Bis(2-ethylhexyl) phthalate, also called di-2-ethylhexyl phthalate, diethylhexyl phthalate (DEHP), and incorrectly called dioctyl phthalate (DOP), is an organic compound with the formula C6H4(CO2C8H17)2. DEHP is the most common member of the class of phthalates, which are used as 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 DEHP is produced commercially by the reaction of excess 2-ethylhexanol with phthalic anhydride in the presence of an acid catalyst such as sulfuric acid or para-toluenesulfonic acid. It was first produced in commercial quantities in Japan circa 1933 and in the United States in 1939.
DEHP has two stereocenters,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 located at the carbon atoms carrying the ethyl groups. As a result, it has three distinct stereoisomers, consisting of an (R,R) form, an (S,S) form (diastereomers), and a meso (R, S) form. As most 2-ethylhexanol is produced as a racemic mixture, commercially-produced DEHP is therefore racemic as well, and consists of a 1:1:2 statistical mixture of stereoisomers.
Use
Due to its suitable properties and the low cost, DEHP is widely used as a plasticizer in manufacturing of articles made of PVC. Flexible PVC compounds contain 5% to 65% plasticizer by weight, and DEHP has long been the reference plasticizer against which substitutes are measured. DEHP is also used as a hydraulic fluid and as a dielectric fluid in capacitors. DEHP also finds use as a solvent in glowsticks.
Approximately three million tonnes are produced and used annually worldwide.
Manufacturers of flexible PVC articles can choose among several alternative plasticizers offering similar technical properties as DEHP. These alternatives include other phthalates such as diisononyl phthalate (DINP), di-2-propyl heptyl phthalate (DPHP), diisodecyl phthalate (DIDP), and non-phthalates such as 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH), dioctyl terephthalate (DOTP), and citrate esters.
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. DEHP is an indoor air pollutant in homes and schools. Common exposures come from the use of DEHP as a fragrance carrier in cosmetics, personal care products, laundry detergents, colognes, scented candles, and air fresheners. The most common exposure to DEHP comes through food with an average consumption of 0.25 milligrams per day. It can also leach into a liquid that comes in contact with the plastic; it extracts faster into nonpolar solvents (e.g. oils and fats in foods packed in PVC). Fatty foods such as milk products, fish or seafood, and oils that are packaged in plastics that contain DEHP are more likely to have higher concentrations; The US FDA therefore permits use of DEHP-containing packaging only for foods that primarily contain water.
DEHP can leach into drinking water from discharges from rubber and chemical factories; The US EPA limits for DEHP in drinking water is 6 ppb. It is also commonly found in bottled water, but unlike tap water, the EPA does not regulate levels in bottled water. 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. Additionally, workers in factories that utilize DEHP in production experience greater exposure. The U.S. agency OSHA's limit for occupational exposure is 5 mg/m3 of air.
Use in medical devices DEHP is the most common phthalate plasticizer in medical devices such as intravenous tubing and bags, IV catheters, 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 in intensive care nursery settings, hemophiliacs, kidney dialysis patients, neonates, premature babies, lactating, and pregnant women. According to the European Commission Scientific 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. The American Academy of Pediatrics has advocated not to use medical devices that can leach DEHP into patients and, instead, to resort to DEHP-free alternatives. 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;FDA Public Health Notification: PVC Devices Containing the Plasticizer DEHP, USFDA July 12, 2002 they mention a database of alternatives.Products for Hazard: DEHP , Sustainable Hospitals The CBC documentary The Disappearing Male raised concerns about sexual development in male fetal development, miscarriage, and as a cause of dramatically lower sperm counts in men.The Disappearing Male – Sunday February 14, 2010 at 3 pm on CBC-TV, CBC 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.
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.
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). Concerns instead focus on its potential as an endocrine disruptor.
Endocrine disruption DEHP, along with other phthalates, is believed to cause endocrine disruption in males, through its action as an androgen antagonist, 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. In another study, airborne concentrations of DEHP at a PVC pellet plant were significantly associated with a reduction in sperm motility and chromatin DNA integrity. 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 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 as PCBs in 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 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. 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. 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.
Obesity When DEHP is ingested intestinal lipases 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 plasma thyroxine levels and decreased uptake of iodine in thyroid 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.
Cardiotoxicity Even at relatively low doses of DEHP, cardiovascular reactivity was significantly affected in mice. A clinically relevant dose and duration of exposure to DEHP has been shown to have a significant impact on the behavior of cardiac cells in culture. This includes an uncoupling effect that leads to irregular rhythms in 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 of gap junctional connexin proteins, specifically connexin-43, in cardiomyocytes treated with DEHP.
The decrease in expression and instability of connexin-43 may be due to the down regulation of tubulin and kinesin genes, and the alteration of microtubule 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 as 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.
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.
Once metabolized into MEHP, the molecule has been shown to lengthen action potential duration and slow epicardial conduction velocity in Langendorff perfused rodent hearts.
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. There is also a correlation between DEHP plasma levels in women and endometriosis.