Diethyl phthalate
Encyclopedia
Diethyl phthalate is a phthalate ester
, namely the diethyl ester of phthalic acid. It is a clear substance that is liquid at room temperature and which does not occur in nature. It has a faint, disagreeable odor and can be transferred from the plastics that contain it. When burned, DEP produces toxic gases.
Since the compound is a suitable solvent for many organic molecules
, it is often used to bind cosmetics and fragrances. 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.
There is also general evidence of widespread human exposure
.
Non-occupational exposure results from the diet, for example phthalate-coated medicines and nutritional supplements, and through consumer products. High occupational exposure was observed in workers directly manufacturing plasticizers.
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.
(1,2) pattern. 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, and they are ortho to each other, so all positions in the ring are more or less equally activated. Diethyl phthalate is likely to undergo biodegradation
in the environment. Abiotic degradation processes such as hydrolysis
, oxidation, and photolysis are unlikely to play significant roles in the environmental fate of diethyl phthalate.
with ethanol
in the presence of a catalytic amount of concentrated sulfuric acid
. Phthalic anhydride is produced by either the oxo process or the Ald-Ox process from ethanol and the oxidation of naphthalene
or o-xylene. 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
.
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. 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. Furthermore DEP induces the enzyme activity of catalase
, which leads to hepatic peroxisome proliferation and possibly causes hyperplasia
.
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
. 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.
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.
of diethyl phthalate, but existing information suggests only a low toxic potential. 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. 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
. Chitobiase plays an important role in degradation of the old chitin
exoskeleton
during the pre-moult phase.
. The amount of skeletal malformations was highest at highest dose. 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.
and antiandrogen
ic activity and the cause of premature breast development in girls. Other studies show that phthalates in PVC
flooring can influence the behaviour of children. Phthalate dusts have been linked to higher rates of ASD
and ADHD symptoms. Prenatal exposure to phthalates is associated with childhood social impairment, which can have important adverse effects over a child's lifetime.
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
, namely the diethyl ester of phthalic acid. It is a clear substance that is liquid at room temperature and which does not occur in nature. It has a faint, disagreeable odor and can be transferred from the plastics that contain it. When burned, DEP produces toxic gases.
Since the compound is a suitable solvent for many organic molecules
Organic compound
An organic compound is any member of a large class of gaseous, liquid, or solid chemical compounds whose molecules contain carbon. For historical reasons discussed below, a few types of carbon-containing compounds such as carbides, carbonates, simple oxides of carbon, and cyanides, as well as the...
, it is often used to bind cosmetics and fragrances. 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
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
as well as to the reproductive organs in males and females.
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.There is also general evidence of widespread human exposure
Exposure
-Entertainment:* Exposure , the practice of revealing the secrets of magic to non-magicians* Exposure , a short film anthology series on Sci-Fi Channel from 2000–2002* Exposure , a current affairs strand on ITV in 2011...
.
Non-occupational exposure results from the diet, for example phthalate-coated medicines and nutritional supplements, and through consumer products. High occupational exposure was observed in workers directly manufacturing plasticizers.
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.
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 orthoOrtho
Ortho may refer to:In science* An arene substitution pattern in which two substituents occupy adjacent positions on an aromatic ring...
(1,2) pattern. It is a highly conjugated system
Conjugated system
In chemistry, a conjugated system is a system of connected p-orbitals with delocalized electrons in compounds with alternating single and multiple bonds, which in general may lower the overall energy of the molecule and increase stability. Lone pairs, radicals or carbenium ions may be part of the...
, 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, and they are ortho to each other, so all positions in the ring are more or less equally activated. Diethyl phthalate is likely to undergo biodegradation
Biodegradation
Biodegradation or biotic degradation or biotic decomposition is the chemical dissolution of materials by bacteria or other biological means...
in the environment. Abiotic degradation processes such as hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
, 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 anhydridePhthalic anhydride
Phthalic anhydride is the organic compound with the formula C6H42O. It is the anhydride of phthalic acid. This colourless solid is an important industrial chemical, especially for the large-scale production of plasticizers for plastics. In 2002, approximately 4.6 billion kilograms were...
with ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
in the presence of a catalytic amount of concentrated sulfuric acid
Sulfuric acid
Sulfuric acid is a strong mineral acid with the molecular formula . Its historical name is oil of vitriol. Pure sulfuric acid is a highly corrosive, colorless, viscous liquid. The salts of sulfuric acid are called sulfates...
. Phthalic anhydride is produced by either the oxo process or the Ald-Ox process from ethanol and the oxidation of naphthalene
Naphthalene
Naphthalene is an organic compound with formula . It is a white crystalline solid with a characteristic odor that is detectable at concentrations as low as 0.08 ppm by mass. As an aromatic hydrocarbon, naphthalene's structure consists of a fused pair of benzene rings...
or o-xylene. The purity of manufactured phthalate esters is reportedly between 99.70% and 99.97% with the main impurities being isophthalic acid
Isophthalic acid
Isophthalic acid is an organic compound with the formula C6H42. This colourless solid is an isomer of phthalic acid and terephthalic acid. These aromatic dicarboxylic acids are used as precursors to commercially important polymers, e.g. the fire-resistant material Nomex...
, terephthalic acid
Terephthalic acid
Terephthalic acid is the organic compound with formula C6H42. This colourless solid is a commodity chemical, used principally as a precursor to the polyester PET, used to make clothing and plastic bottles. Several billion kilograms are produced annually...
, and maleic anhydride
Maleic anhydride
Maleic anhydride is an organic compound with the formula C2H22O. It is the acid anhydride of maleic acid and in its pure state it is a colourless or white solid with an acrid odour....
.
Metabolism
Diethyl phthalate is hydrolyzed to monoester, monoethyl phthalate and ethanol after oral administration in the lumenLumen
Lumen can mean:* Lumen , the SI unit of luminous flux* Lumen , the cavity or channel within a tubular structure* Thylakoid lumen, the inner membrane space of the chloroplast* Phenobarbital...
of the gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
or in the intestinal mucosal cells. Hydrolysis of DEP also takes place at the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
and liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
after systemic absorption. After tissue distribution throughout the body, DEP accumulates in the liver and kidney. The metabolites are excreted in the urine. 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. Furthermore DEP induces the enzyme activity of catalase
Catalase
Catalase is a common enzyme found in nearly all living organisms that are exposed to oxygen, where it catalyzes the decomposition of hydrogen peroxide to water and oxygen...
, which leads to hepatic peroxisome proliferation and possibly causes hyperplasia
Hyperplasia
Hyperplasia means increase in number of cells/proliferation of cells. It may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia/ benign tumor....
.
Biodegradation by microorganisms
BiodegradationBiodegradation
Biodegradation or biotic degradation or biotic decomposition is the chemical dissolution of materials by bacteria or other biological means...
of DEP in soil occurs by sequential hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
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
Methanol
Methanol, also known as methyl alcohol, wood alcohol, wood naphtha or wood spirits, is a chemical with the formula CH3OH . It is the simplest alcohol, and is a light, volatile, colorless, flammable liquid with a distinctive odor very similar to, but slightly sweeter than, ethanol...
, that would produce another three intermediate compounds, ethyl methyl phthalate, dimethyl phthalate and monomethyl phthalate. This biodegradation has been observed in several soil bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
. 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.
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.
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. .Toxicity
Little is known about the chronic toxicityChronic toxicity
Chronic toxicity is a property of a substance that has toxic effects on a living organism, when that organism is exposed to the substance continuously or repeatedly. Compared with acute toxicity.Two distinct situations need to be considered:...
of diethyl phthalate, but existing information suggests only a low toxic potential. Studies suggest that some phthalates affect male reproductive development via inhibition of androgen
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
biosynthesis. In rats, for instance, repeated administration of DEP results in loss of germ cell
Germ cell
A germ cell is any biological cell that gives rise to the gametes of an organism that reproduces sexually. In many animals, the germ cells originate near the gut of an embryo and migrate to the developing gonads. There, they undergo cell division of two types, mitosis and meiosis, followed by...
populations in the testis. However, diethyl phthalate doesn't alter sexual differentiation
Sexual differentiation
Sexual differentiation is the process of development of the differences between males and females from an undifferentiated zygote...
in male rats. 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
Hepatopancreas
The hepatopancreas, digestive gland or midgut gland is an organ of the digestive tract of arthropods, molluscs and fish. It provides the functions which in mammals are provided separately by the liver and pancreas, including the production of digestive enzymes, and absorption of digested...
. Chitobiase plays an important role in degradation of the old chitin
Chitin
Chitin n is a long-chain polymer of a N-acetylglucosamine, a derivative of glucose, and is found in many places throughout the natural world...
exoskeleton
Exoskeleton
An exoskeleton is the external skeleton that supports and protects an animal's body, in contrast to the internal skeleton of, for example, a human. In popular usage, some of the larger kinds of exoskeletons are known as "shells". Examples of exoskeleton animals include insects such as grasshoppers...
during the pre-moult phase.
Teratogenicity
When pregnant rats where treated with diethyl phthalate, it became evident that certain doses caused skeletal malformations, whereas the untreated control group showed no resorptionsBone resorption
Bone resorption is the process by which osteoclasts break down bone and release the minerals, resulting in a transfer of calcium from bone fluid to the blood....
. The amount of skeletal malformations was highest at highest dose. 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.
Long-term effects on children
There is a study that suggests a possible association between plasticizers (such as diethyl phthalate) with known estrogenicXenoestrogen
Xenoestrogens are a type of xenohormone that imitates estrogen. They are widely used industrial compounds such as PCB, BPA and Phthalates, that have estrogenic effects on a living organism even though they differ chemically from the naturally occurring estrogenic substances internally produced by...
and antiandrogen
Antiandrogen
Antiandrogens, or androgen antagonists, first discovered in the 1960s, prevent androgens from expressing their biological effects on responsive tissues. Antiandrogens alter the androgen pathway by blocking the appropriate receptors, competing for binding sites on the cell's surface, or affecting...
ic activity and the cause of premature breast development in girls. Other studies show that phthalates in PVC
Polyvinyl chloride
Polyvinyl chloride, commonly abbreviated PVC, is a thermoplastic polymer. It is a vinyl polymer constructed of repeating vinyl groups having one hydrogen replaced by chloride. Polyvinyl chloride is the third most widely produced plastic, after polyethylene and polypropylene. PVC is widely used in...
flooring can influence the behaviour of children. Phthalate dusts have been linked to higher rates of ASD
Autism spectrum
The term "autism spectrum" is often used to describe disorders that are currently classified as pervasive developmental disorders. Pervasive developmental disorders include autism, Asperger syndrome, Childhood disintegrative disorder, Rett syndrome and Pervasive Developmental Disorder Not Otherwise...
and ADHD symptoms. Prenatal exposure to phthalates is associated with childhood social impairment, which can have important adverse effects over a child's lifetime.