Phthalates are esters of phthalic acid and various alcohols. A number of diesters are of special practical importance. These are mainly the diesters of methanol, ethanol, butanol, isobutanol, iso-octanol, 2-ethylhexanol, isononanol, isodecanol and alfols with linear chains. The synthesis of the phthalates is generally carried out by combining phthalic anhydride and two molecules of the corresponding alcohol.
Uses
Phthalate esters are used in nonplasticizer products such as perfumes and cosmetics, and plasticized products such as vinyl swimming pools, plasticized vinyl seats on furniture and in cars, and clothing including jackets, raincoats and boots. The main uses of these compounds are found in the plastics industry, which consumes about 87% of all phthalate esters for producing “soft-PVC”. The remaining 13% is used for the production of lacquers, dispersion, cellulose, polystyrole, colours, synthetic and natural rubber, lubricants, polyamides, insect repellents, fixatives for perfumes, congealing agents for explosives and working fluids for high-vacuum pumps. Among the phthalates, di-sec-octyl phthalate (DOP) and diisononylphthalate are the most important standard softeners.
Dimethyl phthalate and dibutyl phthalate (DBP) have additional uses in numerous industries, including textiles, dyestuffs, cosmetics and glass. Dimethyl phthalate is a dye carrier and a plasticizer in hair spray and in safety glass. Dibutyl phthalate is useful as an insect repellent for the impregnation of clothing and as a plasticizer in nitrocellulose lacquers, elastomers, explosives, nail polish and solid rocket propellants. It functions as a solvent for perfume oils, a perfume fixative and a textile lubricating agent. In addition, dibutyl phthalate is used in safety glass, printing inks, paper coatings, dental impression materials, and as a component of PVC plastisol for carpet backcoating.
Many diallyl phthalate compounds are sold under military specification and are utilized for reliable electrical and electronic applications in long-term, adverse environmental conditions. These compounds are used in electronic connectors for communications, computer and aerospace systems, as well as in circuit boards, insulators and potentiometers.
Hazards
The first step of biotransformation of the esters of phthalic acid is their scission to monoesters. The next step in mammals is oxidation of the remaining alcohol of the monoester. The corresponding excretion products are detected in the urine.
Phthalates, especially those with a short alcohol chain, can be absorbed through the skin. Twenty-four hours after dermal application of radioactive diethyl phthalate (DEP), 9% of the radioactivity was found in the urine, and after 3 days the radioactive material was evident in various organs. There seems to be a certain connection between metabolism and toxicity of the phthalates, because the phthalates with a short alcohol chain, which have a higher toxicity, are split particularly fast to monoesters, and many of the toxic effects of phthalates are provoked by the monoesters in the animal experiments.
Acute toxicity. The acute toxicity of phthalates is very slight and decreases generally with increasing molecular weight. In the literature the oral LD50 (rat) for DBP is indicated as 8 to 23 g/kg, and for DOP as 30.6 to 34 g/kg. Phthalates do not cause inflammation of the skin or eyes in rabbits. Cases of skin sensitization have not been described, but phthalates are said to cause light irritation of the mucosa of the respiratory tract. The combination of low toxicity and low vapour pressure implies in general only a slight inhalation risk.
Chronic toxicity. In subchronic and chronic feeding experiments, phthalates had in general a relatively low toxicity. Daily feeding of DOP to rats at 65 mg/kg body weight showed no adverse effects after 2 years. No adverse effect levels are reported for other phthalates after feeding experiments over 1 or 2 years in rats or dogs, with a dose ranging from 14 to 1,250 mg/kg weight/day. Nevertheless recently observed testicle changes and weight increases in the liver of rats after application of 0.2% DOP with food over 17 weeks may require a correction of the “no adverse effect level”.
DOP and DBP exceeding the “no adverse effect levels” led to retardation of weight increase, liver and kidney changes, changes of enzyme activities in liver tissue, and degeneration of testicles. The last effect may be attributed to an interference with zinc metabolism. However, it could be provoked not only by DBP but also by the monoester and by DOP. Both DOP and the monoester led to similar changes of liver tissue.
According to this study DOP and the linear chain isomer di-n-octylphthalate are the compounds with the highest cumulative toxicity among the eight substances tested. Two other esters of phthalic acid, bis (2-methoxyethyl)phthalate and butylcarbutoxymethylphthalate, had a relatively low cumulative toxicity (factor 2.53 and 2.06 respectively). It is uncertain, however, whether the observed cumulative effects are important even for low dosage or merely under the condition that the capacities of the enzymes engaged in the biotransformation are insufficient to provide an adequate rate of elimination after high-dose parenteral administration.
Local irritation. Undiluted DOP did not produce inflammation of the skin or the eye of the rabbit, nor necrosis of the cornea. Calley and co-workers found distinct inflammation after intradermal injection. These results were not confirmed by other authors and are probably due to the use of inappropriate solvents. The absence of irritation of the rabbit’s eye was, however, replicated. Experiments with humans (23 volunteers) did not give any hint of irritation of the skin of the back after contact over 7 days, or support for the assumption of sensitization after repeated application at the same site. Both absorption of the compound through the intact skin, and local irritation are obviously slight.
Inhalation toxicity. In inhalation experiments rats tolerated air saturated with DOP vapour over 2 h without fatalities. When the exposure time was extended, all animals died within the following 2 h. In another experiment, air at 50 °C was led through a DOP solution and the vapour was cooled and delivered to an inhalation chamber. In this chamber mice were exposed to the vapour three times per week for 1 h over 12 weeks. All animals survived. Histologic evidence for diffuse chronic pneumonia in these animals, sacrificed after 12 weeks, could not be affirmed when 20 animals were examined in a detailed check-up.
Embryotoxicity and teratogenicity. Several phthalates are embryotoxic and teratogenic for chicken embryos and pregnant rats in high doses (one-tenth of the acute LD50 or 10 ml/kg DOP intraperitoneal). The harmful effect to the embryo increases with the solubility of the phthalates. DEP and DOP can reach the embryo through the placenta of the female rat. In contrast to six other phthalates, DOP and di-n-octylphthalate with linear chains did not produce anomalies of the skeleton in the offspring of Sprague-Dawley rats.
Mutagenicity. DOP exceeded the mutagenicity of dimethoxyethyl phthalate in the dominant-lethal test with the mouse and showed a clear mutagenic effect when one-third, one-half and two-thirds of the acute LD50 was given. Teratogenic experiments had shown a contrary rank of adverse effects. Although Ames tests indicating mutagenic activity in vitro showed differing results, a weak mutagenic activity can be assumed proven by this test procedure. This effect could depend, among other things, on the extent of the splitting of the ester in vitro.
Carcinogenicity. Animal feeding experiments with rats and mice have produced increase rates of of hepatocellular changes in both sexes. The human data are insufficient for evaluating risk; however, the International Agency for Research on Cancer (IARC) has classified DOP as a probable human carcinogen.
Human data. After an oral uptake of 10 g DOP, mild gastric disorders and diarrhoea appeared in one volunteer. A second volunteer tolerated the uptake of 5 g without any symptoms. Some authors report an absence of irritation or only slight irritation of the skin after local application of DOP in volunteers. A second application at the site of former application gave no indication of sensitization.
An average exposure time of 12 years (range from 4 months to 35 years) to workroom concentrations between 0.0006 and 0.001 ppm DOP neither provoked health disorders nor an augmented rate of chromosome aberrations in the exposed personnel. Plastics containing esters of phthalic acid—especially DOP as a softener—are widely used as medical equipment, for example as blood containers for haemodialysis. The problem of possible direct intravenous uptake of phthalates in humans has thus been thoroughly studied. Stocks of blood stored in plastic containers at 4 °C showed a DOP concentration of 5 to 20 mg/100 ml blood after 21 days. This could lead to a DOP uptake of 300 mg or 4.3 mg/kg after a whole-body blood exchange transfusion in a human of 70 kg. Theoretical considerations show a possible uptake of 150 mg DOP during a haemodialysis of 5 h.
Phthalates tables
Table 1 - Chemical information.
Table 2 - Health hazards.
Table 3 - Physical and chemical hazards.
Table 4 - Physical and chemical properties.