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EC number: 220-548-6 | CAS number: 2807-30-9
Dermal Administration of [Ethylene-UL- 14C]-EGPE
Recovery of radioactivity: Male rats received an average applied dose of 475.5 ± 31.3
mg of EGPE/kg body weight. Based on the amount and the specific activity of the
[14C]-EGPE administered (366.37 µCi/g), this corresponded to a mean administered activity of 42.499 ± 2.006 µCi/rat.
Little of the applied dose was absorbed during the: 6 hr exposure period. A total of 73.5 % of the applied dose was recovered unabsorbed from the site of application following 6 hr of dermal exposure: the liquid dose remaining at the site accounted for 38.3 % of this with the remaining 35.1 % recovered in soap and water ,washings of the application site. Urinary elimination was rapid, with 5.1 % of the administered dose recovered in urine and cage wash samples by 12 hr and a total of 5.50% by 72 hr.
Elimination as 14CO2 accounted for 0.11 % of the applied dose by 72 hr. Most of the radioactivity eliminated as 14CO2 was recovered during the first 12-hr collection period (0.08 %). An additional 0.35 % of the administered dose was recovered from feces and 2.46% as volatile organics. The majority of volatile organics recovered is presumed to represent evaporation of residual EGPE from the exposed dermal sites. At the final
collection period, mean cumulative recovered radioactivity amounted to 83.42% of the
A number of fractions (4 to 6) were isolated by preparative HPLC analysis of urine from rats treated with [14C]-EGPE. A component eluting at approximately 7 min under the preparative chromatographic conditions was presumed to be ethylene glycol (EG). The presence of this metabolite was confirmed by conversion to the dibenzoyl derivative followed by GC/MS quantitation. The acid, PAA, eluted at approximately 20 min and its structure was confirmed by extraction followed by GC/MS analysis. The glycine conjugate of PAA (N-propoxyscetyl glycine) eluted at approximately 29 min and its structure confirmed by conversion to the methyl ester followed by GC/MS analysis. In addition, components intermediate in retention times between that of the acid and the glycine conjugate were tentatively identified as the glucuronide and sulfate conjugates of EGPE by thermospray liquid chromatography/mass spectrometry.
Further characterization of urinary metabolites was obtained by chemical and enzymatic treatment of 12-hr, composite urine samples followed by analytical HPLC analysis. Treatment with P-glucuronidase resulted in the complete or nearly complete loss of a component having a retention time of 9.2 to 9.5 min. Comparable increases in levels of EGPE, seen following this β-glucuronidase treatment, confirmed the identity of this component as the glucuronic acid conjugate of EGPE. Treatment with arylsulfatase resulted in a consistent but small reduction in the amount of the glucuronic acid conjugate, presumably due to the presence of β-glucuronidase activity in the arylsulfatase. Thus, the presence of a sulfate conjugate based on sulfatase treatment could not be confirmed by enzymatic treatment. Treatment with 3 N HCl nearly eliminated the glycine conjugate peak (retention time of 9.8 to 10.6 min) with the production of a comparable amount of the acid, PAA. In addition, acid treatment caused the apparent loss of an unidentified component from some samples. This unknown component, present at levels as high as 3.2 % in buffer-treated samples, may be an acid-labile conjugate of either EGPE or PAA.
As many as 7 components were quantified by analytical HPLC analysis of 12-hr urine samples. The acid, PAA, accounted for the majority of the urinary radioactivity (41.6 % to 60.5 %) in these samples. The glycine conjugate accounted for 23.5 % to 37.6% of the radioactivity in urine samples. Lesser amounts of several other metabolites were also quantitated: ethylene glycol accounted for 6.0% to 14.4% of the radioactivity; EGPE –glucuronide accounted for 2.3% to 6.3% of the radioactivity; and EGPE itself was present at levels of 1.67 % to 4.55 % . The parent compound, EGPE, although detected was not consistently present in urine from all animals within any given dose group. In addition, two other unidentified components (Unknowns 1 and 2) were also present at levels of from 1.3 % to 5.0% of the urinary radioactivity.
Following iv administration, the parent alcohol was rapidly removed from blood with a calculated first-order elimination rate constant (λel) of 5.57 hr-1 and corresponding half-life of 0.124 hr. The concentration of the acid, PAA, rose rapidly through a peak value at 0.5 hr of 21.5 µg/g (182 nmole/g) and was subsequently eliminated with a first-order rate constant of 0.924 hr-1, corresponding to a half-life in blood of 0.750 hr.
Similar to the results obtained in the iv study, a first-order elimination rate constant of 5.17 hr-1 and calculated half-life of 0.134 hr were obtained for EGPE following oral administration of 15 mg/kg. In addition, a rapid uptake phase was seen at this dose level with a calculated λel, of 24.73 hr-1. At the higher dose of 150 mg/kg, uptake and elimination of the parent alcohol was again rapid.
A single-compartment elimination rate constant for EGPE of 3.46 hr-1 was calculated, yielding an elimination half-life of 0.20 hr. The less rapid elimination at the higher oral dose level suggests more prolonged absorption or saturation of metabolism and/or elimination. In the case of the acid, PAA, formation and elimination kinetics following oral administration at 15 mg/kg were similar to those found in the iv study. Thus, the acid was eliminated with a first-order rate constant of 0.527 hr-1, corresponding to a half-life of the acid in blood of 1.32 hr. At the higher dose of 150 mg/kg, elimination of the acid appeared saturated. Analyzed concentrations of the acid reached 145 µg/g (1228 nmole/g) at the 2-hr sampling point. It was not possible to fit early (< 6 hr) blood concentrations of the acid in the 150 mg/kg oral study to an exponential uptake and elimination model. However, blood concentrations of the acid obtained following 6 hr were fitted to a single exponential function yielding an elimination rate constant of 0.293 hr-1 and corresponding half-life of 2.37 hr. This elevated half-life may represent saturation of metabolism or renal elimination of the acid.
Concentrations of the alcohol in blood increased during the 6-hr exposure reaching a peak level of 1.14 µg/g (10.9 nmole/g) at the 6-hr collection point. Following removal of excess test material at 6 hr, EGPE blood concentrations were too low to afford quantitation. PAA concentrations also rose steadily during the 6-hr exposure reaching a maximum level of 17.0 µg/g (144 nmole/g) at the 6-hr collection. Following the 6-hr exposure, blood concentrations of the acid declined with a first-order elimination rate constant of 0.45 hr-l, corresponding to a half-life of 1.54 hr.
In both studies, blood concentrations of the parent alcohol remained low but relatively constant over the duration of the 6-hr exposures. Curve-fitting analysis of EGPE concentrations during the exposures yielded steady-state (blood concentrations (Css) of 0.45 and 3.42 µg/g for the 25 and 175 ppm exposures, respectively. Following the cessation of exposure at 25 ppm, EGPE blood concentrations were too low to afford quantitation. Following the 6-hr exposure at 175 ppm, EGPE blood concentrations declined with a first order elimination rate constant of 5.20 hr-1, corresponding to a half-life of 0.133 hr. Concentrations of PAA increased steadily during the 6-hr exposures. The acid declined in concentration in blood subsequent to exposures with first-order rate constants for the elimination of 0.757 hr-1 and 0.479 hr-1 for the low and high concentrations, respectively. These values correspond to elimination half-lives of 0.92 and 1.45 hr, respectively.
Radioactivity in blood of rats dosed with [14C]-EGPE: The majority of 14C-activity is accounted for as EGPE and PAA prior to 2 hr. In later samples of blood, 14C-activity is present which cannot be accounted for as parent compound or acid metabolite. This residual blood activity presumably represents incorporation of label into normal metabolic intermediates, thus leading to complete metabolism to 14CO2. Activity in blood persisted through the end of the study. Similar results were obtained following oral, dermal, or inhalation exposures to [14C]-EGPE
The absorption, distribution, elimination, metabolism, and pharmacokinetics of ethylene glycol mono-n-propyl ether (EGPE) were determined following either intravenous, oral, dermal, or inhalation exposures of male Sprague-Dawley rats to 2-[ethylene-1,2-14C]-EGPE ([14C]-EGPE).
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