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Revision as of 15:24, 10 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'ChEMBL').← Previous edit		Latest revision as of 23:33, 27 August 2024 edit undoNorth747 (talk | contribs)Extended confirmed users706 editsmNo edit summaryTag: Visual edit
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			{{short description|Organic compound used as a plasticizer to soften polymer matrix}}
	{{chembox
			{{Chembox
	| Verifiedfields = changed		| Verifiedfields = changed
	| Watchedfields = changed		| Watchedfields = changed
	| verifiedrevid = 387899776		| verifiedrevid = 459979401
	| Name = Bis(2-ethylhexyl) phthalate		| ImageName = Bis(2-ethylhexyl) phthalate
			| ImageSize2 = 160px
	| ImageFile = Bis(2-ethylhexyl)phthalate.png
			| ImageFileL1 = Bis(2-ethylhexyl)phthalate.svg
	<!-- | ImageSize = 250px -->
	| ImageName = Bis(2-ethylhexyl) phthalate		| ImageFileR1 = Bis(2-ethylhexyl) phthalate 3D.png
	| IUPACName = Bis(2-ethylhexyl)phthalate (BEHP)		| ImageFile2 = Bis(2-ethylhexyl) phthalate.png
			| PIN = Bis(2-ethylhexyl) benzene-1,2-dicarboxylate
	| Section1 = {{Chembox Identifiers
			| OtherNames = Bis(2-ethylhexyl) phthalate<br />Di-sec octyl phthalate<ref>Diethylhexyl ester of phthalic acid</ref> (archaic)<br />DEHP<br />Isooctyl phthalate, di-<ref>Bis(2-ethylhexyl)phthalate</ref>
	| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
			| Section1 = {{Chembox Identifiers
	| ChemSpiderID = 8040
			| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
			| ChemSpiderID = 21106505
	| ChEMBL_Ref = {{ebicite|changed|EBI}}		| ChEMBL_Ref = {{ebicite|changed|EBI}}
	| ChEMBL = <!-- blanked - oldvalue: 402794 -->		| ChEMBL = 402794
	| UNII_Ref = {{fdacite|correct|FDA}}		| UNII_Ref = {{fdacite|correct|FDA}}
	| UNII = C42K0PH13C		| UNII = C42K0PH13C
	| CASNo_Ref = {{cascite|correct|CAS}}		| CASNo_Ref = {{cascite|correct|CAS}}
	| CASNo = 117-81-7		| CASNo = 117-81-7
	| KEGG_Ref = {{keggcite|changed|kegg}}		| KEGG_Ref = {{keggcite|correct|kegg}}
	| KEGG = C03690		| KEGG = C03690
			| ChEBI_Ref = {{ebicite|changed|EBI}}
	| SMILES = O=C(OCC(CC)CCCC)<br />C1=CC=CC=C1C(OCC(CC)CCCC)=O
			| ChEBI = 17747
	}}
			| PubChem = 8343
	| Section2 = {{Chembox Properties
			| EC_number = 204-211-0 617-060-4
	| Formula = C<sub>24</sub>H<sub>38</sub>O<sub>4</sub>
			| RTECS = TI0350000
	| MolarMass = 390.56
			| SMILES = O=C(OCC(CC)CCCC)C1=CC=CC=C1C(OCC(CC)CCCC)=O
	| MeltingPt = -50°C
			| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
	| BoilingPt = 385°C
			| StdInChI = 1S/C24H38O4/c1-5-9-13-19(7-3)17-27-23(25)21-15-11-12-16-22(21)24(26)28-18-20(8-4)14-10-6-2/h11-12,15-16,19-20H,5-10,13-14,17-18H2,1-4H3
	}}
			| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
			| StdInChIKey = BJQHLKABXJIVAM-UHFFFAOYSA-N}}
			| Section2 = {{Chembox Properties
			| C=24 | H=38 | O=4
			| MeltingPtC = -50
			| BoilingPtC = 385
			| Appearance = Colorless, oily liquid<ref name=PGCH/>
			| Solubility = 0.00003% (23.8 °C)<ref name=PGCH/>
			| VaporPressure = < 0.01 mmHg (20 °C)<ref name=PGCH/>
			| Density = 0.99 g/mL (20°C)<ref name=PGCH/>
			| RefractIndex = 1.4870<ref>{{cite web |last1=Alfa Aesar |title=117-81-7 - Bis(2-ethylhexyl) phthalate, 98+% - Dioctyl phthalate - Phthalic acid bis(2-ethylhexyl)ester - A10415|url=https://www.alfa.com/en/catalog/A10415/ |website=www.alfa.com |publisher=Thermo Fisher Scientific |access-date=30 April 2020}}</ref>}}
			| Section3 = {{Chembox Hazards
			| NFPA-H = 0
			| NFPA-F = 1
			| NFPA-R = 0
			| PEL = TWA 5 mg/m<sup>3</sup><ref name=PGCH>{{PGCH|0236}}</ref>
			| FlashPtF = 420
			| FlashPt_notes = (open cup)<ref name=PGCH/>
			| ExploLimits = 0.3%-?<ref name=PGCH/>
			| IDLH = Ca <ref name=PGCH/>
			| LD50 = 34,000 mg/kg (oral, rabbit)<br />26,000 mg/kg (oral, guinea pig)<br />30,600 mg/kg (oral, rat)<br />30,000 mg/kg (oral, mouse)<ref>{{cite web |url = https://www.cdc.gov/niosh/idlh/117817.html |title = Di-sec octyl phthalate |work = Immediately Dangerous to Life or Health Concentrations (IDLH) |publisher = National Institute for Occupational Safety and Health (NIOSH) |date = 4 December 2014 |access-date = 17 March 2015}}</ref>
			| REL = Ca TWA 5 mg/m<sup>3</sup> ST 10 mg/m<sup>3</sup><ref name=PGCH/>
			| MainHazards = Irritant, teratogen
			| GHS_ref=<ref>{{Sigma-Aldrich|sial|id=36735|name=Bis(2-ethylhexyl) phthalate|accessdate=2022-05-12}}</ref>
			| GHSPictograms = {{GHS08}}
			| GHSSignalWord = Danger
			| HPhrases = {{H-phrases|H360FD}}
			| PPhrases = {{P-phrases|P201 | P202 | P280 | P308 + P313|P405|P501}}
			}}
	}}		}}
	'''Bis(2-ethylhexyl)phthalate''', commonly abbreviated '''DEHP''', is an ] with the ] C<sub>6</sub>H<sub>4</sub>(C<sub>8</sub>H<sub>17</sub>COO)<sub>2</sub>. It is sometimes called '''dioctyl phthalate''' and abbreviated '''DOP'''. It is the most important "]," being the ] of ] and the branched-chain ]. This colourless viscous liquid is soluble in oil, but not in water. It possesses good plasticizing properties. Being produced on a massive scale by many companies, it has acquired many names and acronyms, including '''BEHP''' and '''di-2-ethyl hexyl phthalate'''.		'''Bis(2-ethylhexyl) phthalate''' ('''di-2-ethylhexyl phthalate''', '''diethylhexyl phthalate''', '''diisooctyl phthalate''', '''DEHP'''; incorrectly — '''dioctyl phthalate''', '''DIOP''') is an ] with the ] C<sub>6</sub>H<sub>4</sub>(CO<sub>2</sub>C<sub>8</sub>H<sub>17</sub>)<sub>2</sub>. DEHP is the most common member of the class of ]s, which are used as ]. It is the ] of ] and the branched-chain ]. This colorless viscous liquid is soluble in oil, but not in water.
	==Production==		==Production==
			Di(2-ethylhexyl) phthalate is produced commercially by the reaction of excess ] with ] in the presence of an acid catalyst such as ] or ]. It was first produced in commercial quantities in Japan circa 1933 and in the United States in 1939.<ref>{{cite book |title=IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans Volume 29: Some industrial chemicals and dyestuffs. |date=1982 |publisher=] |location= |isbn=978-92-832-1229-4 |page=271 |url=https://publications.iarc.fr/_publications/media/download/1577/2f8d8229f8923fd2509f7f95e848ba6bf7f88766.pdf}}</ref>
	The process entails the reaction of ] with ]:
	:C<sub>6</sub>H<sub>4</sub>(CO)<sub>2</sub>O + 2 C<sub>8</sub>H<sub>17</sub>OH → C<sub>6</sub>H<sub>4</sub>(CO<sub>2</sub> C<sub>8</sub>H<sub>17</sub>)<sub>2</sub> + H<sub>2</sub>O
			:]
	Approximately three billion kilograms are produced annually.<ref name=Ullmanns>Peter M. Lorz, Friedrich K. Towae, Walter Enke, Rudolf Jäckh, Naresh Bhargava, Wolfgang Hillesheim "Phthalic Acid and Derivatives" in Ullmann's Encyclopedia of Industrial Chemistry, Wiley-VCH: Weinheim, 2002.</ref>
			DEHP has two stereocenters,<ref name=sheikh>Sheikh, I. A. (2016) Stereoselectivity and the potential endocrine disrupting activity of di-(2-ethylhexyl)phthalate (DEHP) against human progesterone receptor: a computational perspective. Journal of applied toxicology. 36 (5), 741–747. https://doi.org/10.1002/jat.3302</ref> located at the carbon atoms carrying the ethyl groups. As a result, it has three distinct stereoisomers,<ref name=sheikh/> consisting of an (''R'',''R'') form, an (''S'',''S'') form (]s), and a '']'' (''R'', ''S'') form. As most 2-ethylhexanol is produced as a ] mixture, commercially-produced DEHP is therefore racemic as well, and consists of a 1:1:2 statistical mixture of stereoisomers.
			:]
			{{clear|left}}
	==Use==		==Use==
			]
	Due to its suitable properties and the low cost, DEHP is widely used as a ] in manufacturing of articles made of ].<ref name=Ullmanns/> Plastics may contain 1% to 40% of DEHP. It is also used as a ] and as a ] fluid in ]s. DEHP also finds use as a ] in ]s.		Due to its suitable properties and the low cost, DEHP is widely used as a ] in manufacturing of articles made of ].<ref name=Ullmanns/> Plastics may contain 1% to 40% of DEHP. It is also used as a ] and as a ] fluid in ]s. DEHP also finds use as a ] in ]s.
			Approximately three million tonnes are produced and used annually worldwide.<ref name=Ullmanns>{{cite book |last1=Lorz |first1=Peter M. |last2=Towae |first2=Friedrich K. |last3=Enke |first3=Walter |last4=Jäckh |first4=Rudolf |last5=Bhargava |first5=Naresh |last6=Hillesheim |first6=Wolfgang |display-authors=3|title=Ullmann's Encyclopedia of Industrial Chemistry |chapter=Phthalic Acid and Derivatives |year=2007 |doi=10.1002/14356007.a20_181.pub2 |isbn=978-3527306732 }}</ref>
			Manufacturers of flexible PVC articles can choose among several alternative plasticizers offering similar technical properties as DEHP. These alternatives include other phthalates such as ] (DINP), ] (DPHP), ] (DIDP), and non-phthalates such as ] (DINCH), ] (DOTP), and ] ]s.<ref>{{Cite web |title=Plasticizers {{!}} ExxonMobil Product Solutions |url=https://www.exxonmobilchemical.com/en/products/plasticizers?ds_k=plasticizers&gclsrc=aw.ds&&ppc_keyword=plasticizers&gclid=CjwKCAjw77WVBhBuEiwAJ-YoJO9bn2xMZjHR-dEW-24RE9_URZaPqNOGE1ZLJQMDLdTtnj4xKZassBoCjHsQAvD_BwE |access-date=2022-06-18 |website=www.exxonmobilchemical.com |language=en}}</ref>
	==Environmental exposure==		==Environmental exposure==
			DEHP is a component of many household items, including tablecloths, floor tiles, shower curtains, garden hoses, rainwear, dolls, toys, shoes, medical tubing, furniture upholstery, and swimming pool liners.<ref name=":0">{{Cite web|title = ATSDR - ToxFAQs™: Di(2-ethylhexyl)phthalate (DEHP)|url = https://wwwn.cdc.gov/TSP/ToxFAQs/ToxFAQsLanding.aspx?id=377&tid=65|website = www.atsdr.cdc.gov|access-date = 2015-10-27}}</ref> DEHP is an indoor air pollutant in homes and schools. Common exposures come from the use of DEHP as a fragrance carrier in ], ] products, laundry ]s, colognes, ]s, and ]s.<ref name=":1">{{Cite web|title = EHHI :: Plastics :: EHHI Releases Original Research Report:Plastics That May be Harmful to Children and Reproductive Health|url = http://www.ehhi.org/plastics/pr_plastics_report08.shtml|website = www.ehhi.org|access-date = 2015-10-27}}</ref>
	DEHP has a low vapor pressure, but the temperatures for processing PVC articles are often high, leading to release of elevated levels, raising concerns about health risks (see ]). It can be absorbed from food and water. Higher levels have been found in milk and cheese. It can also leach into a liquid that comes in contact with the plastic; it extracts faster into ] ]s (e.g. ]s and ]s in foods packed in PVC). ] (FDA) therefore permits use of DEHP-containing packaging only for foods that primarily contain water. In soil, DEHP contamination moves very slowly because of its low solubility in water. Therefore, leaching from disposed plastics in ]s is generally slow. The US ] limits for DEHP in ] is 6 ]. The U.S. agency ]'s limit for occupational exposure is 5&nbsp;mg/m<sup>3</sup> of air.
			The most common exposure to DEHP comes through food with an average consumption of 0.25 milligrams per day.<ref name=":2">{{Cite web|title = Basic Information about Di(2-ethylhexyl) phthalate in Drinking Water|url = http://water.epa.gov/drink/contaminants/basicinformation/di_2-ethylhexyl_phthalate.cfm|website = water.epa.gov|access-date = 2015-10-27|first = US EPA|last = OW|date = 21 September 2015}}</ref> It can also ] into a liquid that comes in contact with the plastic; it extracts faster into ] ]s (e.g. ]s and ]s in foods packed in ]). Fatty foods that are packaged in plastics that contain DEHP are more likely to have higher concentrations such as milk products, fish or seafood, and oils.<ref name=":0" /> The US ] therefore permits use of DEHP-containing packaging only for foods that primarily contain water.
			DEHP can leach into ] from discharges from rubber and chemical factories; The US ] limits for DEHP in drinking water is 6&nbsp;].<ref name=":2" /> It is also commonly found in bottled water, but unlike tap water, the EPA does not regulate levels in bottled water.<ref name=":1" /> DEHP levels in some European samples of milk, were found at 2000 times higher than the EPA Safe Drinking Water limits (12,000&nbsp;ppb). Levels of DEHP in some European cheeses and creams were even higher, up to 200,000&nbsp;ppb, in 1994.<ref>{{cite journal | pmid = 7926171 | year = 1994 | last1 = Sharman | first1 = M | last2 = Read | first2 = WA | last3 = Castle | first3 = L | last4 = Gilbert | first4 = J | title = Levels of di-(2-ethylhexyl)phthalate and total phthalate esters in milk, cream, butter and cheese | volume = 11 | issue = 3 | pages = 375–85 | doi = 10.1080/02652039409374236 | journal = Food Additives and Contaminants}}</ref> Additionally, workers in factories that utilize DEHP in production experience greater exposure.<ref name=":0" /> The U.S. agency ]'s limit for occupational exposure is 5&nbsp;mg/m<sup>3</sup> of air.<ref>{{Cite web|title = Chemical Sampling Information {{!}} Di-(2-Ethylhexyl)phthalate|url = https://www.osha.gov/dts/chemicalsampling/data/CH_235155.html|website = www.osha.gov|access-date = 2015-10-27|archive-date = 2017-07-31|archive-url = https://web.archive.org/web/20170731224743/https://www.osha.gov/dts/chemicalsampling/data/CH_235155.html|url-status = dead}}</ref>
	===Use in medical devices===		===Use in medical devices===
	DEHP has been used as a plasticiser in ]s such as intravenous tubing and bags, catheters, nasogastric tubes, dialysis bags and tubing, and blood bags and transfusion tubing, and air tubes. For this reason, concern has been expressed about leachates transported into the patient, especially for those requiring extensive infusions, e.g. ]s in ] settings, ]cs, and ] patients. According to the European Commission ] (SCHER), exposure to DEHP may exceed the tolerable daily intake in some specific population groups, namely people exposed through medical procedures such as kidney dialysis.<ref>{{cite web | title=Phthalates in school supplies| publisher=GreenFacts Website | accessdate=2009-06-10 | url= http://copublications.greenfacts.org/en/phthalates-school-supplies/}}</ref> The ] has advocated not to use medical devices that can leach DEHP into patients and, instead, to resort to DEHP-free alternatives.{{Citation needed|date=January 2008}} In July 2002, the U.S. FDA issued a Public Health Notification on DEHP, stating in part, "We recommend considering such alternatives when these high-risk procedures are to be performed on male neonates, pregnant women who are carrying male fetuses, and peripubertal males" noting that the alternatives were to look for non-DEHP exposure solutions;<ref>, USFDA July 12, 2002</ref> they mention a database of alternatives.<ref>, Sustainable Hospitals</ref> The ] documentary ''The Disappearing Male'' raised concerns about sexual development in male fetal development, miscarriage (as DEHP is a pseudo-estrogen and a hormone modifier found in most plastic products such as PVC, polycarbonate, nearly all cosmetic chemical products, and many others), and as a cause of dramatically lower sperm counts in men. <ref>, CBC</ref>		DEHP is the most common phthalate plasticizer in ]s such as intravenous tubing and bags, IV ]s, nasogastric tubes, ] bags and tubing, blood bags and transfusion tubing, and air tubes. DEHP makes these plastics softer and more flexible and was first introduced in the 1940s in blood bags. For this reason, concern has been expressed about leachates of DEHP transported into the patient, especially for those requiring extensive infusions or those who are at the highest risk of developmental abnormalities, e.g. ]s in ] settings, ]cs, ] patients, neonates, premature babies, lactating, and pregnant women. According to the European Commission ] (SCHER), exposure to DEHP may exceed the tolerable daily intake in some specific population groups, namely people exposed through medical procedures such as kidney dialysis.<ref>{{cite web | title=Phthalates in school supplies| publisher=GreenFacts Website | access-date=2009-06-10 | url= http://copublications.greenfacts.org/en/phthalates-school-supplies/}}</ref> The ] has advocated not to use medical devices that can leach DEHP into patients and, instead, to resort to DEHP-free alternatives.<ref>{{cite journal |last1=Shea |first1=Katherine M. |title=Pediatric exposure and potential toxicity of phthalate plasticizers |journal=Pediatrics |volume=111 |issue=6 Pt 1 |pages=1467–74 |year=2003 |doi=10.1542/peds.111.6.1467 |pmid=12777573 |url=http://pediatrics.aappublications.org/cgi/pmidlookup?view=long&pmid=12777573 |doi-access=free }}</ref> In July 2002, the U.S. FDA issued a Public Health Notification on DEHP, stating in part, "We recommend considering such alternatives when these high-risk procedures are to be performed on male neonates, pregnant women who are carrying male fetuses, and peripubertal males" noting that the alternatives were to look for non-DEHP exposure solutions;<ref>, USFDA July 12, 2002</ref> they mention a database of alternatives.<ref> {{Webarchive |url=https://web.archive.org/web/20100715011214/http://www.sustainablehospitals.org/cgi-bin/DB_Report.cgi?px=W&rpt=Haz&id=10 |date=2010-07-15 }}, Sustainable Hospitals</ref> The ] documentary ''The Disappearing Male'' raised concerns about ] in male fetal development, ], and as a cause of dramatically lower ]s in men.<ref> – Sunday February 14, 2010 at 3 pm on CBC-TV, CBC</ref> A review article in 2010 in the ''Journal of Transfusion Medicine'' showed a consensus that the benefits of lifesaving treatments with these devices far outweigh the risks of DEHP leaching out of these devices. Although more research is needed to develop alternatives to DEHP that gives the same benefits of being soft and flexible, which are required for most medical procedures, if a procedure requires one of these devices and if patient is at high risk to suffer from DEHP then a DEHP alternative should be considered if medically safe.<ref>{{cite journal |last1=Sampson |first1=J |last2=de Korte |first2=D |title=DEHP-plasticised PVC: relevance to blood services |journal=Transfusion Medicine |volume=21 |issue=2 |pages=73–83 |year=2011 |pmid=21143327 |doi=10.1111/j.1365-3148.2010.01056.x |s2cid=32481051 }}</ref>
	===Metabolism===		===Metabolism===
	DEHP hydrolyzes to MEHP (mono-ethylhexyl phthalate) and subsequently to ] salts. The released alcohol is susceptible to oxidation to the ] and carboxylic acid.<ref name=Ullmanns/>		DEHP hydrolyzes to mono-ethylhexyl phthalate (MEHP) and subsequently to ] salts. The released alcohol is susceptible to oxidation to the ] and carboxylic acid.<ref name=Ullmanns/>
	==Effects on living organisms==		==Effects on living organisms==
			===Toxicity===
	===Smaller penis size and other feminizing links===
			The ] of DEHP is low in animal models: 30&nbsp;g/kg in rats (oral) and 24&nbsp;g/kg in rabbits (dermal).<ref name=Ullmanns/> Concerns instead focus on its potential as an ].
	DEHP metabolites measured from the blood of pregnant women have been significantly associated with the decreased ], shorter ], and the incomplete descent of ] of their newborn sons, replicating effects identified in animals.<ref name=pel>{{cite journal |last=Pelley |first=Janet |authorlink= |coauthors= |year=2008 |month=November |title=Plasticizer may make boys less masculine |journal=Environ Sci Technol |volume= |issue= |pages= |id= |url=http://pubs.acs.org/action/showStoryContent?doi=10.1021%2Fon.2008.11.12.154968 |accessdate=2009-01-19 |quote= |doi=10.1021/on.2008.11.12.154968 }}</ref> Approximately 25% of US women have phthalate levels similar to those in the study.<ref name=pel/>
	===Obesity===		===Endocrine disruption===
			DEHP, along with other ], is believed to cause endocrine disruption in males, through its action as an ],<ref>{{ cite web |title= Biomonitoring Summary Phthalates Overview |author=CDC Main |date=7 September 2021 |url=https://www.cdc.gov/biomonitoring/DEHP_BiomonitoringSummary.html}}</ref> and may have lasting effects on reproductive function, for both childhood and adult exposures. Prenatal phthalate exposure has been shown to be associated with lower levels of reproductive function in adolescent males.<ref>{{cite journal |last1=Axelsson |first1=Jonatan |last2=Rylander |first2=Lars |last3=Rignell-Hydbom |first3=Anna |last4=Lindh |first4=Christian H. |last5=Jönsson |first5=Bo A.G. |last6=Giwercman |first6=Aleksander |display-authors=3|title=Prenatal phthalate exposure and reproductive function in young men |journal=Environmental Research |volume=138 |pages=264–70 |year=2015 |pmid=25743932 |bibcode=2015ER....138..264A |doi=10.1016/j.envres.2015.02.024 }}</ref> In another study, airborne concentrations of DEHP at a ] pellet plant were significantly associated with a reduction in sperm motility and ] DNA integrity.<ref>{{cite journal |last1=Huang |first1=Li-Ping |last2=Lee |first2=Ching-Chang |last3=Hsu |first3=Ping-Chi |last4=Shih |first4=Tung-Sheng |title=The association between semen quality in workers and the concentration of di(2-ethylhexyl) phthalate in polyvinyl chloride pellet plant air |journal=Fertility and Sterility |volume=96 |issue=1 |pages=90–4 |year=2011 |pmid=21621774 |doi=10.1016/j.fertnstert.2011.04.093 |doi-access=free }}</ref> Additionally, the authors noted the daily intake estimates for DEHP were comparable to the general population, indicating a "high percentage of men are exposed to levels of DEHP that may affect sperm motility and chromatin DNA integrity". The claims have received support by a study<ref>{{cite journal |last1=Sumner |first1=R.N. |last2=Byers |first2=A. |last3=Zhang |first3=Z. |title=Environmental chemicals in dog testes reflect their geographical source and may be associated with altered pathology |journal=Scientific Reports |date=2021 |volume=11 |issue=7361 |page=7361 |doi=10.1038/s41598-021-86805-y|pmid=33795811 |pmc=8016893 |bibcode=2021NatSR..11.7361S }}</ref> using dogs as a "sentinel species to approximate human exposure to a selection of chemical mixtures present in the environment". The authors analyzed the concentration of DEHP and other common chemicals such as ] in ] from dogs from five different world regions. The results showed that regional differences in concentration of the chemicals are reflected in dog testes and that pathologies such as ] and ]s were more prevalent in testes of dogs from regions with higher concentrations.
	A study on ] data, published in ''Environmental Health Perspectives'' (EHP), "revealed that American men with abdominal ] or ] (a precursor to ]) were more likely to have high levels of ]] metabolites in their urine than men without those problems."<ref>{{cite web|title=Fat's Hidden Trigger|author=Emily Main|url=http://www.thegreenguide.com/doc/121/fat|archiveurl=http://web.archive.org/web/20080829164208/http://www.thegreenguide.com/doc/121/fat|archivedate=20080829}}</ref>
	===Toxicity===		===Development===
			Numerous studies of DEHP have shown changes in sexual function and development in mice and rats. DEHP exposure during pregnancy has been shown to disrupt placental growth and development in mice, resulting in higher rates of low birthweight, premature birth, and fetal loss.<ref>{{cite journal |first1=Ming-Lu |last1=Lin |first2=Dean-Chuan |last2=Wang |first3=Shih-Chieh |last3=Chen |date=April 2013 |title=Lactational exposure to DEHP induced adrenocortical hypertrophy and anxiety-like behavior in rats |journal=The FASEB Journal |volume=27 |issue=1 Supplement |pages=936.15 |url=http://www.fasebj.org/content/27/1_Supplement/936.15.short |doi=10.1096/fasebj.27.1_supplement.936.15|doi-access= free}}</ref> In a separate study, exposure of neonatal mice to DEHP through lactation caused hypertrophy of the adrenal glands and higher levels of anxiety during puberty.<ref>{{cite journal |last1=Zong |first1=Teng |last2=Lai |first2=Lidan |last3=Hu |first3=Jia |last4=Guo |first4=Meijun |last5=Li |first5=Mo |last6=Zhang |first6=Lu |last7=Zhong |first7=Chengxue |last8=Yang |first8=Bei |last9=Wu |first9=Lei |last10=Zhang |first10=Dalei |last11=Tang |first11=Min |last12=Kuang |first12=Haibin |display-authors=3 |title=Maternal exposure to di-(2-ethylhexyl) phthalate disrupts placental growth and development in pregnant mice |journal=Journal of Hazardous Materials |volume=297 |pages=25–33 |year=2015 |pmid=25935407 |doi=10.1016/j.jhazmat.2015.04.065 }}</ref> In another study, pubertal administration of higher-dose DEHP delayed puberty in rats, reduced testosterone production, and inhibited androgen-dependent development; low doses showed no effect.<ref>{{cite journal |last1=Noriega |first1=N. C. |last2=Howdeshell |first2=K. L. |last3=Furr |first3=J. |last4=Lambright |first4=C. R. |last5=Wilson |first5=V. S. |last6=Gray |first6=L. E. |display-authors=3|title=Pubertal Administration of DEHP Delays Puberty, Suppresses Testosterone Production, and Inhibits Reproductive Tract Development in Male Sprague-Dawley and Long-Evans Rats |journal=Toxicological Sciences |volume=111 |issue=1 |pages=163–78 |year=2009 |pmid=19528224 |doi=10.1093/toxsci/kfp129 |doi-access=free }}</ref>
	The acute toxicity of DEHP is 30g/kg in rats (oral) and 24g/kg in rabbits (dermal).<ref name=Ullmanns/> Concerns instead focus on its potential as an ]. Some countries have banned DEHP from toys; see ] for legal status.
			===Obesity===
			When DEHP is ingested intestinal ]s convert it to MEHP, which then is absorbed. MEHP is suspected to have an obesogenic effect. ] and human studies have shown DEHP to be a possible disruptor of thyroid function, which plays a key role in energy balance and metabolism. Exposure to DEHP has been associated with lower plasma ] levels and decreased uptake of iodine in thyroid ]. Previous studies have shown that slight changes in thyroxine levels can have dramatic effects on resting energy expenditure, similar to that of patients with ], which has been shown to cause increased weight gain in those study populations.<ref name=":3">{{cite journal |last1=Kim |first1=Shin Hye |last2=Park |first2=Mi Jung |title=Phthalate exposure and childhood obesity |journal=Annals of Pediatric Endocrinology & Metabolism |volume=19 |issue=2 |pages=69–75 |year=2014 |pmid=25077088 |pmc=4114051 |doi=10.6065/apem.2014.19.2.69 }}</ref>
	===Cardiotoxicity===		===Cardiotoxicity===
	A clinically relevant dose and duration of exposure to DEHP has been shown to have a significant impact on the behavior of ] cells in culture. This includes an uncoupling effect that leads to ] ]. This is observed in conjunction with a significant decrease in the amount of ]al ] proteins in ] treated with DEHP.<ref></ref><ref></ref>		Even at relatively low doses of DEHP, cardiovascular reactivity was significantly affected in mice.<ref>{{cite journal |last1=Jaimes |first1=Rafael |title=Plastics and cardiovascular health: phthalates may disrupt heart rate variability and cardiovascular reactivity. |pmid=28842438 |doi=10.1152/ajpheart.00364.2017 |volume=313 |pmc=5792203 |year=2017 |journal=Am J Physiol Heart Circ Physiol |issue=5 |pages=H1044–H1053}}</ref> A clinically relevant dose and duration of exposure to DEHP has been shown to have a significant impact on the behavior of ] cells in culture. This includes an uncoupling effect that leads to ] ]. Untreated cells had fast conduction velocity, along with homogenous activation wave fronts and synchronized beating. Cells treated with DEHP exhibited fractured wave fronts with slow propagation speeds. This is observed in conjunction with a significant decrease in the amount of expression and instability of ]al ] proteins, specifically ], in ] treated with DEHP.<ref>{{cite journal |last1=Gillum |first1=Nikki |last2=Karabekian |first2=Zaruhi |last3=Swift |first3=Luther M. |last4=Brown |first4=Ronald P. |last5=Kay |first5=Matthew W. |last6=Sarvazyan |first6=Narine |display-authors=3|title=Clinically relevant concentrations of di (2-ethylhexyl) phthalate (DEHP) uncouple cardiac syncytium |journal=Toxicology and Applied Pharmacology |volume=236 |issue=1 |pages=25–38 |year=2009 |pmid=19344669 |pmc=2670944 |doi=10.1016/j.taap.2008.12.027 }}</ref>
			The decrease in expression and instability of ] may be due to the down regulation of ] and ] genes, and the alteration of ] structure, caused by DEHP; all of which are responsible for the transport of protein products. Also, DEHP caused down regulation of several growth factors, such as ], ], ] and ], and endothelial-1. The DEHP-induced down regulation of these growth factors may also contribute to the reduced expression and instability of connexin-43.<ref>{{cite journal |last1=Yang |first1=Oneyeol |last2=Kim |first2=Hye Lim |last3=Weon |first3=Jong-Il |last4=Seo |first4=Young Rok |title=Endocrine-disrupting Chemicals: Review of Toxicological Mechanisms Using Molecular Pathway Analysis |journal=Journal of Cancer Prevention |volume=20 |issue=1 |pages=12–24 |year=2015 |pmid=25853100 |pmc=4384711 |doi=10.15430/JCP.2015.20.1.12 }}</ref>
	== Alternative plasticizers ==
	Manufacturers of flexible PVC articles can choose among several alternative plasticizers offering similar technical properties as DEHP. These alternatives include other phthalates such as ], ], ], and non-phthalates, e.g. ] and ].
			DEHP has also been shown, ''in vitro'' using cardiac muscle cells, to cause activation of PPAR-alpha gene, which is a key regulator in lipid metabolism and ] proliferation; both of which can be involved in ] and ], which are precursors of cardiovascular disease.<ref>{{cite journal |last1=Posnack |first1=Nikki Gillum |last2=Lee |first2=Norman H. |last3=Brown |first3=Ronald |last4=Sarvazyan |first4=Narine |title=Gene expression profiling of DEHP-treated cardiomyocytes reveals potential causes of phthalate arrhythmogenicity |journal=Toxicology |volume=279 |issue=1–3 |pages=54–64 |year=2011 |pmid=20920545 |pmc=3003946 |doi=10.1016/j.tox.2010.09.007 }}</ref>
	== Government and industry response ==
	=== Taiwan ===
	In October 2009, Consumers' Foundation, Chinese Taipei (CFCT) published test results<ref>{{cite web|title=《消費者報導雜誌》342期 第4至11頁「跟著流行走？踩著危機走！園丁鞋逾4成可塑劑超量」|url=http://www.consumers.org.tw/unit412.aspx?id=1245|publisher=Consumers' Foundation, Chinese Taipei (CFCT)|language=zh-tw}}</ref> that found 5 out of the sampled 12 shoes contained over 0.1% of phthalate plasticizer content, including DEHP, which exceeds the government's ]. CFCT recommend that users should first wear socks to avoid direct skin contact.
			Once metabolized into MEHP, the molecule has been shown to lengthen action potential duration and slow epicardial conduction velocity in Langendorff perfused rodent hearts.<ref>{{cite journal | pmid=31248280 | year=2019 | last1=Jaimes III | first1=R | last2=McCullough | first2=D. | last3=Siegel | first3=B. | last4=Swift | first4=L. | last5=McInerney | first5=D. | last6=Hiebert | first6=J. | last7=Perez-Alday | first7=E. A. | last8=Trenor | first8=B. | last9=Sheng | first9=J. | last10=Saiz | first10=J. | last11=Tereshchenko | first11=L. G. | last12=Posnack | first12=N. G. |display-authors=3 | title=Plasticizer Interaction with the Heart: Chemicals Used in Plastic Medical Devices Can Interfere with Cardiac Electrophysiology | journal=Circulation: Arrhythmia and Electrophysiology | volume=12 | issue=7 | pages=e007294 | doi=10.1161/CIRCEP.119.007294 | pmc=6693678 }}</ref>
	In May 2011, the illegal use of the plasticizer DEHP in ]s for use in food and beverages has been reported in ].<ref>, Taipei Times, May 29, 2011 </ref> An inspection of products initially discovered the presence of plasticizers. As more products were tested, inspectors found more manufacturers using DEHP and DINP.<ref>{{cite news | language = zh-tw | author = 生活中心綜合報導 | coauthors = | url = http://www.nownews.com/2011/05/23/327-2714830.htm | title = 塑化劑危機！台灣海洋深層水等4廠商飲料緊急下架 | work = | publisher = NOWnews | date = 2011-05-23 | accessdate = 2011-5-25查閱 }}</ref> The ] confirmed that contaminated food and beverages had been exported to other countries and regions, which reveals the widespread prevalence of toxic plasticizers.
	{{Details|2011 Taiwan food scandal}}
			=== Other health effects ===
			Studies in mice have shown other adverse health effects due to DEHP exposure. Ingestion of 0.01% DEHP caused damage to the blood-testis barrier as well as induction of experimental autoimmune orchitis.<ref>{{cite journal |last1=Hirai |first1=Shuichi |last2=Naito |first2=Munekazu |last3=Kuramasu |first3=Miyuki |last4=Ogawa |first4=Yuki |last5=Terayama |first5=Hayato |last6=Qu |first6=Ning |last7=Hatayama |first7=Naoyuki |last8=Hayashi |first8=Shogo |last9=Itoh |first9=Masahiro |display-authors=3|title=Low-dose exposure to di-(2-ethylhexyl) phthalate (DEHP) increases susceptibility to testicular autoimmunity in mice |journal=Reproductive Biology |volume=15 |issue=3 |pages=163–71 |year=2015 |pmid=26370459 |doi=10.1016/j.repbio.2015.06.004 }}</ref> There is also a correlation between DEHP plasma levels in women and endometriosis.<ref>{{cite journal |last1=Kim |first1=Sung Hoon |last2=Chun |first2=Sail |last3=Jang |first3=Jin Yeon |last4=Chae |first4=Hee Dong |last5=Kim |first5=Chung-Hoon |last6=Kang |first6=Byung Moon |display-authors=3 |title=Increased plasma levels of phthalate esters in women with advanced-stage endometriosis: a prospective case-control study |journal=Fertility and Sterility |volume=95 |issue=1 |pages=357–9 |year=2011 |pmid=20797718 |doi=10.1016/j.fertnstert.2010.07.1059 |doi-access=free }}</ref>
			DEHP is also a possible cancer causing agent in humans, although human studies remain inconclusive, due to the exposure of multiple elements and limited research. In vitro and rodent studies indicate that DEHP is involved in many molecular events, including increased cell proliferation, decreased ], ], and selective clonal expansion of the initiated cells; all of which take place in multiple sites of the human body.<ref>{{cite journal |last1=Rusyn |first1=Ivan |last2=Corton |first2=J. Christopher |title=Mechanistic considerations for human relevance of cancer hazard of di(2-ethylhexyl) phthalate |journal=Mutation Research/Reviews in Mutation Research |volume=750 |issue=2 |pages=141–58 |year=2012 |pmid=22198209 |doi=10.1016/j.mrrev.2011.12.004 |pmc=3348351}}</ref>
			==Government and industry response==
			===Taiwan===
			In October 2009, Consumers' Foundation, Taiwan (CFCT) published test results<ref>{{cite web|script-title=zh:《消費者報導雜誌》342期 第4至11頁「跟著流行走？踩著危機走！園丁鞋逾4成可塑劑超量」|url=http://www.consumers.org.tw/unit412.aspx?id=1245|publisher=Consumers’ Foundation, Taiwan (CFCT)|language=zh}}</ref> that found 5 out of the sampled 12 shoes contained over 0.1% of phthalate plasticizer content, including DEHP, which exceeds the government's ]. CFCT recommend that users should first wear socks to avoid direct skin contact.
			In May 2011, the illegal use of the plasticizer DEHP in ]s for use in food and beverages has been reported in ].<ref>, Taipei Times, May 29, 2011</ref> An inspection of products initially discovered the presence of plasticizers. As more products were tested, inspectors found more manufacturers using DEHP and DINP.<ref>{{cite news | author = 生活中心綜合報導 | url = http://www.nownews.com/2011/05/23/327-2714830.htm | script-title=zh:塑化劑危機！台灣海洋深層水等4廠商飲料緊急下架 | publisher = NOWnews | date = 2011-05-23 | access-date = 2011-05-25| language = zh }}</ref> The ] confirmed that contaminated food and beverages had been exported to other countries and regions, which reveals the widespread prevalence of toxic plasticizers.
			{{Further|2011 Taiwan food scandal}}
			===European Union===
			Concerns about chemicals ingested by children when chewing plastic toys prompted the ] to order a temporary ban on phthalates in 1999, the decision of which is based on an opinion by the Commission's Scientific Committee on Toxicity, Ecotoxicity and the Environment (CSTEE). A proposal to make the ban permanent was tabled. Until 2004, EU banned the use of DEHP along with several other phthalates (], ], ], ] and DNOP) in toys for young children.<ref>{{cite news | url = http://www.euractiv.com/health/eu-ministers-agree-ban-chemicals-news-212475 | title = EU ministers agree to ban chemicals in toys | publisher = EurActiv.com | date = 2004-10-07}}</ref> In 2005, the Council and the Parliament compromised to propose a ban on three types of phthalates (], ], and DNOP) "in toys and childcare articles which can be placed in the mouth by children". Therefore, more products than initially planned will thus be affected by the directive.<ref>{{cite news | url = http://www.euractiv.com/health/phthalates-banned-toys-childcare-news-214242 | title = Phthalates to be banned in toys and childcare articles | publisher = EurActiv.com | date = 2005-06-27 | access-date = 2013-10-24 | archive-date = 2013-06-03 | archive-url = https://web.archive.org/web/20130603153502/http://www.euractiv.com/health/phthalates-banned-toys-childcare-news-214242 | url-status = dead }}</ref> In 2008, six substances were considered to be of very high concern (]s) and added to the Candidate List including ], MDA, ], DEHP, ], and ]. In 2011, those six substances have been listed for Authorization in Annex XIV of ] by Regulation (EU) No 143/2011.<ref>{{Citation | title = REACH - First Six Substances Subject To Authorisation| date = 25 Feb 2011| publisher = Intertek| series = Sparkle| volume = 559| url = http://www.intertek.com/uploadedFiles/Intertek/Divisions/Consumer_Goods/Media/PDFs/Sparkles/2011/sparkle559.pdf }}</ref> According to the regulation, phthalates including DEHP, BBP and DBP will be banned from February 2015.<ref>{{cite news | title = First REACH substance bans to apply from 2014 | publisher = European Solvents Industry Group | date = 2011-02-18 | url = http://www.esig.org/mediaroom/642/53/first-reach-substance-bans-to-apply-from-2014/ | access-date = 2013-10-24 | archive-url = https://web.archive.org/web/20150721235904/http://www.esig.org/mediaroom/642/53/first-reach-substance-bans-to-apply-from-2014/ | archive-date = 2015-07-21 | url-status = dead }}</ref>
			In 2012, Danish Environment Minister ] announced the ban of DEHP, DBP, DIBP and BBP, pushing ] ahead of the European Union which has already started a process of phasing out phthalates.<ref>{{cite news | url = http://www.euractiv.com/consumers/danish-minister-bans-endocrine-d-news-514424 | title = Denmark defies EU with planned ban on phthalate chemicals | publisher = EurActiv.com | date = 2012-08-27}}</ref> However, it was postponed by two years and would take effect in 2015 and not in December 2013, which was the initial plan. The reason is that the four phthalates are far more common than expected and that producers cannot phase out phthalates as fast as the Ministry of Environment requested.<ref>{{cite press release |date= 28 May 2013|title= Danish prohibition against four low molecular weight phthalates postponed|url= http://www.dehp-facts.com/module/news/display/newsdisplay.aspx?news=45|publisher= European Council for Plasticisers and Intermediates|agency= Danish Environment Ministry|archive-url=https://web.archive.org/web/20150602083235/http://www.dehp-facts.com/module/news/display/newsdisplay.aspx?news=45|archive-date= 2 June 2015}}</ref>
			In 2012, ] became the first country in the EU to ban the use of DEHP in pediatrics, neonatal, and maternity wards in hospitals.<ref>{{Cite web|title=The legacy of Healthier Hospitals|url=https://practicegreenhealth.org/healthierhospitals|access-date=2021-01-18|website=practicegreenhealth.org}}</ref>
			DEHP has now been classified as a Category 1B reprotoxin,<ref>{{Cite web|title=Classifications - CL Inventory|url=https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/10536|access-date=2021-01-18|website=echa.europa.eu}}</ref> and is now on the Annex XIV of the European Union's ] legislation. DEHP has been phased out in Europe under REACH<ref>{{cite web| url = https://pvcmed.org/wp-content/uploads/2020/08/DEHP_Timeline_5.pdf| title = Timeline of European regulations on DEHP| publisher = PVC Med Alliance| access-date = 2020-10-26| archive-date = 2021-04-27| archive-url = https://web.archive.org/web/20210427042541/https://pvcmed.org/wp-content/uploads/2020/08/DEHP_Timeline_5.pdf| url-status = dead}}</ref> and can only be used in specific cases if an authorization has been granted. Authorizations are granted by the European Commission, after obtaining the opinion of the Committee for Risk Assessment (RAC) and the Committee for Socio-economic Analysis (SEAC) of the European Chemicals Agency (ECHA).
			===California===
			DEHP is classified as a "chemical known to the State of California to cause cancer and birth defects or other reproductive harm" (in this case, ''both'') under the terms of ].<ref>{{Cite web|last=|first=|date=|title=Di(2-ethylhexyl)phthalate (DEHP)|url=https://oehha.ca.gov/proposition-65/chemicals/di2-ethylhexylphthalate-dehp|url-status=live|archive-url=https://web.archive.org/web/20160730012122/http://oehha.ca.gov:80/proposition-65/chemicals/di2-ethylhexylphthalate-dehp |archive-date=2016-07-30 |access-date=2021-01-18|website=oehha.ca.gov}}</ref>
	==References==		==References==
			{{Reflist|30em}}
	<references/>
			==Further reading==
			*{{cite journal |last1=Maradonna |first1=Francesca |last2=Evangelisti |first2=Matteo |last3=Gioacchini |first3=Giorgia |last4=Migliarini |first4=Beatrice |last5=Olivotto |first5=Ike |last6=Carnevali |first6=Oliana |display-authors=3|title=Assay of vtg, ERs and PPARs as endpoint for the rapid in vitro screening of the harmful effect of Di-(2-ethylhexyl)-phthalate (DEHP) and phthalic acid (PA) in zebrafish primary hepatocyte cultures |journal=Toxicology in Vitro |volume=27 |issue=1 |pages=84–91 |year=2013 |pmid=23063876 |doi=10.1016/j.tiv.2012.09.018 }}
	==External links==		==External links==
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			* accessed 25 March 2014
	* (pro-DEHP, industry-backed group)
			* accessed 25 March 2014
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	{{HealthIssuesOfPlastics}}		{{HealthIssuesOfPlastics}}
			{{Authority control}}
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