Diethyl phthalate

Diethyl phthalate is produced by the reaction of ethanol with phthalic anhydride, in the presence of a strong acid catalyst:

File:Synthesis-DEP.png

It finds some use as a specialist plasticiser in PVC, it has also been used as a blender and fixative in perfume.{{cite journal |last1=Api |first1=A.M. |title=Toxicological profile of diethyl phthalate: a vehicle for fragrance and cosmetic ingredients |journal=Food and Chemical Toxicology |date=February 2001 |volume=39 |issue=2 |pages=97–108 |doi=10.1016/s0278-6915(00)00124-1|pmid=11267702 }}

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.{{cite journal|last=Cartwright|first=C.D.|date=March 2000|title=Biodegradation of diethyl phthalate in soil by a novel pathway|journal=FEMS Microbiology Letters|volume=186|issue=1|pages=27–34|doi=10.1016/S0378-1097(00)00111-7|pmid=10779708|doi-access=free}} 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.{{cite journal|last=Saito|first=T.|author2=Peng, H.|author3=Tanabe, R.|author4=Nagai, K.|author5=Kato, K.|title=Enzymatic hydrolysis of structurally diverse phthalic acid esters by porcine and bovine pancreatic cholesterol esterases.|journal=Chemosphere|date=December 2010|volume=81|issue=1|doi=10.1016/j.chemosphere.2010.08.020|pages=1544–1548|pmid=20822795|bibcode=2010Chmsp..81.1544S|s2cid=6958344 }}

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.

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.

Little is known about the chronic toxicity of diethyl phthalate, but existing information suggests only a low toxic potential.{{cite journal|journal=Environmental Health Perspectives|year=1973|volume=4|pages=3–25|title=Toxicity and health threats of phthalate esters: review of the literature|author=J. Autian|pmc=1474854|pmid=4578674|doi=10.2307/3428178|jstor=3428178}} 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 does not alter sexual differentiation in male rats.{{cite journal|author1=Antonia M. Calafat |author2=Richard H. McKee |year=2006|title=Integrating Biomonitoring Exposure Data into the Risk Assessment Process: Phthalates [Diethyl Phthalate and Di(2-ethylhexyl) Phthalate] as a Case Study|journal=Environmental Health Perspectives|volume=114|issue=11|pages=1783–1789|doi=10.1289/ehp.9059|pmc=1665433|pmid=17107868}}{{cite journal|journal=Toxicology and Applied Pharmacology|volume=54|issue=3|year=1980|pages=392–398|doi=10.1016/0041-008X(80)90165-9|title=Study of the testicular effects and changes in zinc excretion produced by some n-alkyl phthalates in the rat|author=Paul M. D. Foster|pmid=7394794|display-authors=etal}}{{cite journal|journal=Chemico-Biological Interactions|volume=34|issue=2|year=1981|pages=233–238|doi=10.1016/0009-2797(81)90134-4|title=Studies on the testicular effects and zinc excretion produced by various isomers of monobutyl-o-phthalate in the rat|author=P. M. D. Foster |display-authors=etal |pmid=7460085}}{{cite journal|journal=Toxicological Sciences|volume=58|issue=2|pages=350–365|title=Perinatal Exposure to the Phthalates DEHP, BBP, and DINP, but Not DEP, DMP, or DOTP, Alters Sexual Differentiation of the Male Rat|author=L. Earl Gray Jr |year=2000|doi=10.1093/toxsci/58.2.350|pmid=11099647|display-authors=etal|doi-access=}} 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.{{cite journal|journal=Comparative Biochemistry and Physiology C|volume=122|issue=1|year=1999|pages=115–120|doi=10.1016/S0742-8413(98)10093-2|title=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|last1=Zou|first1=Enmin|last2=Fingerman|first2=Milton|pmid=10190035}} Chitobiase plays an important role in degradation of the old chitin exoskeleton during the pre-moult phase.{{citation|url=http://www.nioz.nl/public/annual_report/2006/baars.pdf |contribution=Free chitobiase, a marker enzyme for the growth of crustaceans |author=M. A. Baars & S.S. Oosterhuis |title=NIOZ Annual Report 2006 |publisher=Royal Netherlands Institute for Sea Research, Texel |pages=62–64 |archive-url=https://web.archive.org/web/20110720210742/http://www.nioz.nl/public/annual_report/2006/baars.pdf |archive-date=2011-07-20 }}

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.{{cite journal|title=Teratogenicity of Phthalate Esters in Rats |author=A. R. Singh |author2=W. H. Lawrence |author3=J. Autian|journal=Journal of Pharmaceutical Sciences|volume=61|issue=1|pages=51–55|year=1972|doi=10.1002/jps.2600610107|pmid=5058645}} 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.{{cite journal|title=Maternal-Fetal transfer of ¹⁴C-Di-2-ethylhexyl phthalate and ¹⁴C-diethyl phthalate in rats |author=A. R. Singh |author2=W. H. Lawrence |author3=J. Autian|journal=Journal of Pharmaceutical Sciences|volume=64|issue=8|pages=1347–1350|year=1975|doi=10.1002/jps.2600640819|pmid=1151708}}

Some data suggest that exposure to multiple phthalates at low doses significantly increases the risk in a dose additive manner.{{cite journal|journal=International Journal of Andrology|title=Adverse effects of environmental antiandrogens and androgens on reproductive development in mammals|author1=L. Earl Gray Jr |volume=29|issue=1|pages=96–104|year=2006|doi=10.1111/j.1365-2605.2005.00636.x|pmid=16466529|display-authors=etal|doi-access=}}{{cite journal|journal=Toxicological Sciences|volume=105|issue=1|pages=153–165|title=A Mixture of Five Phthalate Esters Inhibits Fetal Testicular Testosterone Production in the Sprague-Dawley Rat in a Cumulative, Dose-Additive Manner|author=Kembra L. Howdeshell|year=2008|doi=10.1093/toxsci/kfn077|pmid=18411233|display-authors=etal|doi-access=free}}{{cite journal|journal=Environmental Research|volume=108|issue=2|year=2008|pages=168–176|doi=10.1016/j.envres.2008.08.009|title=Mechanisms of action of phthalate esters, individually and in combination, to induce abnormal reproductive development in male laboratory rats|author=Kembra L. Howdeshell|pmid=18949836|bibcode = 2008ER....108..168H |url=https://zenodo.org/record/1258923|display-authors=etal|doi-access=free}} 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.{{cite journal|author=Shanna H. Swan|author-link=Shanna Swan|year=2008|title=Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humans|journal=Environmental Research|volume=108|issue=2|pages=177–184|bibcode=2008ER....108..177S|doi=10.1016/j.envres.2008.08.007|pmc=2775531|pmid=18949837}}

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Category:Ethyl esters

Category:Phthalate esters

Category:Endocrine disruptors