Phthalates diesters

Albro PW, Moore B. 1974. Identification of the metabolites of simple phthalate diesters in rat urine. J Chromatogr 94 209-218. 

Lake BG, Phillips JC, Linnell JC, et al. 1977. The in vitro hydrolysis of some phthalate diesters by hepatic and intestinal preparations from various species. Toxicol Appl Pharmacol 39 239-248. 

Hydrolysis of phthalate diesters to the respective monoesters appears to be the first and the major biotransformation reaction in all of these species, but subsequent oxidative metabolism also may occur. 

In an homologous series of phthalate diesters (7.24, R = Me, Et, allyl, 2-methoxyethyl, Bu, i-Bu, and PhCH2), hydrolysis by some human and rat liver carboxylesterases was fastest for the diethyl and diallyl esters [50], This suggested a maximal rate of hydrolysis for phthalate esters with a lipophilic-ity (log P in the octanol/water system) of 3 - 4. Interestingly, and compatible with this interpretation, monoesters were not hydrolyzed. However, that re-gioisomeric monoesters are hydrolyzed clearly indicates that factors other than lipophilicity (e.g., steric factors) are also influential. 

Hogberg J, Hanherg A, Berglund M, Skerfving S, Remherger M, Calafat AM, Filipsson AF, Jansson B, Johansson N, Appelgren M, Hakansson H (2008) Phthalate diesters and their metabolites in human breast milk, blood or serum, and urine as biomarkers of exposure in vulnerable populations. Environ Health Perspect 116 334—339... 

Generally, phthalates are metabolized and excreted quickly and do not accumulate in the body [23]. Ingested phthalate diesters are initially hydrolyzed in the intestine to their corresponding monoester, which is then absorbed [24], and could be further oxidized in the body. 

Anderson WAC, Castle L, Scotler MJ, Massey RC, Springall C (2001) A biomarker approach to measuring human dietary exposure to certain phthalate diesters. Food Addit Contam 18 1068-1074... 

Okubo T, Suzuki T, Yokoyama Y, Kano K, Kano I (2003) Estimation of estrogenic and antiestrogenic activities of some phthalate diesters and monoesters by MCF-7 cell proliferation assay in vitro. Biol Pharm Bull 26 1219-1224... 

Schwartz, H.E., Anzion, C.J.M., Van Vliet, H.P.M., Copius-Peereboom, J.W. Brinkman, U.A.T. (1979) Analysis of phthalate in sediments from Dutch rivers by means of high performance liquid chromatography. Int. J. environ, anal. Chem., 6, 133-134 Scott, R.C., Dugard, P.H., Ramsey, J.D. Rhodes, C. (1987) In vitro absorption of some o-phthalate diesters through human and rat skin. Environ. Health Perspect, 74, 223-227 Shaffer, C.B., Carpenter, C.P Smyth, H.F., Jr (1945) Acute and subacute toxicity of di(2-ethylhexyl) phthalate with note upon its metabolism. J. ind. Hyg. Toxicol., 27, 130-135 Sharman, M., Read, W.A., Castle, L. Gilbert, J. (1994) Levels of di-(2-ethylhexyl) phthalate and total phthalate esters in milk, cream, butter and cheese. Eood Addit Contam., 11, 375-385... 

Table 8.5 Tolerable Daily Intakes for phthalate diesters...

Application of LC-MS/MS techniques to the analysis of phthalate ester metabolites in urine have also been developed. For example, Blount et al. (2000b) have developed an assay to quantify the monoester metabolites (including MEHP) of eight phthalate diesters in urine, utilizing HPLC coupled with atmospheric pressure chemical ionization and tandem mass spectrometric (APCI-MS/MS) detection techniques. Urine samples were treated with -glucuronidase to release the free phthalate monoesters followed by a two-step solid phase extraction procedure. After evaporative concentration of the eluant, the analytes in the purified samples are further separated on a phenyl reverse phase HPLC column and quantified by APCI-MS/MS, following careful optizimation of the APCI-MS/MS instrument. The limits of detection for MEHP were determined to be 1.2 ng/ml urine with recovery efficiencies of between 78 and 91%. 

Elsisi AE, Carter DE, Sipes IG. 1989. Dermal absorption of phthalate diesters in rats. FundamAppl Toxicol 12 70-77. 

Scott RC, Dugard PH, Ramsey JD, et al. 1987. In vitro absorption of some o-phthalate diesters through human and rat skin. Environ Health Perspect 74 223-227. 

White RD, Carter DE, Earnest O, et al. 1980. Absorption and metabolism of three phthalate diesters by the rat small intestine. Food Cosmet Toxicol 18 383-386. 

The packaging material must not interact with the product either to adsorb substances from the product or to leach chemicals into the product. Plastics contain additives to enhance polymer performance. PVC may contain phthalate diester plasticizer, which can leach into infusion fluids from packaging. Antimicrobial preservatives such as phenylmercuric acetate are known to partition into rubbers and plastics during storage, thus reducing the formulation concentration below effective antimicrobial levels. 

Although 2,7-octadien-l-ol itself has a variety of uses, its main market involves hydrogenation to -octanol, whose phthalate diester is utilized as a plasticizer with superior properties to the currently used branched octanol (2-ethyl-hexanol). 

The alkaline hydrolysis of phthalate diesters has been fit to the Taft-Pavelich equation (Eq. 9). Dimethyl phthalate (DMP) hydrolyzes to phthalic acid (PA) in two steps DMP + H20->MMP + CH30H and MMP + H20- PA + CH30H. The first step is about 12 times faster than the second, and nearly all the diester is converted to the monoester before product PA is formed. Other diesters are assumed to behave similarly. An LFER was obtained from rate measurements on five phthalate esters (Wolfe et al., 1980b). The reaction constants, p and S, were determined by multiple regression analysis of the measured rate constants and reported values of cr and Es for the alkyl substituents. The fitted intercept compares favorably with the measured rate constant (log kOH = — 1.16 0.02) for the dimethyl ester (for which a and s = 0 by definition). Calculated half-lives under pseudo-first-order conditions (pH 8.0, 30°C) range from about 4 months for DMP to over 100 years for di-2-ethylhexyl phthalate. 

Phthalate diesters are sufficiently volatile and thermally stable to be analyzed by GC. 

The analysis of phthalate metabolites has recently become of environmental concern. Primary metabolites of phthalate diesters are monoesters, in which one ester function is hydrolyzed. These monoesters have a carboxylic function that is currently derivatized to avoid adsorption during GC determination. Several derivatization agents have been used to block the free acid group. Methyl-esterification was used by Hashizume et al. and Suzuki et al. Silylation was preferred by Jonsson and Boren,and Jonsson et al. to simultaneously determine the diesters, monoesters and phthalic acid in the same analysis. Wahl et al. performed the analysis of three acid metabolites of... 

Figure 7.2. Diffusion coefficients of homologous series of phthalate diesters of alcohols having different number of carbon atoms. [Data from Storey R F, Mauritz K...

A halogenated flame-retardant plasticizer is produced by Uniplex, containing bromine and chlorine. It improves low-temperature brittleness and provides lower smoke than conventional brominated phthalate diesters, for use primarily in wire and cable applications of flexible PVC, EPDM, and thermoplastic olefins. 

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