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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
Study period:
14 May to 20 June 2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009
Report Date:
2009

Materials and methods

Objective of study:
absorption
distribution
Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
no
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: liquid
Radiolabelling:
yes

Test animals

Species:
mouse
Strain:
NMRI
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan, Netherlands
- Age at study initiation: 8 weeks
- Weight at study initiation: 31 +/- 2.1g males; 24 +/- 1.4g females
- Fasting period before study: no
- Housing: groups of 7 or 8 in macrolon type 3 cages
- Individual metabolism cages: yes/no
- Diet (ad libitum): pelleted 3433 Kliba standard (PROVIMI KLIBA, Switzerland)
- Water (ad libitum): facility tap water
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 30 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 14 May 2008 To: 20 June 2008

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

Dosing solution was prepared on the day of administration. For administration at the target dose level of 2000 mg/kg, an aliquot of 300 mg of the radiolabelled test item, an aliquot of 2700 mg of the non-labelled test item and 12 mL corn oil were mixed to give a target concentration of 2000 mg/kg/10 mL. The exact amount of radioactivity in the application solution was determined by Liquid Scintillation Counting (LSC) resulting in 21.5 MBq, equivalent to 308 mg of undiluted 14C-Silan 449029 VP. The total amount of diluted 14C-Silan 449029 VP was 3008 mg, resulting in a new specific activity of 0.0072 MBq/mg. The concentration of Silan 449029 VP (= Silan 449029 VP & 14C-Silan 449029 VP) in the formulation was 200.5 mg/mL.

Duration and frequency of treatment / exposure:
single dose
Doses / concentrations
Dose / conc.:
2 000 mg/kg bw (total dose)
Remarks:
0.007 MBq/mg
No. of animals per sex per dose:
12
Control animals:
no
Details on study design:
- Dose selection rationale: not stated
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, plasma, femur, stomach, small intestine, large intestine, GI contents, liver, kidney, cage wash
- Time and frequency of sampling: 1, 4 or 24 hours after dosing. Urine and faeces at 24 hours after dosing only.
- 3 animals per sex per timepoint at 1 and 4 hours, 6 animals per sex at 24 hours

Animals were killed by carbon dioxide asphyxiation. blood was collected from the thoracic cavity.
Statistics:
none

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
After an oral dose of 2000 mg/kg test substance was rapidly absorbed
Type:
distribution
Results:
Distributed in blood, plasma and all organs investigated. Peak concentrations were at 1 hour after dosing in blood, plasma, femur, liver and kidney.
Type:
other: oral bioavailability
Results:
approximately 28%

Toxicokinetic / pharmacokinetic studies

Details on absorption:
After an oral dose of 2000 mg/kg, test substance was rapidly absorbed and distributed in blood, plasma and all organs investigated. Peak concentrations were found at t = 1 h in blood, plasma, femur, liver and kidney.

Cmax in blood, plasma, femur, liver and kidney of male mice were 70.0 ± 11.2 µgeq/g, 72.7 ± 12.9 µgeq/g, 49.2 ± 12.7 µgeq/g, 179.2 ± 40.1 µgeq/g, and 481.3 ± 340.4 µgeq/g. The corresponding values in female mice were 74.6 ± 12.3 µgeq/g, 78.2 ± 11.9 µgeq/g, 177 ± 36.3 µgeq/g and 332.8 ± 98.7 µgeq/g

Peak concentrations in stomach, small intestine, large intestine, combined GI tract contents were found at t = 1 h or t = 4 h.

Cmax in stomach, small intestine, large intestine and combined GI tract contents were 12986.0 ± 7940.9 µgeq/g, 4543.4 ± 1710.2 µgeq/g, 1524.0 ± 1311.7 µgeq/g and 30171.4 ± 4649.0 µgeq/g. The corresponding values in female mice were 9183.3 ± 3435.5 µgeq/g, 2867.6 ± 503.0 µgeq/g, 3170.4 ± 1792.8 µgeq/g and 28315.7 ± 1552.2 µgeq/g.

Mean plasma concentrations declined during the 24 h observation period to approximately 6.8% of the peak value in male mice and to 6.0% of the peak value in female mice. A comparable effect was seen in all tissues analysed.

Oral bioavailability was approximately 28%.
Details on excretion:
After 24 hours 24.9% and 17.4% of applied dose was detected in the urine in males and females respectively. During the same period at total of 63.8% and 64.2% of the applied dose was excreted via the faeces in males and females respectively.

Metabolite characterisation studies

Metabolites identified:
not specified

Applicant's summary and conclusion

Conclusions:
Interpretation of results: low bioaccumulation potential based on study results
After a nominal oral dose of 2000 mg/kg test substance VP to male and female mice, blood, plasma and femur were exposed to test item and/or its metabolites.