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_phthalate.png) | |||
| Names | |||
|---|---|---|---|
| Preferred IUPAC name Bis(2-ethylhexyl) benzene-1,2-dicarboxylate | |||
| Other names | |||
| Identifiers | |||
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3D model (JSmol) | |||
| ChEBI | |||
| ChEMBL | |||
| ChemSpider |
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| ECHA InfoCard | 100.003.829 | ||
| EC Number |
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| KEGG |
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| RTECS number |
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| UNII | |||
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| Properties | |||
| C24H38O4 | |||
| Molar mass | 390.564 g·mol−1 | ||
| Appearance | Colorless, oily liquid[3] | ||
| Density | 0.99 g/mL (20°C)[3] | ||
| Melting point | −50 °C (−58 °F; 223 K) | ||
| Boiling point | 385 °C (725 °F; 658 K) | ||
| 0.00003% (23.8 °C)[3] | |||
| Vapor pressure | < 0.01 mmHg (20 °C)[3] | ||
Refractive index (nD) | 1.4870[4] | ||
| Hazards | |||
| Occupational safety and health (OHS/OSH): | |||
Main hazards | Irritant, teratogen | ||
| GHS labelling:[6] | |||
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| Danger | |||
| H360FD | |||
| P201,P202,P280,P308+P313,P405,P501 | |||
| NFPA 704 (fire diamond) | |||
| Flash point | 216 °C; 420 °F; 489 K (open cup)[3] | ||
| Explosive limits | 0.3%-?[3] | ||
| Lethal dose or concentration (LD, LC): | |||
LD50 (median dose) | 34,000 mg/kg (oral, rabbit) 26,000 mg/kg (oral, guinea pig) 30,600 mg/kg (oral, rat) 30,000 mg/kg (oral, mouse)[5] | ||
| NIOSH (US health exposure limits): | |||
PEL (Permissible) | TWA 5 mg/m3[3] | ||
REL (Recommended) | Ca TWA 5 mg/m3 ST 10 mg/m3[3] | ||
IDLH (Immediate danger) | Ca [5000 mg/m3][3] | ||
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |||
Bis(2-ethylhexyl) phthalate,di-2-ethylhexyl phthalate,diethylhexyl phthalate,diisooctyl phthalate,DEHP; incorrectly —dioctyl phthalate,DIOP) is anorganic compound with theformula C6H4(CO2C8H17)2. DEHP is the most common member of the class ofphthalates, which are used asplasticizers. It is thediester ofphthalic acid and the branched-chain2-ethylhexanol. This colorless viscous liquid is soluble in oil, but not in water.
Di(2-ethylhexyl) phthalate is produced commercially by the reaction of excess2-ethylhexanol withphthalic anhydride in the presence of an acid catalyst such assulfuric acid orpara-toluenesulfonic acid. It was first produced in commercial quantities in Japan circa 1933 and in the United States in 1939.[7]
DEHP has two stereocenters,[8] located at the carbon atoms carrying the ethyl groups. As a result, it has three distinct stereoisomers,[8] consisting of an (R,R) form, an (S,S) form (diastereomers), and ameso (R,S) form. As most 2-ethylhexanol is produced as aracemic mixture, commercially-produced DEHP is therefore racemic as well, and consists of a 1:1:2 statistical mixture of stereoisomers.
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Due to its suitable properties and the low cost, DEHP is widely used as aplasticizer in manufacturing of articles made ofPVC.[9] Plastics may contain 1% to 40% of DEHP[citation needed]. DEHP It is also used as ahydraulic fluid and as adielectric fluid incapacitors. DEHP also finds use as asolvent inglowsticks.
Approximately three million tonnes are produced and used annually worldwide.[9]
Manufacturers of flexible PVC articles can choose among several alternative plasticizers offering similar technical properties as DEHP. These alternatives include other phthalates such asdiisononyl phthalate (DINP),di-2-propyl heptyl phthalate (DPHP),diisodecyl phthalate (DIDP), and non-phthalates such as1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH),dioctyl terephthalate (DOTP), andcitrateesters.[10]
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.[11] DEHP is an indoor air pollutant in homes and schools. Common exposures come from the use of DEHP as a fragrance carrier incosmetics,personal care products, laundrydetergents, colognes,scented candles, andair fresheners.[12]The most common exposure to DEHP comes through food with an average consumption of 0.25 milligrams per day.[13] It can alsoleach into a liquid that comes in contact with the plastic; it extracts faster intononpolarsolvents (e.g.oils andfats in foods packed inPVC). 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.[11] The USFDA therefore permits use of DEHP-containing packaging only for foods that primarily contain water.
DEHP can leach intodrinking water from discharges from rubber and chemical factories; The USEPA limits for DEHP in drinking water is 6 ppb.[13] It is also commonly found in bottled water, but unlike tap water, the EPA does not regulate levels in bottled water.[12] DEHP levels in some European samples of milk, were found at 2000 times higher than the EPA Safe Drinking Water limits (12,000 ppb). Levels of DEHP in some European cheeses and creams were even higher, up to 200,000 ppb, in 1994.[14] Additionally, workers in factories that utilize DEHP in production experience greater exposure.[11] The U.S. agencyOSHA's limit for occupational exposure is 5 mg/m3 of air.[15]
DEHP is the most common phthalate plasticizer inmedical devices such as intravenous tubing and bags, IVcatheters, nasogastric tubes,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.newborns inintensive care nursery settings,hemophiliacs,kidney dialysis patients, neonates, premature babies, lactating, and pregnant women. According to the European CommissionScientific 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.[16] TheAmerican Academy of Pediatrics has advocated not to use medical devices that can leach DEHP into patients and, instead, to resort to DEHP-free alternatives.[17] 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;[18] they mention a database of alternatives.[19] TheCBC documentaryThe Disappearing Male raised concerns aboutsexual development in male fetal development,miscarriage, and as a cause of dramatically lowersperm counts in men.[20] A review article in 2010 in theJournal 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.[21]
DEHP hydrolyzes to mono-ethylhexyl phthalate (MEHP) and subsequently tophthalate salts. The released alcohol is susceptible to oxidation to thealdehyde and carboxylic acid.[9]
Theacute toxicity of DEHP is low in animal models: 30 g/kg in rats (oral) and 24 g/kg in rabbits (dermal).[9] Concerns instead focus on its potential as anendocrine disruptor.
DEHP, along with otherphthalates, is believed to cause endocrine disruption in males, through its action as anandrogen antagonist,[22] 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.[23] In another study, airborne concentrations of DEHP at aPVC pellet plant were significantly associated with a reduction in sperm motility andchromatin DNA integrity.[24] 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[25] 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 asPCBs intestes 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 astubule atrophy andgerm cells were more prevalent in testes of dogs from regions with higher concentrations.
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.[26] 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.[27] 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.[28]
When DEHP is ingested intestinallipases convert it to MEHP, which then is absorbed. MEHP is suspected to have an obesogenic effect.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 plasmathyroxine levels and decreased uptake of iodine in thyroidfollicular cells. Previous studies have shown that slight changes in thyroxine levels can have dramatic effects on resting energy expenditure, similar to that of patients withhypothyroidism, which has been shown to cause increased weight gain in those study populations.[29]
Even at relatively low doses of DEHP, cardiovascular reactivity was significantly affected in mice.[30] A clinically relevant dose and duration of exposure to DEHP has been shown to have a significant impact on the behavior ofcardiac cells in culture. This includes an uncoupling effect that leads toirregular rhythmsin 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 ofgap junctionalconnexin proteins, specificallyconnexin-43, incardiomyocytes treated with DEHP.[31]
The decrease in expression and instability ofconnexin-43 may be due to the down regulation oftubulin andkinesin genes, and the alteration ofmicrotubule 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 asangiotensinogen,transforming growth factor-beta,vascular endothelial growth factor C andA, and endothelial-1. The DEHP-induced down regulation of these growth factors may also contribute to the reduced expression and instability of connexin-43.[32]
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 andperoxisome proliferation; both of which can be involved inatherosclerosis andhyperlipidemia, which are precursors of cardiovascular disease.[33]
Once metabolized into MEHP, the molecule has been shown to lengthen action potential duration and slow epicardial conduction velocity in Langendorff perfused rodent hearts.[34]
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.[35] There is also a correlation between DEHP plasma levels in women and endometriosis.[36]
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, decreasedapoptosis,oxidative damage, and selective clonal expansion of the initiated cells; all of which take place in multiple sites of the human body.[37]
In October 2009, Consumers' Foundation, Taiwan (CFCT) published test results[38] that found 5 out of the sampled 12 shoes contained over 0.1% of phthalate plasticizer content, including DEHP, which exceeds the government'sToy 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 inclouding agents for use in food and beverages has been reported inTaiwan.[39] An inspection of products initially discovered the presence of plasticizers. As more products were tested, inspectors found more manufacturers using DEHP and DINP.[40] TheDepartment of Health confirmed that contaminated food and beverages had been exported to other countries and regions, which reveals the widespread prevalence of toxic plasticizers.
Concerns about chemicals ingested by children when chewing plastic toys prompted theEuropean 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 (DBP,BBP,DINP,DIDP and DNOP) in toys for young children.[41] 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.[42] In 2008, six substances were considered to be of very high concern (SVHCs) and added to the Candidate List includingmusk xylene, MDA,HBCDD, DEHP,BBP, andDBP. In 2011, those six substances have been listed for Authorization in Annex XIV ofREACH by Regulation (EU) No 143/2011.[43] According to the regulation, phthalates including DEHP, BBP and DBP will be banned from February 2015.[44]
In 2012, Danish Environment MinisterIda Auken announced the ban of DEHP, DBP, DIBP and BBP, pushingDenmark ahead of the European Union which has already started a process of phasing out phthalates.[45] 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.[46]
In 2012,France became the first country in the EU to ban the use of DEHP in pediatrics, neonatal, and maternity wards in hospitals.[47]
DEHP has now been classified as a Category 1B reprotoxin,[48] and is now on the Annex XIV of the European Union'sREACH legislation. DEHP has been phased out in Europe under REACH[49] 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).
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 ofProposition 65.[50]
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