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Toxicological information

Basic toxicokinetics

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basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference Type:
Nomeir, A.A. et al.
Bibliographic source:
Journal of Toxicology and Environmental Health, 44:203-217, 1995

Materials and methods

Objective of study:
Test guideline
no guideline followed
Principles of method if other than guideline:
This study was undertaken to compare the disposition characteristics of glycidol in rats following oral (where glycidol is exposed to stomach HCI) or
intravenous (i.v.) (bypass stomach HCI) administration.
GLP compliance:
not specified

Test material

Details on test material:
Unlabeled glycidol, 96% chemically pure [Aldrich Chemical Co., Milwaukee, Wis., USA].
[1,3-14C]Glycidol, 4.20 mCi/mmol, 99% radiochemically pure [New England Nuclear Corp., Boston, Mass., USA].

Test animals

Fischer 344
Details on test animals and environmental conditions:
- Source: laconic Farms (Germantown, N.Y., USA)
- Age at study initiation: 10-11 weeks
- Weight at study initiation: 190-229 g
- Housing: individual metabolism cages
- Acclimation period: at least 1 week

Administration / exposure

Route of administration:
other: oral (po) or intravenous (iv)
Details on exposure:
Not documented
Duration and frequency of treatment / exposure:
single exposure
Doses / concentrations
Doses / Concentrations:
37.5 and 75 mg/kg bw
po study:
conc.: 10 and 20 mg/mL, respectively
dose vol.: 3.75 and 2.5 mL/kg, respectively
iv study:
conc.: 15 and 30 mg/mL, respectively
dose vol.: 3.75 and 2.5 mL/kg, respectively

The specific activity was approximately 2800 dpm/µg.
No. of animals per sex per dose:
oral study: 8 to 11 rats
i.v. study: 16 rats
Control animals:
not specified
Positive control:
Not documented
Details on study design:
oral study: Four rats from each dose group were sacrificed at 24 h to determine radioactivity in tissues; 4 rats per group were housed in Nalgene cages for collection of urine and faeces at intervals for up to 72 h; and the remaining 3 rats from the high-dose group were housed in Roth glass metabolism cages for the collection of 14CO2.
i.v. study: Four rats of each group were sacrificed at each of 24 and 72 h to determine radioactivity in tissues. Rats sacrificed at 24 h were housed in individual Nalgene metabolism cages (Nalge Co., Rochester, N.Y.). Rats sacrificed at 72 h were used for the collection of urine, feces, and radioactivity in the expired air and were housed in individual glass metabolism cages.
Details on dosing and sampling:
Urine and faeces were collected at 0-4, 4-8, 8-24, 24-48, and 48-72 h after administration of [14C]glycidol. For the po study, 14CO2 was collected in
8 M KOH at 0-8, 8-24, 24-32, and 32-48 h from 3 animals in the 75 mg/kg dose group. For the iv study, expired 14CO2 was collected at 0-1, 1-2, 2-4, 4-8, 8-12, 12-24, 24-32, 32-48, 48-56, and 56-72 h.
At sacrifice, the rats were anesthetized with sodium pentobarbital and blood was collected by cardiac puncture and transferred into heparinized Vacutainer tubes. Plasma and blood cells were obtained by centrifugation. Liver, kidney, heart, lung, brain, adipose tissue (representative sample), skeletal muscle (representative sample), tail (demarcated area), spleen, testes, seminal vesicles, thyroid, and both ears (representative of skin) were weighed.
Radioactivity in urine, plasma, cage rinse, and 8 M KOH traps was determined by liquid scintillation counting. Radioactivity in faeces and tissues was determined by oxygen combustion, and the radioactivity was determined by liquid scintillation counting. Duplicate samples were analyzed. The concentration of radioactivity was corrected for the recovery efficiency of the combustion system.
Urine samples from individual rats were pooled by collection interval. A 20% portion of the urine volume of each collection interval for each dose level was pooled and analyzed by HPLC. Only urine from the 0—4, 4-8, 8-24, and 24-48 h intervals following iv dosing and from the first 3 intervals following po dosing was pooled and analyzed as the levels of radioactivity in urine from the other time intervals were below detection by HPLC radioactive flow detector.
Not documented

Results and discussion

Preliminary studies:
No data

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Glycidol was readily absorbed from the gastrointestinal tract of the rat following gavage administration at 37.5 or 75 mg/kg. Based on urinary radioactivity following iv or po administration, it is estimated that 87-92% of the dose was absorbed from the gastrointestinal tract.
At the two time intervals studied, for both the po and iv routes of administration, the concentrations of glycidol equivalents were generally proportional to the dose; the exceptions were that, at 24 h, blood cells, heart, testes, spleen, forestomach, and skin following iv dosing, and spleen and seminal vesicles following po dosing, contained disproportionately higher concentrations of glycidol equivalents at the higher dose compared to the lower dose.
Details on distribution in tissues:
Glycidol-derived radioactivity was extensively distributed throughout the body following both oral and i.v. administration. The patterns of distribution
and the concentrations of [14C]glycidol equivalents in tissues were, in general, similar for both the iv and po administration at the two doses studied.

In general, the highest concentrations of glycidol equivalents were observed in blood cells, followed by thyroid, liver, kidney, and spleen; the lowest concentrations were found in adipose tissue, skeletal muscle, and plasma. At 72 h, the concentrations of glycidol equivalents declined in most tissues relative to those observed at 24 h. Following iv administration at both dose levels, a marked decline was observed in plasma, kidney, lung, skin, testes, seminal vesicles, and forestomach; this decline was less marked in blood cells, liver, brain, and skeletal muscle, while the concentrations remained essentially unchanged in thyroid, spleen, glandular stomach, and adipose tissue. Following po dosing at both doses, a marked decline in the concentrations of glycidol equivalents was observed in plasma, liver, kidney, lung, brain, spleen, testes, seminal vesicles, skin, forestomach, and glandular stomach, while a less marked decline was observed in blood cells, heart, adipose tissue, and thyroid. The concentrations of glycidol equivalents in tissues were similar following po and iv administration at the same doses, the exceptions being that blood cells, lungs, and brain following iv dosing, and forestomach following po dosing, contained relatively higher concentrations. At 24 and 72 h, each tissue contained < 1% of the dose, with the exceptions of skeletal muscle, skin, blood cells, and liver (liver at 24 h only), where the amounts ranged from 1 to 4% of the dose.
Details on excretion:
Glycidol-derived radioactivity was excreted primarily in the urine (40-48% of dose), as CO2 in the expired air (26-32%), and to a lesser extent in
the faeces (5-12%).
The pattern, extent, and rate of excretion of radioactivity in urine and expired air were linear and similar for both routes of administration, with the exception that a greater percentage of dose was recovered in faeces following oral administration (10-12% following po vs. 5-6% following i.v.).
At the 2 doses studied, the recovery (including CO2) was in the range of 87-91% of the dose.

Metabolite characterisation studies

Metabolites identified:
Details on metabolites:
Radioactivity in pooled urine samples from oral- and i.v.-dosed rats was resolved by HPLC into 15 metabolites. In all cases there was one major metabolite, VIII (14-21% of the dose), and four minor metabolites, II (4-5%), XI (4-5%), XII (7-8%), and XIII (2-3%). The other metabolites were minor, each representing 1% or less of the dose. (Further details on metabolites not presented)
Generally, the urinary metabolite profile and the ratio of each metabolite were unaffected by the dose level over the range studied and were similar following both po and iv dosing.
Results indicate that very little, if any, b-chlorolactic acid was found as a urinary metabolite of glycidol following po or iv administration
to rats. The conversion of glycidol to a-chlorohydrin in the stomach following po administration is quantitatively insignificant at the doses studied.

Any other information on results incl. tables

No further information

Applicant's summary and conclusion

Interpretation of results (migrated information): low bioaccumulation potential based on study results
In conclusion, this study demonstrates that the disposition characteristics of glycidol were similar following oral and i.v. administration. Also, the conversion of glycidol to a-chlorohydrin by HCI in the stomach was quantitatively insignificant.
Executive summary:

This study by Nomeir et al., was carried out to determine the comparitive disposition of 2,3-epoxy-1-propanol (glycidol) in rats following oral and intravenous administrations. This study demonstrates that the disposition characteristics of glycidol were similar following oral and i.v. administration. Also, the conversion of glycidol to a-chlorohydrin by HCI in the stomach was quantitatively insignificant. There is low potential for bioaccumulation based on the study results.