Bis[2-[2-(2-butoxyethoxy)ethoxy]ethyl] adipate

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Metabolism of the diesters in animals would be expected to occur initially via enzymatic hydrolysis leading to the corresponding diacids [e.g. adipic acid] and the corresponding linear or branched alcohols. These diacids and alcohols can be further metabolized or conjugated (e.g., glucuronides, sulfates, etc.) to polar products that are excreted in the urine (Cragg, 2001; Bevan, 2001; Thurman, 1992; available from EPA, 2003). Metabolic hydrolytic reactions of esters have been extensively reviewed in the literature (Testa and Mayer, 2003; David et al., 2001; Buchwald, 2001; Parkinson, 2001; Satoh et al., 1998; Heyman, 1982; available form EPA, 2003).

The absorption, distribution, and elimination of diethylhexyl adipate were studied in mice and rats. Male Sprague Dawley rats, male NMRI mice, and pregnant female NMRI mice on day 17 of gestation were administered (14)C labeled diethylhexyl adipate dissolved in dimethyl sulfoxide or corn oil intravenously or intragastrically. The diethylhexyl adipate was labeled on the carbonyl or alcohol moiety. Animals were killed 5 minutes to 4 days after dosing, and the tissue distribution of (14)C activity was determined by whole body autoradiography. The tissue distribution of (14)C activity from carbonyl labeled diethylhexyl adipate was similar in all animals. Highest levels of radioactivity were observed in the body fat, liver and kidney after intragastrically or intravenous administration. (14)C activity from alcohol labeled diethylhexyl adipate was found in the bronchi of male mice. In pregnant mice, (14)C activity was observed in the fetal liver, intestine, and bone marrow during the first 24 hours after carbonyl labeled DEHA was given. Very little radiolabel was found in fetuses of mice given alcohol labeled diethylhexyl adipate. No diethylhexyl adipate derived radioactivity was found in mice 4 days after dosing. Blood diethylhexyl adipate concentration in rats increased faster and were two or three times higher when the dose was given in DMSO rather than corn oil. Significant amounts of diethylhexyl adipate were excreted in the bile of rats treated with diethylhexyl adipate in DMSO. Very little biliary elimination of radiolabel occurred in animals given carbonyl labeled diethylhexyl adipate. Diethylhexyl adipate was excreted in the urine, the amounts being smaller in animals used in the bile collection experiments. The vehicle had very little effect on the amount excreted. Diethylhexyl adipate is poorly absorbed from an oil solution (Bergman and Albanus, 1987; available from HSDB, online ).

In addition, in vivo and in vitro metabolism of the diethylhexyl adipate was examined in the rat to determine the different steps involved in the hepatic concentration of peroxisomal proliferators. In the in vivo studies, different doses of diethylhexyl adipate and mono-(2-ethylhexyl)-adipate were administered by gavage to Wistar rats for 5 days. In the in vitro studies, hepatocytes were isolated by in situ perfusion. No diethylhexyl adipate was recovered in rat urine 24 hours after administration; adipic acid was the main metabolite. Only the 2-ethylhexanol pathway showed further metabolites, mainly 2-ethylhexanoic acid which was either conjugated or submitted to other pathways. While 2-ethylhexanoic acid glucuronidation appeared to be dose and time dependent, 2-ethylhexanol glucuronidation was more stable. In vitro, the first hydrolysis of diethylhexyl adipate appeared to be a rate limiting step. When mono-(2-ethylhexyl) adipate was added directly to the culture medium, all the metabolites identified in the in vivo study were found. Glucuronidation of both 2-ethylhexanol and 2-ethylhexanoic acid was dose and time dependent (Cornu MC et al., 1988, available from HSDB, online).

The main metabolic pathway for metabolism of ethylene glycol monoalkyl ethers (EGME, EGEE, and EGBE) is oxidation via alcohol and aldehyde dehydrogenases (ALD/ADH) that leads to the formation of an alkoxy acid (Boatman and Knaak, 2001) (OECD SIDS). However, DEGBE was excreted primarily in urine following oral, dermal or parenteral administration to rats (Dugard et al, 1984; Unilever 1984b; Boatman et al, 1993). The major urinary metabolite was 2-(2-butoxyethoxy)acetic acid (BEAA) (available from ECETOC, 2005).

Toxicokinetic studies conducted on DEGEE in the rat have shown that the main metabolite is ethoxyethoxyacetic acid (EEAA) and not the final metabolite, ethoxyacetic acid (EAA). Associated with toxicity studies on the metabolites themselves, this type of data enables, first, enhanced evaluation of the toxic potential of di- or triethylene derivatives and, secondly, determination of the metabolite to be assayed in the context of human exposure studies (INSERM, 2006).