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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
14 May to 20 June 2008
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted to an appropriate guideline and in compliance with GLP and was considered to be Reliability 1. Read across is considered to be scientifically valid and reliability 2.

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 radiolabeled test item, an aliquot of 2700 mg of the non-labeled 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 Scinitillation 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
Remarks:
Doses / Concentrations:
2000 mg/kg
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 susbtance 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 (migrated information): low bioaccumulation potential based on study results
After a nominal oral dose of 2000 mg/kg test susbtance VP to male and female mice, blood, plasma and femur were exposed to test item and/or its metabolites.