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'''Diethyl phthalate''' ('''DEP''') is a [[phthalate]] [[ester]], namely the diethyl ester of [[phthalic acid]]. It is a clear substance that is liquid at room temperature and is only slightly denser than liquid water. When burned, DEP produces toxic gases.<ref>[https://www.cdc.gov/niosh/ipcsneng/neng0258.html ICSC:NENG0258 (International Chemical Safety Card for 1,2-Benzenedicarboxylic acid diethyl ester)]</ref>
'''Diethyl phthalate''' ('''DEP''') is a [[phthalate]] [[ester]], namely the diethyl ester of [[phthalic acid]]. It is a clear substance that is liquid at room temperature and is only slightly denser than liquid water.


Since the compound is a suitable solvent for many [[Organic compound|organic molecules]], it is often used to bind cosmetics and fragrances.<ref name="Api 2001 97–108">{{cite journal|last=Api|first=A.M.|title=Toxicological profile of diethyl phthalate: a vehicle for fragrance and cosmetic ingredients|journal=[[Food and Chemical Toxicology]]|year=2001|volume=39|issue=2|pages=97–108|doi=10.1016/S0278-6915(00)00124-1}}</ref> Other industrial uses include plasticizers, detergent bases and aerosol sprays.<ref>{{cite journal|last=Ghorpade|first=N.|author2=Mehta, V.|author3=Khare, M.|title=Toxicity Study of Diethyl Phthalate on Freshwater Fish Cirrhina mrigala|journal=Ecotoxicology and Environmental Safety|year=2002|volume=53|issue=2|pages=255–258|doi=10.1006/eesa.2002.2212}}</ref> Because of the frequent dermal exposure of humans to the chemical, the question of toxicity is crucial. Several studies suggest that DEP can cause damage to the [[nervous system]] as well as to the [[reproductive organs]] in males and females.<ref>{{cite journal|last=Miodovnik|first=A.|title=Endocrine disruptors and childhood social impairment|journal=Neurotoxicology|date=March 2011|volume=32|issue=2|pages=261–267|doi=10.1016/j.neuro.2010.12.009|pmid=21182865|pmc=3057338}}</ref><ref name="Colon00">{{cite journal|journal=Environmental Health Perspectives|title=Identification of Phthalate Esters in the Serum of Young Puerto Rican Girls with Premature Breast Development|authors=Ivelisse Colón|year=2000|volume=108|issue=9|pages=895–900|doi=10.1289/ehp.00108895|pmid=11017896|pmc=2556932|display-authors=etal}}</ref><ref name="Swan08">{{cite journal|journal=Environmental Research|volume=108|issue=2|year=2008|pages=177–184|doi=10.1016/j.envres.2008.08.007|title=Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humans|author=Shanna H. Swan|pmc=2775531|pmid=18949837|bibcode=2008ER....108..177S}}</ref>
Since the compound is a suitable solvent for many [[Organic compound|organic molecules]], it is often used to bind cosmetics and fragrances.<ref name="Api 2001 97–108">{{cite journal|last=Api|first=A.M.|title=Toxicological profile of diethyl phthalate: a vehicle for fragrance and cosmetic ingredients|journal=[[Food and Chemical Toxicology]]|year=2001|volume=39|issue=2|pages=97–108|doi=10.1016/S0278-6915(00)00124-1}}</ref> Other industrial uses include plasticizers, detergent bases and aerosol sprays. Because of the frequent dermal exposure of humans to the chemical, the question of toxicity is crucial. Several studies suggest that DEP can cause damage to the [[nervous system]] as well as to the [[reproductive organs]] in males and females.<ref>{{cite journal|last=Miodovnik|first=A.|title=Endocrine disruptors and childhood social impairment|journal=Neurotoxicology|date=March 2011|volume=32|issue=2|pages=261–267|doi=10.1016/j.neuro.2010.12.009|pmid=21182865|pmc=3057338}}</ref><ref name="Colon00">{{cite journal|journal=Environmental Health Perspectives|title=Identification of Phthalate Esters in the Serum of Young Puerto Rican Girls with Premature Breast Development|authors=Ivelisse Colón|year=2000|volume=108|issue=9|pages=895–900|doi=10.1289/ehp.00108895|pmid=11017896|pmc=2556932|display-authors=etal}}</ref><ref name="Swan08">{{cite journal|journal=Environmental Research|volume=108|issue=2|year=2008|pages=177–184|doi=10.1016/j.envres.2008.08.007|title=Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humans|author=Shanna H. Swan|pmc=2775531|pmid=18949837|bibcode=2008ER....108..177S}}</ref>


==Exposure==
==Exposure==

Revision as of 09:33, 17 May 2020

Diethyl phthalate[1]
Skeletal formula of diethyl phthalate
Ball-and-stick model of the diethyl phthalate molecule
Names
Preferred IUPAC name
Diethyl benzene-1,2-dicarboxylate
Other names
Diethyl phthalate
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.001.409 Edit this at Wikidata
KEGG
UNII
  • InChI=1S/C12H14O4/c1-3-15-11(13)9-7-5-6-8-10(9)12(14)16-4-2/h5-8H,3-4H2,1-2H3 checkY
    Key: FLKPEMZONWLCSK-UHFFFAOYSA-N checkY
  • InChI=1/C12H14O4/c1-3-15-11(13)9-7-5-6-8-10(9)12(14)16-4-2/h5-8H,3-4H2,1-2H3
    Key: FLKPEMZONWLCSK-UHFFFAOYAV
  • CCOC(=O)c1ccccc1C(=O)OCC
Properties
C12H14O4
Molar mass 222.24 g/mol
Appearance colourless, oily liquid
Density 1.12 g/cm3 at 20 °C
Melting point −4 °C (25 °F; 269 K)
Boiling point 295 °C (563 °F; 568 K)
1080 mg/L at 25 °C
log P 2.42
Vapor pressure 0.002 mmHg (25°C)[2]
-127.5·10−6 cm3/mol
Hazards
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth 1: Exposure would cause irritation but only minor residual injury. E.g. turpentineFlammability 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
1
1
0
Flash point 161.1 °C (322.0 °F; 434.2 K)[2]
Explosive limits 0.7%-?[2]
Lethal dose or concentration (LD, LC):
8600 mg/kg (Rat)
NIOSH (US health exposure limits):
PEL (Permissible)
 none[2]
REL (Recommended)
 TWA 5 mg/m3[2]
IDLH (Immediate danger)
 N.D.[2]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Diethyl phthalate (DEP) is a phthalate ester, namely the diethyl ester of phthalic acid. It is a clear substance that is liquid at room temperature and is only slightly denser than liquid water.

Since the compound is a suitable solvent for many organic molecules, it is often used to bind cosmetics and fragrances.[3] Other industrial uses include plasticizers, detergent bases and aerosol sprays. Because of the frequent dermal exposure of humans to the chemical, the question of toxicity is crucial. Several studies suggest that DEP can cause damage to the nervous system as well as to the reproductive organs in males and females.[4][5][6]

Exposure

Due to their use as plasticizers, diethyl phthalates are ubiquitous in the environment, especially near places of production and use. Biodegradation through microbially-mediated processes can result in products that can potentially harm microorganisms.[7] There is also general evidence of widespread human exposure.[8][9][10][11] Non-occupational exposure results from the diet, for example phthalate-coated medicines and nutritional supplements, and through consumer products.[11] High occupational exposure was observed in workers directly manufacturing plasticizers.[12] Studies suggest a high correlation between air and urine sample concentrations of short side-chain phthalates such as DEP, making inhalation an important route of exposure.[9][12]

Structure and reactivity

Diethyl phthalate, or o-Benzenedicarboxylic acid diethyl ester consists of a benzene ring with two carboxylic acid ethyl esters attached to it in the ortho (1,2) pattern.[1] It is a highly conjugated system, as the pi-cloud on the benzene ring, the p-orbitals on the carbonyl atoms and the lone pairs on the oxygens are all conjugated. The substituents are meta-directing,[13] and they are ortho to each other, so all positions in the ring are more or less equally deactivated. Diethyl phthalate is likely to undergo biodegradation in the environment.[14] Abiotic degradation processes such as hydrolysis, oxidation, and photolysis are unlikely to play significant roles in the environmental fate of diethyl phthalate.

Synthesis

Diethyl phthalate is produced by the reaction of phthalic anhydride with ethanol in the presence of a catalytic amount of concentrated sulfuric acid.[1] Phthalic anhydride is produced by either the oxo process or the Ald-Ox process from ethanol and the oxidation of naphthalene or o-xylene.[15] The purity of manufactured phthalate esters is reportedly between 99.70% and 99.97% with the main impurities being isophthalic acid, terephthalic acid, and maleic anhydride.[15]

Metabolism

Diethyl phthalate is hydrolyzed to monoester, monoethyl phthalate and ethanol after oral administration in the lumen of the gastrointestinal tract or in the intestinal mucosal cells. Hydrolysis of DEP also takes place at the kidney and liver after systemic absorption. After tissue distribution throughout the body, DEP accumulates in the liver and kidney. The metabolites are excreted in the urine.[3] DEP is metabolized by carboxyl esterase, which is synthesized in the human liver. In vitro studies show that DEP reduces the glucuronyl transferase activity. It was also observed that the activity of peroxisomal enzyme carnitine acetyl transferase is increased in cultures of rat liver cells.[3] Furthermore, DEP induces the enzyme activity of catalase, which leads to hepatic peroxisome proliferation and possibly causes hyperplasia.[16]

Biodegradation

Biodegradation by microorganisms

Biodegradation of DEP in soil occurs by sequential hydrolysis of the two diethyl chains of the phthalate to produce monoethyl phthalate, followed by phthalic acid. This reaction occurs very slowly in an abiotic environment. Thus there exists an alternative pathway of biodegradation which includes transesterification or demethylation by microorganisms, if the soil is also contaminated with methanol, that would produce another three intermediate compounds, ethyl methyl phthalate, dimethyl phthalate and monomethyl phthalate. This biodegradation has been observed in several soil bacteria.[7] Some bacteria with these abilities have specific enzymes involved in the degradation of phthalic acid esters such as phthalate oxygenase, phthalate dioxygenase, phthalate dehydrogenase and phthalate decarboxylase.[17] The developed intermediates of the transesterification or demethylation, ethyl methyl phthalate and dimethyl phthalate, enhance the toxic effect and are able to disrupt the membrane of microorganisms.[7]

Biodegradation by mammals

Recent studies show that DEP, a phthalic acid ester (PAE), is enzymatically hydrolyzed to its monoesters by pancreatic cholesterol esterase (CEase) in pigs and cows. These mammalian pancreatic CEases have been found to be nonspecific for degradation in relation to the diversity of the alkyl side chains of PAEs. .[17]

Toxicity

Little is known about the chronic toxicity of diethyl phthalate, but existing information suggests only a low toxic potential.[18] Studies suggest that some phthalates affect male reproductive development via inhibition of androgen biosynthesis. In rats, for instance, repeated administration of DEP results in loss of germ cell populations in the testis. However, diethyl phthalate doesn't alter sexual differentiation in male rats.[8][19][20][21] Dose response experiments in fiddler crabs have shown that seven-day exposure to diethyl phthalate at 50 mg/L significantly inhibited the activity of chitobiase in the epidermis and hepatopancreas.[22] Chitobiase plays an important role in degradation of the old chitin exoskeleton during the pre-moult phase.[23]

Teratogenicity

When pregnant rats were treated with diethyl phthalate, it became evident that certain doses caused skeletal malformations, whereas the untreated control group showed no resorptions. The amount of skeletal malformations was highest at highest dose.[24] In a following study it was found that both phthalate diesters and their metabolic products were present in each of these compartments, suggesting that the toxicity in embryos and fetuses could be the result of a direct effect.[25]

Future investigation

Some data suggest that exposure to multiple phthalates at low doses significantly increases the risk in a dose additive manner.[26][27][28] Therefore, the risk from a mixture of phthalates or phthalates and other anti-androgens, may not be accurately assessed studying one chemical at a time. The same may be said about risks from several exposure routes together. Humans are exposed to phthalates by multiple exposure routes (predominantly dermal), while toxicological testing is done via oral exposure.[6]

References

  1. ^ a b c "Chemical Information Profile for Diethyl Phthalate" (PDF). Integrated Laboratory Systems, Inc. Archived from the original (PDF) on 1 February 2009. Retrieved 3 March 2009.
  2. ^ a b c d e f NIOSH Pocket Guide to Chemical Hazards. "#0213". National Institute for Occupational Safety and Health (NIOSH).
  3. ^ a b c Api, A.M. (2001). "Toxicological profile of diethyl phthalate: a vehicle for fragrance and cosmetic ingredients". Food and Chemical Toxicology. 39 (2): 97–108. doi:10.1016/S0278-6915(00)00124-1.
  4. ^ Miodovnik, A. (March 2011). "Endocrine disruptors and childhood social impairment". Neurotoxicology. 32 (2): 261–267. doi:10.1016/j.neuro.2010.12.009. PMC 3057338. PMID 21182865.
  5. ^ "Identification of Phthalate Esters in the Serum of Young Puerto Rican Girls with Premature Breast Development". Environmental Health Perspectives. 108 (9): 895–900. 2000. doi:10.1289/ehp.00108895. PMC 2556932. PMID 11017896. {{cite journal}}: Unknown parameter |authors= ignored (help)
  6. ^ a b Shanna H. Swan (2008). "Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humans". Environmental Research. 108 (2): 177–184. Bibcode:2008ER....108..177S. doi:10.1016/j.envres.2008.08.007. PMC 2775531. PMID 18949837.
  7. ^ a b c Cartwright, C.D. (March 2000). "Biodegradation of diethyl phthalate in soil by a novel pathway". FEMS Microbiology Letters. 186 (1): 27–34. doi:10.1016/S0378-1097(00)00111-7. PMID 10779708.
  8. ^ a b "Integrating Biomonitoring Exposure Data into the Risk Assessment Process: Phthalates [Diethyl Phthalate and Di(2-ethylhexyl) Phthalate] as a Case Study". Environmental Health Perspectives. 114 (11): 1783–1789. 2006. doi:10.1289/ehp.9059. PMC 1665433. PMID 17107868. {{cite journal}}: Unknown parameter |authors= ignored (help)
  9. ^ a b Adibi, J.J. (2003). "Prenatal Exposures to Phthalates among Women in New York City and Krakow, Poland". Environmental Health Perspectives. 111 (14): 1719–1722. doi:10.1289/ehp.6235. PMC 1241713. PMID 14594621.
  10. ^ Blount, B.C. (July 2000). "Quantitative Detection of Eight Phthalate Metabolites in Human Urine Using HPLC-APCI-MS/MS". Anal. Chem. 72 (17): 4127–4134. doi:10.1021/ac000422r.
  11. ^ a b Schettler, Ted (February 2006). "Human exposure to phthalates via consumer products" (PDF). International Journal of Andrology. 29 (1): 134–139. doi:10.1111/j.1365-2605.2005.00567.x. PMID 16466533.
  12. ^ a b Hines, Cynthia J. (2008). "Urinary Phthalate Metabolite Concentrations among Workers in Selected Industries: A Pilot Biomonitoring Study". The Annals of Occupational Hygiene. 53 (1): 1–17. doi:10.1093/annhyg/men066. PMID 18948546.
  13. ^ Jones, Jr., Maitland (2005). Organic Chemistry. New York: W.W Norton & Company. p. 715.{{cite book}}: CS1 maint: multiple names: authors list (link)
  14. ^ U.S. Department of Health and Human Services, Agency for Toxic Substances and Disease Registry "Toxicological profile for Diethyl Phthalate" June 1995
  15. ^ a b Peakall D.B. (1975). Phthalate esters: Occurrence and biological effects. Vol. 54. pp. 1–41. doi:10.1007/978-1-4612-9857-1_1. ISBN 978-1-4612-9859-5. PMID 1093245. {{cite book}}: |journal= ignored (help)
  16. ^ Timbrell, J. (2009). Principles of Biochemical Toxicology. London: Informa Healthcare. pp. 179, 200–201.
  17. ^ a b Saito, T.; Peng, H.; Tanabe, R.; Nagai, K.; Kato, K. (December 2010). "Enzymatic hydrolysis of structurally diverse phthalic acid esters by porcine and bovine pancreatic cholesterol esterases". Chemosphere. 81 (1): 1544–1548. Bibcode:2010Chmsp..81.1544S. doi:10.1016/j.chemosphere.2010.08.020. PMID 20822795.
  18. ^ J. Autian (1973). "Toxicity and health threats of phthalate esters: review of the literature". Environmental Health Perspectives. 4: 3–25. doi:10.2307/3428178. JSTOR 3428178. PMC 1474854. PMID 4578674.
  19. ^ "Study of the testicular effects and changes in zinc excretion produced by some n-alkyl phthalates in the rat". Toxicology and Applied Pharmacology. 54 (3): 392–398. 1980. doi:10.1016/0041-008X(80)90165-9. PMID 7394794. {{cite journal}}: Unknown parameter |authors= ignored (help)
  20. ^ "Studies on the testicular effects and zinc excretion produced by various isomers of monobutyl-o-phthalate in the rat". Chemico-Biological Interactions. 34 (2): 233–238. 1981. doi:10.1016/0009-2797(81)90134-4. {{cite journal}}: Unknown parameter |authors= ignored (help)
  21. ^ "Perinatal Exposure to the Phthalates DEHP, BBP, and DINP, but Not DEP, DMP, or DOTP, Alters Sexual Differentiation of the Male Rat". Toxicological Sciences. 58 (2): 350–365. 2000. doi:10.1093/toxsci/58.2.350. PMID 11099647. {{cite journal}}: Unknown parameter |authors= ignored (help)
  22. ^ Zou, Enmin; Fingerman, Milton (1999). "Effects of exposure to diethyl phthalate, 4-(tert)-octylphenol, and 2,4,5-trichlorobiphenyl on activity of chitobiase in the epidermis and hepatopancreas of the fiddler crab, Uca pugilator". Comparative Biochemistry and Physiology C. 122 (1): 115–120. doi:10.1016/S0742-8413(98)10093-2.
  23. ^ M. A. Baars & S.S. Oosterhuis, "Free chitobiase, a marker enzyme for the growth of crustaceans", NIOZ Annual Report 2006 (PDF), Royal Netherlands Institute for Sea Research, Texel, pp. 62–64, archived from the original (PDF) on 2011-07-20
  24. ^ "Teratogenicity of Phthalate Esters in Rats". Journal of Pharmaceutical Sciences. 61 (1): 51–55. 1972. doi:10.1002/jps.2600610107. {{cite journal}}: Unknown parameter |authors= ignored (help)
  25. ^ "Maternal-Fetal transfer of 14C-Di-2-ethylhexyl phthalate and 14C-diethyl phthalate in rats". Journal of Pharmaceutical Sciences. 64 (8): 1347–1350. 1975. doi:10.1002/jps.2600640819. {{cite journal}}: Unknown parameter |authors= ignored (help)
  26. ^ "Adverse effects of environmental antiandrogens and androgens on reproductive development in mammals". International Journal of Andrology. 29 (1): 96–104. 2006. doi:10.1111/j.1365-2605.2005.00636.x. {{cite journal}}: Unknown parameter |authors= ignored (help)
  27. ^ "A Mixture of Five Phthalate Esters Inhibits Fetal Testicular Testosterone Production in the Sprague-Dawley Rat in a Cumulative, Dose-Additive Manner". Toxicological Sciences. 105 (1): 153–165. 2008. doi:10.1093/toxsci/kfn077. PMID 18411233. {{cite journal}}: Unknown parameter |authors= ignored (help)
  28. ^ "Mechanisms of action of phthalate esters, individually and in combination, to induce abnormal reproductive development in male laboratory rats". Environmental Research. 108 (2): 168–176. 2008. Bibcode:2008ER....108..168H. doi:10.1016/j.envres.2008.08.009. {{cite journal}}: Unknown parameter |authors= ignored (help)
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