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Revision as of 13:31, 6 December 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{chembox}} taken from revid 458667545 of page Safrole for the Chem/Drugbox validation project (updated: '').		Latest revision as of 16:06, 25 December 2024 edit 86.144.233.203 (talk) Combine duplicate references
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			{{short description|Chemical compound}}
	{{ambox | text = This page contains a copy of the infobox ({{tl|chembox}}) taken from revid of page ] with values updated to verified values.}}
	{{chembox		{{chembox
			| Verifiedfields = changed
	| Watchedfields = changed		| Watchedfields = changed
	| verifiedrevid = 415320282		| verifiedrevid = 464386125
	| Name = Safrole		| Name = Safrole
	| Reference =<ref>'']'', 11th Edition, '''8287'''</ref>		| Reference =<ref>{{cite book|title=]|edition=11th|at=8287}}</ref>
	| ImageFile = safrole-Line-Structure.png		| ImageFile = safrole-Line-Structure.png
			| ImageName = Skeletal formula of safrole
	| ImageSize = 200px
			| ImageClass = skin-invert
	| IUPACName = 5-(2-propenyl)-1,3-benzodioxole
			| ImageFile1 = Safrole-3D-balls.png
	| OtherNames = 5-allylbenzodioxole; 3,4-methylenedioxyphenyl-2-propene
			| ImageSize1 = 210px
	| Section1 = {{Chembox Identifiers
			| ImageName1 = Ball-and-stick model of safrole
	| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
			| PIN = 5-(Prop-2-en-1-yl)-2''H''-1,3-benzodioxole
			| OtherNames = 5-(2-Propenyl)-1,3-benzodioxole<br />5-Allylbenzodioxole<br />3,4-Methylenedioxyphenyl-2-propene
			|Section2={{Chembox Properties
			| C=10 | H=10 | O=2
			| Density = 1.096 g/cm<sup>3</sup>
			| MeltingPtC = 11
			| BoilingPtC = 232 to 234
			| BoilingPt_notes =
			| MagSus = {{val|-97.5e-6|u=cm<sup>3</sup>/mol}}
			}}
			|Section4={{Chembox Hazards
			| GHSPictograms = {{GHS07}}{{GHS08}}
			| GHSSignalWord = Danger
			| HPhrases = {{H-phrases|302|341|350}}
			| PPhrases = {{P-phrases|201|281|308+313}}
			}}
			|Section5={{Chembox Legal status
			| legal_AU =
			| legal_BR = D1
			| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 – Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 – Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-15 |publisher=] |language=pt-BR |publication-date=2023-04-04}}</ref>
			| legal_US =
			| legal_UK =
			| legal_UN =
			}}
			|Section1={{Chembox Identifiers
			| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
	| ChemSpiderID = 13848731		| ChemSpiderID = 13848731
	| KEGG_Ref = {{keggcite|correct|kegg}}		| KEGG_Ref = {{keggcite|correct|kegg}}
	| KEGG = C10490		| KEGG = C10490
			| ChEBI_Ref = {{ebicite|correct|EBI}}
			| ChEBI = 8994
			| EINECS = 202-345-4
	| InChI = 1/C10H10O2/c1-2-3-8-4-5-9-10(6-8)12-7-11-9/h2,4-6H,1,3,7H2		| InChI = 1/C10H10O2/c1-2-3-8-4-5-9-10(6-8)12-7-11-9/h2,4-6H,1,3,7H2
	| InChIKey = ZMQAAUBTXCXRIC-UHFFFAOYAD		| InChIKey = ZMQAAUBTXCXRIC-UHFFFAOYAD
	| ChEMBL_Ref = {{ebicite|correct|EBI}}		| ChEMBL_Ref = {{ebicite|correct|EBI}}
	| ChEMBL = 242273		| ChEMBL = 242273
			| PubChem = 5144
			| RTECS = CY2800000
			| UNNumber = 3082
	| StdInChI_Ref = {{stdinchicite|correct|chemspider}}		| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChI = 1S/C10H10O2/c1-2-3-8-4-5-9-10(6-8)12-7-11-9/h2,4-6H,1,3,7H2		| StdInChI = 1S/C10H10O2/c1-2-3-8-4-5-9-10(6-8)12-7-11-9/h2,4-6H,1,3,7H2
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	| StdInChIKey = ZMQAAUBTXCXRIC-UHFFFAOYSA-N		| StdInChIKey = ZMQAAUBTXCXRIC-UHFFFAOYSA-N
	| CASNo = 94-59-7		| CASNo = 94-59-7
	| CASNo_Ref = {{cascite|correct|CAS}}		| CASNo_Ref = {{cascite|correct|CAS}}
			| UNII_Ref = {{fdacite|correct|FDA}}
	| SMILES = C=CCc1ccc2OCOc2c1
			| UNII = RSB34337V9
	}}
			| SMILES = C=CCc1ccc2OCOc2c1
	| Section2 = {{Chembox Properties
			}}}}
	| Formula = C<sub>10</sub>H<sub>10</sub>O<sub>2</sub>
	| MolarMass = 162.19 g/mol
			'''Safrole''' is an ] with the formula CH<sub>2</sub>O<sub>2</sub>C<sub>6</sub>H<sub>3</sub>CH<sub>2</sub>CH=CH<sub>2</sub>. It is a colorless oily liquid, although impure samples can appear yellow. A member of the ] family of natural products, it is found in ] plants, among others. Small amounts are found in a wide variety of plants, where it functions as a natural ].<ref name="Chemical Composition of Essential O">{{cite journal |doi=10.1055/s-2006-959379 |title=Chemical Composition of Essential Oil from the Root Bark of ''Sassafras albidum'' |year=2007 |last1=Kamdem |first1=Donatien |last2=Gage |first2=Douglas |journal=Planta Medica |volume=61 |issue=6 |pages=574–575 |pmid=8824955}}</ref> '']'',<ref name="ReferenceA">{{cite journal |doi=10.1021/jo01161a020 |year=1948 |last1=Hickey |first1=Michael J. |journal=Journal of Organic Chemistry |volume=13 |issue=3 |pages=443–446 |pmid=18863852 |title=Investigation of the chemical constituents of Brazilian sassafras oil}}</ref> which grows in ], and '']'',<ref name="Chemical Composition of Essential O"/> which grows in eastern ], are the main natural sources of safrole. It has a characteristic "sweet-shop" aroma.
	| ExactMass = 162.06808 u
	| Density = 1.096 g/cm<sup>3</sup>
			It is a ] in the synthesis of the ] synergist ], the fragrance ] via ], and the empathogenic/entactogenic substance ].
	| MeltingPtC = 11
	| BoilingPt = 232-234 °C}}
			== History ==
	}}
			Safrole was obtained from a number of plants, but especially from the sassafras tree ('']''), which is native to North America, and from Japanese star anise ('']'', called ''shikimi'' in Japan).<ref>The history of research on safrole appears in: {{cite book |last1=Semmler |first1=F.W. |title=Die Ätherischen Öle nach ihren chemischen Bestandteilen unter Berücksichtigung der geschichtlichen Entwicklung |trans-title=The volatile oils according to their chemical components with regard to their historical development |date=1907 |publisher=Veit & Co. |location=Leipzig, Germany |volume=4 |pages=139–144 |url=https://books.google.com/books?id=nA9aAAAAYAAJ&pg=PA139 |language=de}}</ref> In 1844, the French chemist ] (1817–1879)<ref>].<ref>{{cite journal |last1=Saint-Èvre |title=Recherches sur l'huile essentielle de sassafras |journal=Annales de Chimie et de Physique |date=1844 |volume=12 |pages=107–113 |url=https://babel.hathitrust.org/cgi/pt?id=ien.35556042382317;view=1up;seq=113 |series=3rd series |trans-title=Investigations of the essential oil of sassafras |language=fr}}; see p. 108.</ref> In 1869, the French chemists ] (1835–1900) and J. Ruotte investigated and named safrole.<ref name="GrimauxRuotte1869">{{cite journal |last1=Grimaux |first1=E |last2=Ruotte |first2=J. |title=Sur l'essence de sassafras |journal=Comptes Rendus |date=1869 |volume=68 |pages=928–930 |url=https://babel.hathitrust.org/cgi/pt?id=uc1.31822009518978;view=1up;seq=930 |trans-title=On the essential oil of sassafras |language=fr}} From p. 928: ''"Ils sont constitués par une principe oxygéné, la safrol C<sub>10</sub>H<sub>10</sub>O<sub>2</sub> ... "'' (They are composed of an oxygenated substance, safrole C<sub>10</sub>H<sub>10</sub>O<sub>2</sub> ... )</ref>{{rp|928}} They observed its reaction with bromine, suggesting the presence of an ].<ref name="GrimauxRuotte1869"/>{{rp|929}} By 1884, the German chemist ] (1821–1906) suggested that safrole was a derivative of ], to which two oxygen atoms were joined as ]s (cyclic ethers).<ref>{{cite journal |last1=Poleck |first1=Theodor |title=Ueber die chemische Constitution des Safrols |journal=Berichte der Deutschen Chemischen Gesellschaft |date=1884 |volume=17 |issue=2 |pages=1940–1944 |url=https://babel.hathitrust.org/cgi/pt?id=uc1.b3481769;view=1up;seq=372 |trans-title=On the chemical composition of safrole|doi=10.1002/cber.18840170278 }} See structural formula on p. 1941.</ref>
			In 1885, the Dutch chemist ] (1851–1915) investigated shikimol, the essential oil that is obtained from Japanese star anise, and he found that, upon oxidation, shikimol formed piperonylic acid,<ref name="Eijkman1885">{{cite journal |last1=Eijkman |first1=J.F. |title=Sur les principes constituants de l'<nowiki/>''Illicium religiosum'' (Sieb.) (Shikimi-no-ki en japonais) |journal=Recueil des Travaux Chimiques des Pays-Bas |date=1885 |volume=4 |issue=2 |pages=32–54 |url=https://babel.hathitrust.org/cgi/pt?id=uc1.b3961772;view=1up;seq=40 |trans-title=On the substances composing ''Illicium religiosum'' (Sieb.) (Shikimi-no-ki in Japanese) |language=fr|doi=10.1002/recl.18850040202 }}</ref>{{rp|39–40}} whose basic structure had been determined in 1871 by the German chemist ] (1835–1910) and his student, the American chemist ] (1846–1927).<ref>{{cite journal |last1=Fittig |first1=Rud. |last2=Remsen |first2=Ira |title=Untersuchungen über die Constitution des Piperins und seiner Spaltungsproducte Piperinsäure und Piperidin |journal=Annalen der Chemie |date=1871 |volume=159 |issue=2 |pages=129–158 |url=https://babel.hathitrust.org/cgi/pt?id=uva.x002457984;view=1up;seq=141 |trans-title=Investigations into the composition of ] and its cleavage products ] and ] |language=de|doi=10.1002/jlac.18711590202 }}; see the structural formula for ''Piperonylsäure'' on .</ref> Thus Eijkman inferred the correct basic structure for shikimol.<ref name="Eijkman1885"/>{{rp|40–41}} He also noted that shikimol and safrole had the same empirical formula and had other similar properties, and thus he suggested that they were probably identical.<ref name="Eijkman1885"/>{{rp|41–42}} In 1886, Poleck showed that upon oxidation, safrole also formed piperonylic acid, and thus shikimol and safrole were indeed identical.<ref>{{cite journal |last1=Poleck |first1=Th. |title=Ueber die chemische Structur des Safrols |journal=Berichte der Deutschen Chemischen Gesellschaft |date=1886 |volume=19 |pages=1094–1098 |url=https://babel.hathitrust.org/cgi/pt?id=uc1.b3481774;view=1up;seq=1248 |trans-title=On the chemical structure of safrole |language=de|doi=10.1002/cber.188601901243 }}</ref> It remained to be determined whether the molecule's C<sub>3</sub>H<sub>5</sub> group was a ] (R−CH=CH−CH<sub>3</sub>) or an ] (R−CH<sub>2</sub>−CH=CH<sub>2</sub>). In 1888, the German chemist Julius Wilhelm Brühl (1850–1911) determined that the C<sub>3</sub>H<sub>5</sub> group was an allyl group.<ref>{{cite journal |last1=Brühl |first1=J.W. |title=Untersuchungen über die Terpene und deren Abkömmlinge |journal=Berichte der Deutschen Chemischen Gesellschaft |volume=21 |pages=457–477 |url=https://babel.hathitrust.org/cgi/pt?id=hvd.cl1hzt;view=1up;seq=467 |trans-title=Investigations of the terpenes and their derivatives |language=de|doi=10.1002/cber.18880210181 |year=1888 }}; see pp. 474–477.</ref>
			== Natural occurrence ==
			Safrole is the principal component of brown ] oil made from '']'',<ref name="ReferenceA"/> a plant growing in ], and sassafras oil made from '']''.
			In the United States, commercially available ] is usually devoid of safrole due to a rule passed by the U.S. FDA in 1960.<ref>{{Cite web |last=Harvey |first=John L. |date=December 2, 1960 |title=Refusal to Extend Effective Date of Statute for Certain Specified Food Additives |url=https://archives.federalregister.gov/issue_slice/1960/12/3/12406-12416.pdf#page=7 |access-date=November 28, 2022 |website=Federal Register Archive |page=12412 |agency=United States Food & Drug Administration}}</ref>
			Safrole can be obtained through natural ] from '']'' and '']''. Sassafras oil for example is obtained by ] of the root bark of the sassafras tree. The resulting steam distilled product contains about 90% safrole by weight. The oil is dried by mixing it with a small amount of ]. After filtering-off the calcium chloride, the oil is vacuum distilled at 100&nbsp;°C under a vacuum of {{cvt|11|mmHg|kPa}} or frozen to crystallize the safrole out. This technique works with other oils in which safrole is present as well.<ref name="Ledgard"/><ref name="PerkinTrikojus"/>
			Safrole is typically extracted from the root-bark or the fruit of '']''<ref name="Chemical Composition of Essential O"/> (native to eastern North America) in the form of sassafras oil, or from '']'',<ref name="ReferenceA"/> a Brazilian species. Safrole is also present in certain essentials oils and in brown ], which is present in small amounts in many plants. Safrole can be found in ], ], ], and ]. Safrole can be detected in undiluted liquid beverages and pharmaceutical preparations by ].<ref>{{Cite journal|last1=Wisneski|first1=Harris H.|last2=Yates|first2=Ronald L.|last3=Davis|first3=Henry M.|title=High-performance liquid chromatographic—fluorometric determination of safrole in perfume, cologne and toilet water|journal=Journal of Chromatography A|language=en|volume=255|pages=455–461|doi=10.1016/s0021-9673(01)88300-x|year=1983}}</ref>
			== Applications ==
			Safrole is a member of the methylenedioxybenzene group, of which many compounds are used as ] synergists; for example, safrole is used as a precursor in the synthesis of the insecticide ]. Safrole is also used as a precursor in the synthesis of the drug ] (], 3,4-methylenedioxymethamphetamine). Before safrole was banned by the ] in 1960 for use in food, it was used as a ] for its characteristic 'candy-shop' aroma. It was used as an additive in ], ], ], ]s, and certain pharmaceutical preparations.
			Safrole exhibits ]<ref name="Hung 130–134">{{Cite journal|last1=Hung|first1=Shan-Ling|last2=Chen|first2=Yu-Ling|last3=Chen|first3=Yen-Ting|date=2003-04-01|title=Effects of safrole on the defensive functions of human neutrophils|journal=Journal of Periodontal Research|volume=38|issue=2|pages=130–134|issn=0022-3484|pmid=12608906|doi=10.1034/j.1600-0765.2003.01652.x}}</ref> and ]<ref>{{Cite journal|last1=Zhao|first1=Jing|last2=Miao|first2=Junying|last3=Zhao|first3=Baoxiang|last4=Zhang|first4=Shangli|last5=Yin|first5=Deling|date=2005-06-01|title=Safrole oxide inhibits angiogenesis by inducing apoptosis|journal=Vascular Pharmacology|volume=43|issue=1|pages=69–74|doi=10.1016/j.vph.2005.04.004|issn=1537-1891|pmid=15936989}}</ref> functions.
			== Synthesis ==
			It can be synthesized from ]<ref name="PerkinTrikojus">{{Cite journal|last1=Perkin|first1=William Henry|last2=Trikojus|first2=Victor Martin|date=1927-01-01|title=CCXII.—A synthesis of safrole and ''o''-safrole|journal=J. Chem. Soc.|language=en|pages=1663–1666|doi=10.1039/jr9270001663|issn=0368-1769}}</ref> first by conversion to methylenedioxybenzene, which is brominated and coupled with ].<ref>{{Cite web|url=https://erowid.org/archive/rhodium/chemistry/safrole.html|title=Synthesis of Safrole – |website=erowid.org|access-date=2017-04-27}}</ref>
			Safrole is a versatile precursor to many compounds. Examples are ''N''-acylarylhydrazones, isosters,<ref>{{Cite journal|last1=Lima|first1=P. C.|last2=Lima|first2=L. M.|last3=da Silva|first3=K. C.|last4=Léda|first4=P. H.|last5=de Miranda|first5=A. L.|last6=Fraga|first6=C. A.|last7=Barreiro|first7=E. J.|date=2000-02-01|title=Synthesis and analgesic activity of novel ''N''-acylarylhydrazones and isosters, derived from natural safrole|journal=European Journal of Medicinal Chemistry|volume=35|issue=2|pages=187–203|issn=0223-5234|pmid=10758281|doi=10.1016/s0223-5234(00)00120-3}}</ref> aryl-sulfonamide derivatives,<ref>{{Cite journal|last1=Lages|first1=A. S.|last2=Silva|first2=K. C.|last3=Miranda|first3=A. L.|last4=Fraga|first4=C. A.|last5=Barreiro|first5=E. J.|date=1998-01-20|title=Synthesis and pharmacological evaluation of new flosulide analogues, synthesized from natural safrole|journal=Bioorganic & Medicinal Chemistry Letters|volume=8|issue=2|pages=183–188|issn=0960-894X|pmid=9871651|doi=10.1016/s0960-894x(97)10216-5}}</ref> acidic sulfonylhydrazone derivatives,<ref>{{Cite journal|last1=Lima|first1=L.M.|last2=Amarante|first2=E.G.|last3=Miranda|first3=A.L.P.|last4=Fraga|first4=C.A.M.|last5=Barreiro|first5=E.J.|title=Synthesis and Antinociceptive Profile of Novel Acidic Sulphonylhydrazone Derivatives From Natural Safrole|journal=Pharmacy and Pharmacology Communications|volume=5|issue=12|pages=673–678|doi=10.1211/146080899128734370|year=1999}}</ref> benzothiazine derivatives.<ref>{{Cite journal|last1=Fraga|first1=Carlos A. M.|last2=Barreiro|first2=Eliezer J.|date=1992-10-01|title=The synthesis of a new benzothiazine derivative, related to oxicams, synthesized from natural safrole|journal=Journal of Heterocyclic Chemistry|language=en|volume=29|issue=6|pages=1667–1669|doi=10.1002/jhet.5570290652|issn=1943-5193}}</ref> and many more.
			==Isosafrole==
			{{main|Isosafrole}}
			Isosafrole is produced synthetically from safrole. It is not found in nature. Isosafrole comes in two forms, ''trans''-isosafrole and ''cis''-isosafrole. Isosafrole is used as a precursor for the psychoactive drug ] (ecstasy). When safrole is metabolized several metabolites can be identified. Some of these metabolites have been shown to exhibit toxicological effects, such as 1′-hydroxysafrole and 3′-hydroxysafrole in rats. Further metabolites of safrole that have been found in urine of both rats and humans include 1,2-dihydroxy-4-allylbenzene or 1(2)-methoxy-2(1)hydroxy-4-allylbenzene.<ref name=":3">{{Cite journal|last1=Ioannides|first1=C.|last2=Delaforge|first2=M.|last3=Parke|first3=D. V.|date=1981-10-01|title=Safrole: its metabolism, carcinogenicity and interactions with cytochrome P-450|journal=Food and Cosmetics Toxicology|volume=19|issue=5|pages=657–666|issn=0015-6264|pmid=7030889|doi=10.1016/0015-6264(81)90518-6}}</ref>
			== Metabolism ==
			Safrole can undergo many forms of metabolism. The two major routes are the oxidation of the ] side chain and the oxidation of the methylenedioxy group.<ref name=":4">{{Cite journal|last1=Sekizawa|first1=J.|last2=Shibamoto|first2=T.|date=1982-04-01|title=Genotoxicity of safrole-related chemicals in microbial test systems|journal=Mutation Research|volume=101|issue=2|pages=127–140|issn=0027-5107|pmid=6808388|doi=10.1016/0165-1218(82)90003-9}}</ref> The oxidation of the allyl side chain is mediated by a ] complex, which will transform safrole into 1′-hydroxysafrole. The newly formed 1′-hydroxysafrole will undergo a phase II ] reaction with a ] enzyme to create 1′-sulfoxysafrole, which can cause ].<ref>{{Cite journal|last1=Jeurissen|first1=Suzanne M. F.|last2=Bogaards|first2=Jan J. P.|last3=Awad|first3=Hanem M.|last4=Boersma|first4=Marelle G.|last5=Brand|first5=Walter|last6=Fiamegos|first6=Yiannis C.|last7=van Beek|first7=Teris A.|last8=Alink|first8=Gerrit M.|last9=Sudhölter|first9=Ernst J. R.|date=2004-09-01|title=Human cytochrome p450 enzyme specificity for bioactivation of safrole to the proximate carcinogen 1′-hydroxysafrole|journal=Chemical Research in Toxicology|volume=17|issue=9|pages=1245–1250|doi=10.1021/tx040001v|issn=0893-228X|pmid=15377158}}</ref> A different oxidation pathway of the allyl side chain can form ]. So far, this has only been found in rats and guinea pigs. The formed epoxide is a small metabolite due to the slow formation and further metabolism of the compound. An ] enzyme will act on the epoxide to form dihydrodiol, which can be secreted in urine.
			The metabolism of safrole through the oxidation of the methylenedioxy proceeds via the cleavage of the methylenedioxy group. This results in two major metabolites: ] and its isomer, ]. ] is a minor metabolite of safrole in humans, mice, and rats. The intact allyl side chain of allylcatechol may then be oxidized to yield 2′,3′-epoxypropylcatechol. This can serve as a substrate for an epoxide hydratase enzyme, and will hydrate the 2′,3′-epoxypropylcatechol to 2′,3′-dihydroxypropylcatechol. This new compound can be oxidized to form ] (PPA),<ref name=":4" /> which is a substance that is related to an increase in oxidative stress and ] activity. PPA also causes a decrease in glutathione and ] activity.<ref>{{Cite journal|last1=MacFabe|first1=Derrick F.|last2=Cain|first2=Donald P.|last3=Rodriguez-Capote|first3=Karina|last4=Franklin|first4=Andrew E.|last5=Hoffman|first5=Jennifer E.|last6=Boon|first6=Francis|last7=Taylor|first7=A. Roy|last8=Kavaliers|first8=Martin|last9=Ossenkopp|first9=Klaus-Peter|date=2007-01-10|title=Neurobiological effects of intraventricular propionic acid in rats: Possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders|journal=Behavioural Brain Research|series=Animal Models for Autism|volume=176|issue=1|pages=149–169|doi=10.1016/j.bbr.2006.07.025|pmid=16950524|s2cid=3054752}}</ref> The epoxide of allylcatechol may also be generated from the cleavage of the methylenedioxy group of the safrole epoxide. The cleavage of the methylenedioxy ring and the metabolism of the allyl group involve hepatic microsomal mixed-function oxidases.<ref name=":4" />
			==Toxicity==
			Toxicological studies have shown that safrole is a weak ] at higher doses in rats and mice. Safrole requires metabolic activation before exhibiting toxicological effects.<ref name=":4" /> ] conversion of the ] in safrole is able to produce intermediates which are directly capable of binding covalently with ] and ]s. Metabolism of the ] group to a ] allows the molecule to form ] with ] and ]. The formation of this complex leads to lower amounts of available free cytochrome P450. Safrole can also directly bind to cytochrome P450, leading to ]. These two mechanisms result in lowered mixed function ] activity.
			Furthermore, because of the altered structural and functional properties of cytochrome P450, loss of ]s which are attached to the ] through cytochrome P450 may occur.<ref name=":3" /> The allyl group thus directly contributes to ]icity, while the methylenedioxy group is associated with changes in the cytochrome P450 system and epigenetic aspects of carcinogenicity.<ref name=":3" /> In rats, safrole and related compounds produced both benign and malignant ]s after intake through the mouth. Changes in the liver are also observed through the enlargement of ]s and ].
			In the ], it was once widely used as a food additive in ], sassafras tea, and other common goods, but was banned for human consumption by the ] after studies in the 1960s suggested that safrole was ], causing permanent liver damage in rats;<ref>{{cite news|last=O'Mathuna |first=Donal |title=Does it work? Can sassafras be used as a general tonic? |newspaper=] |date=10 August 2010}}</ref><ref>{{Cite journal|last1=Hagan|first1=Ernest C.|last2=Jenner|first2=Paul M.|last3=Jones|first3=Wm. I.|last4=Fitzhugh|first4=O. Garth|last5=Long|first5=Eleanor L.|last6=Brouwer|first6=J. G.|last7=Webb|first7=Willis K.|title=Toxic properties of compounds related to safrole|journal=Toxicology and Applied Pharmacology|language=en|volume=7|issue=1|pages=18–24|doi=10.1016/0041-008x(65)90069-4|year=1965|pmid=14259070}}</ref><ref name="LiuChenChenChi"/> food products sold there purporting to contain sassafras instead contain a safrole-free sassafras extract. Safrole is also banned for use in ] and ]s by the ].
			According to a 1977 study of the metabolites of safrole in both rats and humans, two carcinogenic metabolites of safrole found in the urine of rats, 1′-hydroxysafrole and 3′-hydroxyisosafrole, were not found in human urine.<ref>{{cite journal |doi=10.1016/0300-483X(77)90039-7 |title=Absorption, metabolism and excretion of safrole in the rat and man |year=1977 |last1=Benedetti |first1=M. |last2=Malnoe |first2=A. |last3=Broillet |first3=A. |journal=Toxicology |volume=7 |pages=69–83 |pmid=14422 |issue=1}}</ref> The European Commission on Health and consumer protection assumes safrole to be genotoxic and carcinogenic.<ref>{{cite web|url=http://ec.europa.eu/food/fs/sc/scf/out116_en.pdf |title=Opinion of the Scientific Committee on Food on the safety of the presence of safrole (1-allyl-3,4-methylenedioxybenzene) in flavourings and other food ingredients with flavouring properties}}</ref> It occurs naturally in a variety of spices, such as ], ], and ], and herbs such as ]. In that role, safrole, like many naturally-occurring compounds, may have a small but measurable ability to induce cancer in rodents. Despite this, the effects in humans were estimated by the ] to be similar to risks posed by breathing indoor air or drinking municipally supplied water.<ref>{{cite web | title = Ranking Possible Cancer Hazards on the HERP Index | url = http://toxnet.nlm.nih.gov/cpdb/pdfs/herp.pdf | access-date = 2013-10-22}}</ref>
			== Adverse effects ==
			Besides being a hepatocarcinogen, safrole exhibits further adverse effects in that it will induce the formation of hepatic lipid hydroperoxides.<ref name="LiuChenChenChi">{{Cite journal|last1=Liu|first1=T. Y.|last2=Chen|first2=C. C.|last3=Chen|first3=C. L.|last4=Chi|first4=C. W.|date=1999-07-01|title=Safrole-induced Oxidative Damage in the Liver of Sprague–Dawley Rats|journal=Food and Chemical Toxicology|volume=37|issue=7|pages=697–702|doi=10.1016/S0278-6915(99)00055-1|pmid=10496370}}</ref> Safrole also inhibits the defensive function of ]s against bacteria. In addition to the inhibition of the defensive function of neutrophils, it has also been discovered that safrole interferes with the formation of superoxides by neutrophils.<ref name="Hung 130–134"/> Furthermore, safrole oxide, a metabolite of safrole, has a negative effect on the ]. Safrole oxide inhibits the expression of integrin β4/SOD, which leads to ] of the ]s.<ref>{{Cite journal|last1=Su|first1=Le|last2=Zhao|first2=Baoxiang|last3=Lü|first3=Xin|last4=Wang|first4=Nan|last5=Zhao|first5=Jing|last6=Zhang|first6=Shangli|last7=Miao|first7=Junying|date=2007-02-20|title=Safrole oxide induces neuronal apoptosis through inhibition of integrin β4/SOD activity and elevation of ROS/NADPH oxidase activity|journal=Life Sciences|volume=80|issue=11|pages=999–1006|doi=10.1016/j.lfs.2006.11.041|pmid=17188719}}</ref>
			==Use in MDMA manufacture==
			]
			Safrole is listed as a Table I ] under the ].<ref>{{cite web|url=http://www.incb.org/pdf/e/list/red.pdf |title=International Narcotics Control Board |archive-url=https://web.archive.org/web/20080227224025/http://www.incb.org/pdf/e/list/red.pdf |archive-date=2008-02-27 }}</ref>
			Due to their role in the manufacture of ], safrole, ], and ] are Category I precursors under regulation no. 273/2004 of the ].<ref>{{CELEX|32004R0273|text=Regulation (EC) No 273/2004 of the European Parliament and of the Council of 11 February 2004 on drug precursors}}</ref> In the United States, safrole is currently a ].
			The root bark of American ] contains a low percentage of steam-volatile oil, which is typically 75% safrole.<ref>{{cite book|title=] |edition=13th |publisher=Merck & Co, Inc |location=Whitehorse Station, NJ |date=2001}}</ref> Attempts to refine safrole from sassafras bark in mass quantities are generally not economically viable due to low yield and high effort. However, smaller quantities can be extracted quite easily via ] (about 10% of dry sassafras root bark by mass, or about 2% of fresh bark).<ref name="Ledgard">{{cite book|last1=Ledgard|first1=Jared|title=Kings Chem Guide|date=2010|publisher=UVKCHEM, Inc.|isbn=9780578058658|page=206|edition=2nd |url=https://books.google.com/books?id=-p_MAgAAQBAJ&q=9780578058658|access-date=6 September 2014}}</ref> Demand for safrole is causing rapid and illicit harvesting of the '']'' tree in ], in particular the ] in ].<ref>{{cite web
			|last = Campbell
			|first = Sam
			|title = Harvested to make Ecstasy, Cambodia's trees are felled one by one.
			|publisher = GlobalPost
			|date = 30 August 2009
			|url = http://www.globalpost.com/dispatch/asia/090812/drugs-ecstasy-cambodia?page=0,0
			|access-date = 2 September 2009
			}}</ref> However, it is not clear what proportion of illicitly harvested safrole is going toward MDMA production, as over 90% of the global safrole supply (about {{convert|2,000|t|ST|disp=or}} per year) is used to manufacture pesticides, fragrances, and other chemicals.<ref name=Blickman2009>{{cite web |url=http://www2.irrawaddy.org/article.php?art_id=15050 |title=Harvesting Trees to Make Ecstasy Drug |first1=Tom |last1=Blickman |date=February 3, 2009 |work=]}}</ref><ref name="Rocha1999">{{cite book |chapter-url=http://www.hort.purdue.edu/newcrop/proceedings1999/v4-479.html |chapter=Piper hispidinervum: A Sustainable Source of Safrole |last1=Rocha |first1=Sérgio F. R. |first2=Lin Chau |last2=Ming |year=1999 |editor1-first=Jules |editor1-last=Janick |title=Perspectives on new crops and new uses |publisher=ASHS Press |location=Alexandria, VA |pages=479–481 |isbn=978-0-9615027-0-6}}</ref> Sustainable harvesting of safrole is possible from leaves and stems of certain plants, including the roots of camphor seedlings.<ref name="Blickman2009" /><ref name="Rocha1999"/>
			== See also ==
			* ]
			* ]
			==References==
			{{reflist|30em}}
			==External links==
			*
			{{Phenylpropene}}
			{{Authority control}}
			]
			]
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			]