Bis(2-ethylhexyl) phthalate

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Dioctyl phthalate
)
Bis(2-ethylhexyl) phthalate
Bis(2-ethylhexyl) phthalate
Names
Preferred IUPAC name
Bis(2-ethylhexyl) benzene-1,2-dicarboxylate
Other names
Bis(2-ethylhexyl) phthalate
Di-sec octyl phthalate[1] (archaic)
DEHP
Isooctyl phthalate, di-[2]
Identifiers
3D model (
JSmol
)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard
100.003.829 Edit this at Wikidata
EC Number
  • 204-211-0 617-060-4
KEGG
RTECS number
  • TI0350000
UNII
  • InChI=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 ☒N
    Key: BJQHLKABXJIVAM-UHFFFAOYSA-N ☒N
  • O=C(OCC(CC)CCCC)C1=CC=CC=C1C(OCC(CC)CCCC)=O
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]
1.4870[4]
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
Irritant, teratogen
GHS labelling:[6]
GHS08: Health hazard
Danger
H360FD
P201, P202, P280, P308+P313, P405, P501
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth 0: Exposure under fire conditions would offer no hazard beyond that of ordinary combustible material. E.g. sodium chlorideFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
0
1
0
Flash point 216 °C; 420 °F; 489 K (open cup)[3]
Explosive limits
0.3%-?[3]
Lethal dose or concentration (LD, LC):
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 their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Bis(2-ethylhexyl) phthalate (di-2-ethylhexyl phthalate, diethylhexyl phthalate, diisooctyl phthalate, DEHP; incorrectly — dioctyl phthalate, DIOP) is an

plasticizers. It is the diester of phthalic acid and the branched-chain 2-ethylhexanol
. This colorless viscous liquid is soluble in oil, but not in water.

Production

Di(2-ethylhexyl) phthalate is produced commercially by the reaction of excess

para-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,

racemic
mixture, commercially-produced DEHP is therefore almost always racemic as well, and consists of equal amounts of all three stereoisomers.

Use

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.[9]

Due to its suitable properties and the low cost, DEHP is widely used as a

glowsticks
.

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 as

citrate esters.[10]

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.

The most common exposure to DEHP comes through food with an average consumption of 0.25 milligrams per day.
nonpolar solvents (e.g. oils and fats in foods packed in 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.[11] The US FDA
therefore permits use of DEHP-containing packaging only for foods that primarily contain water.

DEHP can leach into

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. agency OSHA's limit for occupational exposure is 5 mg/m3 of air.[15]

Use in medical devices

DEHP is the most common phthalate plasticizer in

sperm counts in men.[20] 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.[21]

Metabolism

DEHP hydrolyzes to mono-ethylhexyl phthalate (MEHP) and subsequently to phthalate salts. The released alcohol is susceptible to oxidation to the aldehyde and carboxylic acid.[9]

Effects on living organisms

Toxicity

The acute 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 an endocrine disruptor.

Endocrine disruption

DEHP, along with other

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 cells
were more prevalent in testes of dogs proveining 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.[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]

Obesity

When DEHP is ingested intestinal

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.[29]

Cardiotoxicity

Even at relatively low doses of DEHP, cardiovascular reactivity was significantly affected in mice.

cardiomyocytes treated with DEHP.[31]

The decrease in expression and instability of

angiotensinogen, transforming growth factor-beta, vascular endothelial growth factor C and 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.[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 and peroxisome proliferation; both of which can be involved in atherosclerosis and hyperlipidemia, 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]

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.[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, decreased apoptosis, oxidative damage, and selective clonal expansion of the initiated cells; all of which take place in multiple sites of the human body.[37]

Government and industry response

Taiwan

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's 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

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.

European Union

Concerns about chemicals ingested by children when chewing plastic toys prompted the

HBCDD, DEHP, BBP, and DBP. In 2011, those six substances have been listed for Authorization in Annex XIV of REACH 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 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.[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's REACH 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).

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.[50]

References

  1. ^ Diethylhexyl ester of phthalic acid
  2. ^ Bis(2-ethylhexyl)phthalate
  3. ^ a b c d e f g h i NIOSH Pocket Guide to Chemical Hazards. "#0236". National Institute for Occupational Safety and Health (NIOSH).
  4. ^ Alfa Aesar. "117-81-7 - Bis(2-ethylhexyl) phthalate, 98+% - Dioctyl phthalate - Phthalic acid bis(2-ethylhexyl)ester - A10415". www.alfa.com. Thermo Fisher Scientific. Retrieved 30 April 2020.
  5. ^ "Di-sec octyl phthalate". Immediately Dangerous to Life or Health Concentrations (IDLH). National Institute for Occupational Safety and Health (NIOSH). 4 December 2014. Retrieved 17 March 2015.
  6. ^ Sigma-Aldrich Co., Bis(2-ethylhexyl) phthalate. Retrieved on 2022-05-12.
  7. .
  8. ^ a b 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
  9. ^ .
  10. ^ "Plasticizers | ExxonMobil Product Solutions". www.exxonmobilchemical.com. Retrieved 2022-06-18.
  11. ^ a b c "ATSDR - ToxFAQs™: Di(2-ethylhexyl)phthalate (DEHP)". www.atsdr.cdc.gov. Retrieved 2015-10-27.
  12. ^ a b "EHHI :: Plastics :: EHHI Releases Original Research Report:Plastics That May be Harmful to Children and Reproductive Health". www.ehhi.org. Retrieved 2015-10-27.
  13. ^ a b OW, US EPA (21 September 2015). "Basic Information about Di(2-ethylhexyl) phthalate in Drinking Water". water.epa.gov. Retrieved 2015-10-27.
  14. PMID 7926171
    .
  15. ^ "Chemical Sampling Information | Di-(2-Ethylhexyl)phthalate". www.osha.gov. Archived from the original on 2017-07-31. Retrieved 2015-10-27.
  16. ^ "Phthalates in school supplies". GreenFacts Website. Retrieved 2009-06-10.
  17. PMID 12777573
    .
  18. ^ FDA Public Health Notification: PVC Devices Containing the Plasticizer DEHP, USFDA July 12, 2002
  19. ^ Products for Hazard: DEHP Archived 2010-07-15 at the Wayback Machine, Sustainable Hospitals
  20. ^ The Disappearing Male – Sunday February 14, 2010 at 3 pm on CBC-TV, CBC
  21. S2CID 32481051
    .
  22. ^ CDC Main (7 September 2021). "Biomonitoring Summary Phthalates Overview".
  23. PMID 25743932
    .
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  25. .
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  37. .
  38. ^ 《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」 (in Chinese). Consumers’ Foundation, Taiwan (CFCT).
  39. ^ FOOD SCARE WIDENS:Tainted additives used for two decades: manufacturer, Taipei Times, May 29, 2011
  40. ^ 生活中心綜合報導 (2011-05-23). 塑化劑危機!台灣海洋深層水等4廠商飲料緊急下架 (in Chinese). NOWnews. Retrieved 2011-05-25.
  41. ^ "EU ministers agree to ban chemicals in toys". EurActiv.com. 2004-10-07.
  42. ^ "Phthalates to be banned in toys and childcare articles". EurActiv.com. 2005-06-27. Archived from the original on 2013-06-03. Retrieved 2013-10-24.
  43. ^ REACH - First Six Substances Subject To Authorisation (PDF), Sparkle, vol. 559, Intertek, 25 Feb 2011
  44. ^ "First REACH substance bans to apply from 2014". European Solvents Industry Group. 2011-02-18. Archived from the original on 2015-07-21. Retrieved 2013-10-24.
  45. ^ "Denmark defies EU with planned ban on phthalate chemicals". EurActiv.com. 2012-08-27.
  46. ^ "Danish prohibition against four low molecular weight phthalates postponed" (Press release). European Council for Plasticisers and Intermediates. Danish Environment Ministry. 28 May 2013. Archived from the original on 2 June 2015.
  47. ^ "The legacy of Healthier Hospitals". practicegreenhealth.org. Retrieved 2021-01-18.
  48. ^ "Classifications - CL Inventory". echa.europa.eu. Retrieved 2021-01-18.
  49. ^ "Timeline of European regulations on DEHP" (PDF). PVC Med Alliance. Archived from the original (PDF) on 2021-04-27. Retrieved 2020-10-26.
  50. ^ "Di(2-ethylhexyl)phthalate (DEHP)". oehha.ca.gov. Archived from the original on 2016-07-30. Retrieved 2021-01-18.

Further reading

  • Maradonna, Francesca; Evangelisti, Matteo; Gioacchini, Giorgia; et al. (2013). "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". Toxicology in Vitro. 27 (1): 84–91.
    PMID 23063876
    .

External links