595X.2011.00113.x. PMID 23016999.
  28. ^ Mickenautsch, Steffen; Yengopal, Veerasamy (2012). "Anticariogenic effect of xylitol versus fluoride - a quantitative systematic review of clinical trials". International Dental Journal. 62 (1): 6–20. doi:10.1111/j.1875-595X.2011.00086.x. PMID 22251032.
  29. ^ Bader, James D.; et al. (Jan 2013). "Results from the Xylitol for Adult Caries Trial (X-ACT)". The Journal of the American Dental Association. 144 (1): 21–30. doi:10.14219/jada.archive.2013.0010. {{cite journal}}: Explicit use of et al. in: |author= (help)
  30. ^ Ritter, AV, Bader, JD, Leo, MC, Preisser, JS, Shugars, DA, Vollmer, WM, Amaechi, BT, Holland, JC (June 2013). "Tooth-surface-specific Effects of Xylitol: Randomized Trial Results". Journal of Dental Research. 92 (6): 512–517. doi:10.1177/0022034513487211.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  31. ^ "CITE: 21CFR172.395". Code of Federal Regulations Title 21. United States Food and Drug Administration. 2012-04-01.
  32. ^ Martí, N.; Funes, L.L.; Saura, D.; Micol, V. (July 2008). "An update on alternative sweeteners". International sugar journal. 110 (1315): 425–429. ISSN 0020-8841.
  33. ^ Savola, Päivikki. "Xylitol combats cavities". Advanced food development and functional foods from Finland. Finfood - Finnish Food Information. Archived from the original on April 18, 2008. {{cite web}}: |archive-date= / |archive-url= timestamp mismatch; April 11, 2008 suggested (help)
  34. ^ Vasilescu, Razvan; Ionescu, A.M.; Mihai, A.; Carniciu, S.; Ionescu-Tirgoviste, C. (2011). "Sweetners and metabolic diseases: Xylitol as a new player". Proc. Rom. Acad. B. 2: 125–128.
  35. ^ Xi Chen, Zi-Hua Jiang, Sanfeng Chen, and Wensheng Qin. Microbial and Bioconversion Production of D-xylitol and Its Detection and Application. Int J Biol Sci. 2010; 6(7): 834–844. Published online Dec 15, 2010. PMCID: PMC3005349
  36. ^ Azarpazhooh, A; Limeback, H; Lawrence, HP; Shah, PS (Nov 9, 2011). "Xylitol for preventing acute otitis media in children up to 12 years of age". The Cochrane database of systematic reviews (11): CD007095. doi:10.1002/14651858.CD007095.pub2. PMID 22071833.
  37. ^ Jones, A (Summer 2001). "Intranasal Xylitol, Recurrent Otitis Media, and Asthma: Report of Three Cases". Clinical Practice of Alternative Medicine (2): 112–117.
  38. ^ "Xylitol". drugs.com. Retrieved 12 July 2015.
  39. ^ Mattila PT ; et al. "Increased bone volume and bone mineral content in xylitol-fed aged rats". nih.gov. Retrieved 12 July 2015. {{cite web}}: Explicit use of et al. in: |author= (help)
  40. ^ Sato H ; et al. "The effects of oral xylitol administration on bone density in rat femur". nih.gov. Retrieved 12 July 2015. {{cite web}}: Explicit use of et al. in: |author= (help)
  41. ^ Mäkinen, KK (1976). "Long-term tolerance of healthy human subjects to high amounts of xylitol and fructose: general and biochemical findings". Internationale Zeitschrift fur Vitamin und Ernahrungsforschung Beiheft. 15: 92–104. doi:10.1002/14651858.CD010743. PMID 783060.
  42. ^ a b c Wang, Yeu-Ming; van Eys, Jan (1981). "Nutritional significance of fructose and sugar alcohols". Annual Review of Nutrition. 1: 437–75. doi:10.1146/annurev.nu.01.070181.002253. PMID 6821187.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  43. ^ "Sugar Alcohols" (PDF). Canadian Diabetes Association. May 2005. Retrieved March 14, 2012.
  44. ^ Dunayer, Eric K.; Gwaltney-Brant, Sharon M. (October 2006). "Acute hepatic failure and coagulopathy associated with xylitol ingestion in eight dogs". Journal of the American Veterinary Medical Association. 229 (7): 1113–1117. doi:10.2460/javma.229.7.1113. PMID 17014359.
  45. ^ Dunayer, Erik K. (April 2004). "Hypoglycemia following canine ingestion of xylitol-containing gum". Veterinary and human toxicology. 46 (2): 87–88. PMID 15080212.
  46. ^ Dunayer, Erik K. (December 2006). "New findings on the effects of xylitol ingestion in dogs" (PDF). Veterinary Medicine. 101 (12): 791–797. Retrieved March 14, 2012.
  47. ^ Dunayer, Eric K (2004). "Hypoglycemia Following Canine Ingestion of Xylitol-Containing Gum". Vet. Human Toxicol. 46 (2): 87–88.
  48. ^ "Xylitol could kill sugarbirds - and pets". Independent Online. Retrieved 12 July 2015.
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