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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP-compliant study, limited number of parameters examined, acceptable for assessment.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
2004
Report Date:
2004
Reference Type:
publication
Title:
Toxicokinetics of 2-methylimidazole in male and female F344 rats.
Author:
Johnson JD, Reichelderfer D, Zutshi A, Graves S, Walters D, Smith C
Year:
2002
Bibliographic source:
J. Toxicol. Environ. Health Part A, 65, 869-879

Materials and methods

Objective of study:
toxicokinetics
Principles of method if other than guideline:
Male and female rats received a single gavage dose of 25, 50 or 100 mg/kg bw 2-methylimidazole. Postdose plasma samples were analyzed for 2-methylimidazole, and the results were used to calculate toxicokinetic parameters.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 2-methylimidazole
- Physical state: white crystalline solid
- Analytical purity: > 99.5%
- Lot/batch No.: 081497
- Storage condition of test material: at room temperature in the original bottles
Radiolabelling:
no

Test animals

Species:
rat
Strain:
other: F344/N
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 14-15 weeks
- Weight at study initiation: 283.8-330.4 g (males); 151.2-191.8 g (females)
- Individual metabolism cages: no

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
physiological saline
Remarks:
phosphate buffered
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: the gavage doses were formulated in 0.05 M phosphate-buffered saline (pH 7.4 ± 0.1).


Duration and frequency of treatment / exposure:
single dose
Doses / concentrations
Remarks:
Doses / Concentrations:
25, 50 and 100 mg/kg bw
Control animals:
no
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: plasma
- Time and frequency of sampling: after dosing, animals were anesthetized with a CO2/O2 mixture, and blood samples were collected from retroorbital sinus and placed into individual tubes containing EDTA as an anticoagulant. Rats were bled twice (minimum of 55 minutes between bleedings). three rats were bled at each time point. Rats were bled at 5, 10, 15, 30, 60, 120, 240, 460, 720, and 1440 (100 mg/kg bw groups only) minutes after dosing. Samples of approximately 1 mL were gently rocked by hand to ensure adequate mixing with the anticoagulant and placed on wet ice. Approximately 60 minutes after collection, the whole blood was centrifuged and the plasma transferred to a plastic storage vial. The plasma was stored at -70 ºC until analyzed. After blood collection the animals were sacrificed and discarded.
Statistics:
2-Methylimidazole plasma concentration versus time data were evaluated using the nonlinear least-squares estimation program WinNONLIN version 2.1, Scientific Consulting, Inc., Freeman, SD. A one-compartment model with no lag time and first order absorption and elimination was used to fit the data. AUC (area under the plasma concentration versus time curve) values were calculated using the trapezoidal rule. Clearance was calculated as D/AUC(infinity) and the half-lives for the absorption and elimination phases were calculated as 0.693/K01 and 0.693/K10, respectively.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
2-methylimidazole was rapidly absorbed and distributed when administered by gavage in an aqueous formulation. The administration of 2-methylimidazole in an aqueous solution averted any dissolution phase, which is the rate limiting step for solid dosage formulations such as dosed feed, and thereby precluded the presence of a lag time in the plasma concentration time profile. Absorption rate constants were much larger than elimination rate constants and were similar in males and females. The absorption half-life values ranged from 10 to 18 minutes and were generally linear with dose.
The peak 2-methylimidazole concentrations (Cmax) increased proportionally with dose. The Tmax values were reached within approxmately 30 to 45 minutes after gavage dosing and were independent of the dose. The absolute bioavailability values for 2-methylimidazole was calculated to reach 97% or greater.
Details on excretion:
Elimination half-life values ranged from 61 to 96 minutes and were generally increased in the 100 mg/kg bw groups. Differences in clearance across the treatment groups were not all statistically significant, but clearance was decreased in all 100 mg/kg bw groups. These data indicate that the 100 mg/kg bw dose is approaching the upper limit of the linear dosing range and that higher doses would result in higher internal doses than expected based on the lower doses. However, in a repeated dose scenario, the short absorption and elimination half lives of the chemical would prevent accumulation from one dose to the next.
Toxicokinetic parametersopen allclose all
Test no.:
#1
Toxicokinetic parameters:
Cmax: 6.5 ± 0.6 μg/mL (male, 25 mg/kg bw)
Test no.:
#1
Toxicokinetic parameters:
Cmax: 13.6 ± 1.3 μg/mL (male, 50 mg/kg bw)
Test no.:
#1
Toxicokinetic parameters:
Cmax: 27.7 ± 2.5 μg/mL (male, 100 mg/kg bw)
Test no.:
#1
Toxicokinetic parameters:
Cmax: 6.2 ± 0.5 μg/mL (female, 25 mg/kg bw)
Test no.:
#1
Toxicokinetic parameters:
Cmax: 14.7 ± 1.8 μg/mL (female, 50 mg/kg bw)
Test no.:
#1
Toxicokinetic parameters:
Cmax: 31.4 ± 3.0 μg/mL (female, 100 mg/kg bw)
Test no.:
#1
Toxicokinetic parameters:
AUC: 16 ± 1 μg x hour/mL (male, 25 mg/kg bw)
Test no.:
#1
Toxicokinetic parameters:
AUC: 34 ± 3 μg x hour/mL (male, 50 mg/kg bw)
Test no.:
#1
Toxicokinetic parameters:
AUC: 83 ± 7 μg x hour/mL (male, 100 mg/kg bw)
Test no.:
#1
Toxicokinetic parameters:
AUC: 13 ± 1 μg x hour/mL (female, 25 mg/kg bw)
Test no.:
#1
Toxicokinetic parameters:
AUC: 41 ± 5 μg x hour/mL (male, 50 mg/kg bw)
Test no.:
#1
Toxicokinetic parameters:
AUC: 92 ± 7 μg x hour/mL (female, 100 mg/kg bw)

Metabolite characterisation studies

Metabolites identified:
not measured

Applicant's summary and conclusion