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EC number: 222-720-6 | CAS number: 3586-55-8
Results presented in Table 1 have shown that bolus gavage doses of 10 or 1000 mg/kg bw ethylene glycol (EG) were rapidly and almost completely absorbed in female rats, with a bioavailable fraction of 92%. Uptake and elimination of EG from plasma was biexponential; elimination rates and t1/2 beta values were of similar duration between dose levels. Overall, a linear pharmacokinetic relationship for parent EG was apparent for both oral dose levels. Data on oral doses of 400, 600 or 800 mg/kg bw (not shown in Table 1) suggested that plasma 14C elimination is independent of dose in this range.
In contrast to the oral route, the absorption of cutaneously applied EG is comparatively slow in female rats (see Table 1). EG has a bioavailability of only 25%. Total absorption of radioactivity varied between 26-32% (see Table 2).
Recoveries of total radioactivity were within 83 to 92% with exception of the 10 mg/kg bw dermal application with a reduced recovery of 42% only (see Table 2).
Tissue distribution of 14C-activity (see Table 2 and 3)
Intravenous and oral route (10, 1000 mg/kg bw):
Total tissue recovery of 14C accounted to 5.3 and 5.7% at the low dose. At the high dose there was a nearly twofold decrease to 3.3 and 2.2%. Concentrations of 14C in individual tissues showed a dose-dependence being about two orders of magnitude lower at the low dose compared to high dose tissue values. Tissue/plasma ratios > 1.0 were calculated for liver, kidney, and lung, indicating a greater presence of 14C in these tissues than would be accounted by plasma perfusion alone.
Dermal route (10, 1000 mg/kg bw, undiluted ethylene glycol):
The distribution of 14C to tissues showed similar disposition profiles to those observed after i.v. and p.o. dosing. Tissue/plasma ratios > 1.0 were calculated for: liver, kidney, and pelt at 10 mg/kg bw, for liver, kidney, lung and pelt at 1000 mg/kg (undiluted), and for liver and pelt at 1000 mg/kg bw (aqueous dilution), indicating a greater presence of 14C in these tissues than would be accounted by plasma perfusion alone.
Excretion (see Table 2, 4 and 5)
Total excretion of radioactivity
14C-activity was recovered from urine, faeces and as 14CO2 in exhaled air in percentages varying for different application routes and doses.
Intravenous and oral route (10, 1000 mg/kg bw): 10 mg/kg bw: major excretion route: exhalation 44-48%; urine: 25%; faeces: 2.0-2.8%. 1000 mg/kg bw (values for i.v. and p.o. route, respectively): major excretion route: urine 45%, 35%; exhalation 29%, 28%; faeces: 5.4%, 4.4%.
Oral route (400, 600, 800 mg/kg bw): At 400 mg/kg bw excretion via exhalation and urine accounted to approximately equal amounts. In the dose range up to 800 mg/kg bw there was a dose-dependent increase of urinary excretion being accompanied by a decrease of 14CO2 exhalation. This points to saturation of oxidative metabolic pathways.
Dermal route (10, 1000 mg/kg bw, undiluted ethylene glycol): 10 mg/kg bw: major excretion route: exhalation 13.1%; urine 8.2%; faeces 1.1%. 1000 mg/kg bw: exhalation 11.4%; urine 7.6%; faeces 1.4%. Dermal route (1000 mg/kg bw, undiluted ethylene glycol): major excretion route: exhalation 9.3%; urine 4.4%; faeces 0.5%.
Time course of excretion of radioactivity and metabolites
Intravenous and oral route (10, 1000 mg/kg bw): Elimination profiles for total radioactivity were similar in both time-course and amount of the dose excreted for both application routes and for each dosage, indicating that the majority of the oral doses were absorbed. For both routes, at the low dose excretion of radioactivity was mainly via exhalation as 14CO2. In contrast, at the high dose urinary excretion was the dominant route. Urinary excretion: majority of 14C excreted within 12 h, urinary excretion virtually complete within 24-36 h post-dosing. At the high 1000 mg/kg-dose a higher percentage was excreted via urine (i.v. 45%, p.o. 35%) than after the low 10 mg/kg-dose (25%).
10 mg/kg bw: Urinanalysis of metabolites yielded a similar pattern for the low dose for both application routes with unchanged ethylene glycol accounting to ca. 93% of total 14C during the first 12 hours. Glycolic acid (ca. 5%) and oxalic acid (<1%) were found as minor metabolites. 1000 mg/kg bw: During the 12-24 h interval excretion of unchanged ethylene glycol accounted to 53% (i.v.) and 65% (p.o.) besides glycolic acid (46% and 35%). Oxalic acid was found only in minor amounts (<1%).
Exhalation of 14CO2: There was still a slow increase of cumulative exhaled 14CO2 at the end of the 96-h observation period. Within this interval the majority of 14CO2 was exhaled within the first 24 h. Overall levels were inversely related to dose (44-48% at the low dose, 28% at the high dose).
Dermal route (10, 1000 mg/kg bw, undiluted ethylene glycol): Elimination profiles for total radioactivity for both doses showed a continuous increase of excretion during the 96-h observation period up to a final excretion of 8-10% of the dose via urine and of 13% via exhalation. Total excretion was lower than after i.v. or p.o. application. However, taking the low dermal penetration into account, excreted relative amounts were comparable with excretion percentages after i.v. or p.o. dosing. In the urine fractions unchanged ethylene glycol was detected as the major component (87-100%). Dermal route (1000 mg/kg bw, 50 % aqueous dilution of ethylene glycol): Measurable excretion of 14C was retarded until 24 h post-dosing. There was a continuous increase during the 96-h observation period until final levels of 5% in urine and 9% in exhaled air. Radioactivity in urine accounted to 100% to unchanged ethylene glycol.
This study was comparable to OECD guideline 417. 14C-ethylene glycol was administered to female Sprague-Dawley rats (n=4 per group) intravenously, orally or dermally in single doses ranging from 10 – 1000 mg/kg bw. Pharmacokinetic investigations of the fate of ethylene glycol included absorption from the gastrointestinal tract, skin penetration, tissue distribution, identification of metabolites in urine, and pathways and kinetics of excretion.
Results have shown that gavage doses of 10 or 1000 mg/kg bw ethylene glycol (EG) were rapidly and almost completely absorbed in female rats, with a bioavailable fraction of 92%. Uptake and elimination of EG from plasma was biexponential; elimination rates and t1/2 beta values were of similar duration between dose levels. Overall, a linear pharmacokinetic relationship for parent EG was apparent. In contrast to the oral route, the absorption of cutaneously applied EG is comparatively slow in female rats. EG has a bioavailability of only 25%. Total dermal absorption of radioactivity varied between 26-32%. Relative recoveries of 14C in tissues and carcass were higher at the 10 mg/kg bw p.o. and i.v. dose in comparison to the 1000 mg/kg bw dose, whereas individual 14C concentrations in tissues increased dose-dependently. Storage in tissue accounted to total amounts of ca. 2-6 % of the dose after 96 hours. Extensive metabolism via oxidative pathways is indicated by the high amounts of 45-49 % of the dose exhaled as 14CO2 at 10 mg/kg. Expiration of 14CO2 diminishes to 30 % as the dose increases to 1000 mg/kg bw. Parallel to the decrease of excretion via exhalation urinary excretion increases from 25% to 36-46% of the dose. Urinary excretion profiles show unchanged ethylene glycol as the main source of 14C besides glycolate as the major urinary metabolite and minor amounts of oxalate (<1%). Only minor amounts of 14C are both excreted in the faeces (ca. 2-5%) and remain in the carcass (ca. 5-9 %).
Conclusions: Ethylene glycol is very rapidly and almost completely absorbed after oral doses but dermally-applied EG was slowly and rather poorly absorbed; oxidative metabolite pathways appeared to be saturated at high oral doses; linear pharmacokinetic relationship was apparent for the oral route.
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