Bis(2-ethylhexyl) phthalate: Difference between revisions

{{short description|Organic compound used as a plasticizer to soften polymer matrix}}

{{Chembox

| Watchedfields = changed

| verifiedrevid = 459979401

| ImageName = Bis(2-ethylhexyl) phthalate

| ImageSize2 = 160px

| ImageFileL1 = Bis(2-ethylhexyl)phthalate.svg

| ImageFileR1 = Bis(2-ethylhexyl) phthalate 3D.png

| ImageFile2 = Bis(2-ethylhexyl) phthalate.png

| PIN = Bis(2-ethylhexyl) benzene-1,2-dicarboxylate

| 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>

| Section1 = {{Chembox Identifiers

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 21106505

| ChEMBL = 402794

| KEGG_Ref = {{keggcite|correct|kegg}}

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 17747

| PubChem = 8343

| EC_number = 204-211-0 617-060-4

| RTECS = TI0350000

| SMILES = O=C(OCC(CC)CCCC)C1=CC=CC=C1C(OCC(CC)CCCC)=O

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| 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/m³<ref name=PGCH>{{PGCH|0236}}</ref>

| FlashPtF = 420

| FlashPt_notes = (open cup)<ref name=PGCH/>

| ExploLimits = 0.3%-?<ref name=PGCH/>

| IDLH = Ca [5000 mg/m³]<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/m³ ST 10 mg/m³<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''' ('''di-2-ethylhexyl phthalate''', '''diethylhexyl phthalate''', '''diisooctyl phthalate''', '''DEHP'''; incorrectly — '''dioctyl phthalate''', '''DIOP''') is an [[organic compound]] with the [[chemical formula|formula]] C₆H₄(CO₂C₈H₁₇)₂. DEHP is the most common member of the class of [[phthalate]]s, which are used as [[plasticizers]]. It is the [[ester|diester]] of [[phthalic acid]] and the branched-chain [[2-Ethylhexanol|2-ethylhexanol]]. This colorless viscous liquid is soluble in oil, but not in water.

Di(2-ethylhexyl) phthalate is produced commercially by the reaction of excess [[2-ethylhexanol]] with [[phthalic anhydride]] in the presence of an acid catalyst such as [[sulfuric acid]] or [[para-toluenesulfonic acid|''para''-toluenesulfonic acid]]. 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=[[International Agency for Research on Cancer]] |location=[Lyon] |isbn=978-92-832-1229-4 |page=271 |url=https://publications.iarc.fr/_publications/media/download/1577/2f8d8229f8923fd2509f7f95e848ba6bf7f88766.pdf}}</ref>

:[[File:DEHP Synthesis V1.svg|220px]]

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 ([[diastereomer]]s), and a ''[[Meso compound|meso]]'' (''R'', ''S'') form. As most 2-ethylhexanol is produced as a [[racemic]] mixture, commercially-produced DEHP is therefore racemic as well, and consists of a 1:1:2 statistical mixture of stereoisomers.

:[[File:DEHP Isomers V.1.svg|220px]]

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[[File:Laying sewer hi res (2).jpg|thumb|left|PVC is used extensively in sewage pipe due to its low cost, chemical resistance, and ease of jointing. Phthalate plasticizers are essential for the utility of PVC, which is too brittle otherwise.<ref name=Ullmanns/>]]

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 [[diisononyl phthalate]] (DINP), [[di-2-propyl heptyl phthalate]] (DPHP), [[diisodecyl phthalate]] (DIDP), and non-phthalates such as [[1,2-Cyclohexane dicarboxylic acid diisononyl ester|1,2-cyclohexane dicarboxylic acid diisononyl ester]] (DINCH), [[dioctyl terephthalate]] (DOTP), and [[citrate]] [[ester]]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>

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 [[cosmetics]], [[personal care]] products, laundry [[detergent]]s, colognes, [[scented candle]]s, and [[air freshener]]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>

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 [[Leaching (chemistry)|leach]] into a liquid that comes in contact with the plastic; it extracts faster into [[nonpolar]] [[solvent]]s (e.g. [[oil]]s and [[fat]]s in foods packed in [[Polyvinyl chloride|PVC]]). 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 [[Food and Drug Administration|FDA]] therefore permits use of DEHP-containing packaging only for foods that primarily contain water.

DEHP can leach into [[drinking water]] from discharges from rubber and chemical factories; The US [[United States Environmental Protection Agency|EPA]] limits for DEHP in drinking water is 6&nbsp;[[Parts per billion|ppb]].<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 [[Occupational Safety and Health Administration|OSHA]]'s limit for occupational exposure is 5&nbsp;mg/m³ 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>

DEHP is the most common phthalate plasticizer in [[medical device]]s such as intravenous tubing and bags, IV [[catheter]]s, nasogastric tubes, [[Kidney dialysis|dialysis]] 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. [[newborn]]s in [[Neonatal intensive care unit|intensive care nursery]] settings, [[hemophilia]]cs, [[kidney dialysis]] patients, neonates, premature babies, lactating, and pregnant women. According to the European Commission [[Scientific Committee on Health and Environmental Risks]] (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 [[American Academy of Pediatrics]] 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>[https://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/PublicHealthNotifications/ucm062182.htm FDA Public Health Notification: PVC Devices Containing the Plasticizer DEHP], USFDA July 12, 2002</ref> they mention a database of alternatives.<ref>[http://www.sustainablehospitals.org/cgi-bin/DB_Report.cgi?px=W&rpt=Haz&id=10 Products for Hazard: DEHP] {{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 [[Canadian Broadcasting Corporation|CBC]] documentary ''The Disappearing Male'' raised concerns about [[sexual development]] in male fetal development, [[miscarriage]], and as a cause of dramatically lower [[sperm count]]s in men.<ref>[http://www.cbc.ca/documentaries/doczone/2008/disappearingmale/ ''The Disappearing Male''] – 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>

DEHP hydrolyzes to mono-ethylhexyl phthalate (MEHP) and subsequently to [[phthalic acid|phthalate]] salts. The released alcohol is susceptible to oxidation to the [[aldehyde]] and carboxylic acid.<ref name=Ullmanns/>

===Toxicity===

The [[acute toxicity]] 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 [[endocrine disruptor]].

===Endocrine disruption===

DEHP, along with other [[phthalates]], is believed to cause endocrine disruption in males, through its action as an [[androgen antagonist]],<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 [[PVC]] pellet plant were significantly associated with a reduction in sperm motility and [[chromatin]] 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 [[PCBs]] in [[testes]] 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 [[tubule atrophy]] and [[germ cell]]s were more prevalent in testes of dogs from regions with higher concentrations.

===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>

===Obesity===

When DEHP is ingested intestinal [[lipase]]s convert it to MEHP, which then is absorbed. MEHP is suspected to have an obesogenic effect. [[Animal testing on rodents|Rodent studies]] 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 [[thyroxine]] levels and decreased uptake of iodine in thyroid [[Thyroid epithelial cell|follicular cells]]. Previous studies have shown that slight changes in thyroxine levels can have dramatic effects on resting energy expenditure, similar to that of patients with [[hypothyroidism]], 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>

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 [[cardiac]] cells in culture. This includes an uncoupling effect that leads to [[Cardiac arrhythmia|irregular rhythms]] [[in vitro]]. 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 [[gap junction]]al [[connexin]] proteins, specifically [[GJA1|connexin-43]], in [[cardiomyocytes]] 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 [[GJA1|connexin-43]] may be due to the down regulation of [[tubulin]] and [[kinesin]] genes, and the alteration of [[microtubule]] 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 [[angiotensinogen]], [[Transforming growth factor beta|transforming growth factor-beta]], [[vascular endothelial growth factor C]] and [[Vascular endothelial growth factor A|A]], 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>

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 [[peroxisome]] proliferation; both of which can be involved in [[atherosclerosis]] and [[hyperlipidemia]], 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>

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>

=== 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 [[apoptosis]], [[Oxidative stress|oxidative damage]], 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 [[Toy safety#Safety standards|Toy Safety Standard (CNS 4797)]]. CFCT recommend that users should first wear socks to avoid direct skin contact.

In May 2011, the illegal use of the plasticizer DEHP in [[clouding agent]]s for use in food and beverages has been reported in [[Taiwan]].<ref>[http://www.taipeitimes.com/News/taiwan/archives/2011/05/29/2003504450 FOOD SCARE WIDENS:Tainted additives used for two decades: manufacturer], 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 [[Department of Health (Republic of China)|Department of Health]] 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 [[European Commission]] 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 ([[Dibutyl phthalate|DBP]], [[Benzyl butyl phthalate|BBP]], [[DINP]], [[DIDP]] 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 ([[DINP]], [[DIDP]], 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 ([[SVHC]]s) and added to the Candidate List including [[musk xylene]], MDA, [[HBCDD]], DEHP, [[Benzyl butyl phthalate|BBP]], and [[Dibutyl phthalate|DBP]]. In 2011, those six substances have been listed for Authorization in Annex XIV of [[Registration, Evaluation, Authorisation and Restriction of Chemicals|REACH]] 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 [[Ida Auken]] announced the ban of DEHP, DBP, DIBP and BBP, pushing [[Denmark]] 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, [[France]] 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 [[Registration, Evaluation, Authorisation and Restriction of Chemicals|REACH]] 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 [[Proposition 65]].<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>

{{Reflist|30em}}

==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 }}

*[https://web.archive.org/web/20161220115513/https://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/PublicHealthNotifications/ucm062182.htm FDA Public Health Notification: PVC devices containing the plasticizer DEHP (archived page)]

*[https://wwwn.cdc.gov/TSP/ToxFAQs/ToxFAQsLanding.aspx?id=377&tid=65 ATSDR ToxFAQs]

*[https://www.cdc.gov/niosh/npg/npgd0236.html CDC - NIOSH Pocket Guide to Chemical Hazards]

*[https://web.archive.org/web/20060820035041/http://www.npi.gov.au/database/substance-info/profiles/43.html National Pollutant Inventory - DEHP fact sheet]

*[https://web.archive.org/web/20140326042848/http://www.noharm.org/us_canada/issues/toxins/pvc_phthalates/phthalates.php Healthcare without Harm - PVC and DEHP] accessed 25 March 2014

*[https://web.archive.org/web/20140401160028/http://noharm.org/lib/downloads/pvc/Weight_of_Evidence_DEHP.pdf Healthcare without Harm: "Weight of the Evidence on DEHP: Exposures are a Cause for Concern, Especially During Medical Care"; 6p-fact sheet, 16 March 2009] accessed 25 March 2014

*[https://web.archive.org/web/20190413010307/http://www.speclab.com/compound/c117817.htm Spectrum Laboratories Fact Sheet (archived page)]

*[http://chemsub.online.fr/name/dehp.html ChemSub Online : Bis(2-ethylhexyl) phthalate -DEHP]

*[https://web.archive.org/web/20090604085301/http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM080457.pdf Safety Assessment of Di(2-ethylhexyl)phthalate (DEHP) Released from PVC Medical Devices - Center for Devices and Radiological Health U.S. Food and Drug Administration (archived page)]

{{Authority control}}

[[Category:IARC Group 2B carcinogens]]

[[Category:Phthalate esters]]

[[Category:2-Ethylhexyl esters]]