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Toxicological information

Specific investigations: other studies

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Administrative data

Endpoint:
specific investigations: other studies
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
PHARMACOKINETICS OF ETHYLENE GLYCOL I. Plasma Disposition after Single Intravenous, Peroral, or Percutaneous Doses in Female Sprague-Dawley Rats and CD-I Mice
Author:
Frantz SW, Beskitt JL, Grosse CM, Tallant MJ, Dietz FK, Ballantyne B.
Year:
1996
Bibliographic source:
Drug Metab Dispos 24:911-21

Materials and methods

Test guideline
Qualifier:
no guideline followed
GLP compliance:
not specified
Type of method:
in vivo
Endpoint addressed:
basic toxicokinetics

Test material

Reference
Name:
Unnamed
Type:
Constituent
Specific details on test material used for the study:
radiolabelled and unlabelled

Test animals

Species:
other: rat and mouse
Strain:
other: Sprague Dawley rats; CD-1 mice
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS Rats
- Source: Harlan Sprague Dawley, Inc. (Indianapolis, IN)
- Age at study initiation: 10-11 weeks
- Housing: individual Roth-type glass metabolism cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: approx. 2 days

TEST ANIMALS Mice
- Source: Charles River Laboratories Inc. (Portage, MI)
- Age at study initiation: 5-6 weeks
- Housing: individual Roth-type glass metabolism cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: approx. 2 days

Administration / exposure

Route of administration:
other: intravenous (IV), peroral (P0), and percutaneous (PC)
Vehicle:
other: depending on route of administration
Details on exposure:
Rats and mice were dosed by the IV and PO routes with 10 and 1000 mg/kg. Intermediate PO doses of 400, 600, and 800 mg/kg bw for rats and 100, 200, and 400 mg/kg bw for mice were admmnistered.
PC dose applications in rats were 10 and 1000 mg/kg bw. 100 and 1000 mg/kg bw doses were used for mice. An additional PC dose was applied as a 50% aqueous solution (at 1000 mg/kg bw) to both species.
IV doses (10 and 1000 mg/kg, ~5 µCi/animal) were given in physiological saline solution (0.9%, 2 mL/kg bw target volume) via an indwelling jugular cannula in rats or into the lateral tail vein in mice; cannulae were flushed with saline immediately after IV dosing to ensure clearance of 14C residues, which was verified in probe studies.
PG doses were given in water [0.5%, 20%, 30%, 40%, and 50% (w/w); 2 mL/kg target volume] to rats (10, 400, 600, 800, and 1000 mg/kg bw; ~10-15 µCi/animal or as 0.5%, 5%, 10%, 20%, and 50% (w/w) solutions for mice (10, 100, 200, 400, and 1000 mg/kg; ~10-15 µCi/animal).
For PC dosing, [14C]EG dosing solutions (~15-25 µCi/animal) were applied as either:
1) the undiluted chemical (10 and 1000 mg/kg bw in rats or 100 and 1000 mg/kg in mice);
2) a 50% water solution (2 mL/kg target volume). For rats, doses were applied to an ~ 1 cm2 area in the interscapular region of the back with a syringe, and the application site was occluded with polyethylene film covered with a Lycra-Spandex rodent jacket to minimize ingestion from grooming and maximize skin penetration. For mice, doses were also applied to a 1 cm2 area using a syringe to the interscapular region, and the application site was occluded with a sheer plastic bandage.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysis for radioactivity by LSC and gravitmetric determination of amount dosed by GC before and after dosing.

Results and discussion

Details on results:
Orally-administered EG is very rapidly and almost completely absorbed in both rats and mice, with a bioavailable fraction of 92-100% in rats and similar percentages at the higher doses in mice. In contrast, the absorption of cutaneously applied EG is comparatively slow in both species. A species difference in the overall absorption of PC doses was demonstrated, with higher recoveries of 14C observed after PC doses in mice than for rats and a greater penetration of 14C after applying a 50% aqueous PC dose in mice than in rats, as evidenced by quantifiable plasma 14C concentrations only in mice. The major metabolites in both rats and mice are CO2 and glycolate. Oxidative metabolic pathways are saturated at high P0 doses in both species, resulting in a shift from exhaled CO2 as the major excretion route to urinary excretion. The capacity to metabolize more completely EG to CO2 at low doses seems to be greater in the mouse than in the rat, as evidenced by the absence of urinary oxalate from EG-dosed female mice, and saturation of metabolic pathways at a comparatively lower dose in mice than for rats. This evidence suggests that dose-dependent changes in EG excretion in female Sprague-Dawley rats and CD-I mice probably resulted from capacity-limited effects on EG metabolic pathways for the production of CO2 and a compensatory urine clearance of glycolate.

Applicant's summary and conclusion

Conclusions:
The pharmacokinetics of (1,2-14C]ethylene glycol (EG) were evaluated in female Sprague-Dawley rats and CD-I mice to characterize the plasma disposition after intravenous (IV), peroral (P0), and percutaneous (PC) doses. Rats were given doses of 10 or 1000 mg/kg by each route, and additional P0 doses of 400, 600, or 800 mg/kg. Mice were also given IV and P0 (bolus gavage) doses of 10 or 1000 mg/kg, and additional P0 doses of 100, 200, or 400 mg/kg. PC doses in mice were 100 or 1000 mg/kg, and both species were given a 1000 mg/kg PC dose with a 50% (w/w) aqueous solution (2 mL/kg) to simulate antifreeze exposure. Results from this study have shown that orally-administered EG is very rapidly and almost completely absorbed in both rats and mice, with a bioavailable fraction of 92-100% in rats and similar percentages at the higher doses in mice. In contrast, the absorption of cutaneously applied EG is comparatively slow in both species. A species difference in the overall absorption of PC doses was demonstrated, with higher recoveries of 14C observed after PC doses in mice than for rats and a greater penetration of 14C after applying a 50% aqueous PC dose in mice than in rats, as evidenced by quantifiable plasma 14C concentrations only in mice. The major metabolites in both rats and mice are CO2 and glycolate. Oxidative metabolic pathways are saturated at high P0 doses in both species, resulting in a shift from exhaled CO2 as the major excretion route to urinary excretion. The capacity to metabolize more completely EG to CO2 at low doses seems to be greater in the mouse than in the rat, as evidenced by the absence of urinary oxalate from EG-dosed female mice, and saturation of metabolic pathways at a comparatively lower dose in mice than for rats This evidence suggests that dose-dependent changes in EG excretion in female Sprague-Dawley rats and CD-I mice probably resulted from capacity-limited effects on EG metabolic pathways for the production of CO2 and a compensatory urine clearance of glycolate. Results from the present study corroborate previous observations in rats for the lower doses, but demonstrate a substantial difference in single-dose pharmacokinetics for IV and P0 1000 mg/kg doses in mice vs. rats. In summary, these data indicate that mice show a nonlinear plasma disposition of total radioactivity (EG and its metabolites) as dose is increased, whereas in rats plasma kinetics were linear over the dose range evaluated, whereas excretion kinetic patterns were nonlinear in both species as dose is increased.