[14C]bis(2-chloroethoxy)methane: comparative absorption, distribution, metabolism and excretion in rats and mice.

bis(2-Chloroethoxy)methane (BCM) is used primarily as a precursor in the synthesis of polysulfide elastomers. After administration of [(14)C]BCM, radioactivity is readily absorbed from the gastrointestinal tract and moderately absorbed through skin. Following absorption, BCM-derived radioactivity is rapidly distributed to all tissues, rapidly metabolized and excreted primarily in urine. Minimal effects of sex, species or dose in the range studied (0.1-10 mg kg(-1)) were observed on the fate of BCM in rats and mice after all routes of administration. The major metabolite (about 40% of the dose) of BCM in rat was isolated and identified as thiodiglycolic acid (TDGA) indicating that the ether linkage of BCM is cleaved to form 2-chloroethyl fragments that may be further metabolized to 2-chloracetaldehyde, conjugated with glutathione and the latter subsequently metabolized to TDGA. 2-chloroacetaldehyde has also been shown to be cardiotoxic, possibly accounting for BCM cardiotoxicity observed in repeated dose studies.

Lauramide diethanolamine absorption, metabolism, and disposition in rats and mice after oral, intravenous, and dermal administration.

The disposition of carbon-14-labeled lauramide diethanolamine (LDEA) was determined in rats after iv, dermal, and oral administration, and in mice after iv and dermal administration. Intravenous doses of LDEA to rats and mice (25 and 50 mg/kg, respectively) were mostly excreted in the urine (ca. 80-90%), with only about 10% excreted in the feces 72 hr after dosing. No unchanged LDEA, diethanolamine, or diethanolamine-derived metabolites were detected in urine. LDEA concentrated to the highest levels in the adipose tissue, and was only very slowly cleared from that tissue. Residues were also observed in liver and kidney, but clearance from those tissues paralleled the decreases in blood concentrations. Incubations of LDEA with liver slices from rats and humans showed that the compound is well absorbed by hepatic tissue from both species. LDEA was readily converted to metabolites found in vivo in rats, as well as other metabolites that are potentially intermediate products formed after omega- and/or omega-1 to 4 hydroxylation. Treatment with diethylhexylphthalate, an inducer of cytochrome P4504A1, which catalyzes the omega-hydroxylation of lauric and other fatty acids, demonstrated the involvement of that isozyme in the hydroxylation of LDEA. Dermally applied LDEA, at doses of 25 and 400 mg/kg to rats, was moderately (25-30%) well absorbed. Repeat administration (25 mg/kg/day for 3 weeks) did not change the rate of LDEA absorption. The absorption of 100 mg/kg doses was studied in jugular vein-cannulated rats. Steady state levels of LDEA equivalents were reached 24 hr after dermal administration. LDEA comprised about 15% of the radioactivity in plasma, with the remainder present as polar metabolites. A range of 50-70% of the dermal doses to mice, applied at 50, 100, 200, and 800 mg/kg, was absorbed in 72 hr. Absorbed LDEA distributed into the tissues with the same relative profile as that for the iv dose, except that distribution into adipose tissue was considerably lower. High oral doses of LDEA (100 mg/kg) in rats were well absorbed and mostly excreted in the urine as two very polar metabolites. The metabolites were isolated and characterized as the half-acid amides of succinic and of adipic acid, presumably arising from omega-hydroxylation and eventual beta-oxidation to give the chain-shortened products.

Hydroxylation of lauramide diethanolamine by liver microsomes.

Lauramide diethanolamine (LDEA)--a compound used in cosmetics and soap products as an emollient, thickener, and foam stabilizer--was observed to be metabolized by rat liver microsomes to two major products that were identified by GC/MS to be the 11-hydroxy and 12-hydroxy derivatives of LDEA. The specific activities for LDEA 11- and 12-hydroxylation in microsomes prepared from control rats were 2.23 +/- 0.40 and 0.71 +/- 0.17 nmol/min/mg protein, respectively. Treatment of rats with the cytochrome P4504A inducer and peroxisome proliferator, diethylhexyl phthalate, increased the LDEA 12-hydroxylation rate to 3.50 +/- 0.48 nmol/min/mg protein, a 5-fold increase in specific activity, whereas the LDEA 11-hydroxylase activity remained unchanged. Because LDEA contains a 12-carbon side chain, LDEA hydroxylation rates were compared with the hydroxylation rates for lauric acid. The specific activities of lauric acid 11- and 12-hydroxylation reactions in diethylhexyl phthalate-treated rats were 1.7-fold and 3.2-fold greater than the LDEA 11- and 12-hydroxylation rates, respectively. When LDEA hydroxylation reactions were performed in the presence of a polyclonal antibody to the rat P4504A forms, formation of 12-hydroxy-LDEA was inhibited by 80%. Rat kidney microsomes also supported the hydroxylation of LDEA at its 11- and 12-carbon atoms, with specific activities of 0.05 +/- 0.01 and 0.28 +/- 0.02 nmol/min/mg protein, respectively. LDEA was also metabolized to 11- and 12-hydroxy derivatives by human liver microsomes at specific activities of 0.22 +/- 0.06 and 0.84 +/- 0.26 nmol/min/mg protein, respectively.