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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline study
Cross-reference
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2006
Report date:
2006

Materials and methods

Objective of study:
absorption
distribution
excretion
Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Version / remarks:
(adopted 1984)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.36 (Toxicokinetics)
Version / remarks:
(adopted 1994)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.7485 (Metabolism and Pharmacokinetics)
Version / remarks:
(adopted 1998)
Qualifier:
according to guideline
Guideline:
other: M.A.F.F. Notification 12 Nousan, guideline No 8147 (adopted 2001)
Qualifier:
according to guideline
Guideline:
other: PMRA Ref.: DACO 4.5.9
GLP compliance:
yes (incl. QA statement)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of non-radiolabelled test material (as cited in study report): AE 0001789
- Analytical purity: >98.8%
- Lot/batch No.: AE 0001 789001 B99 0001 (DJA132/2)

- Name of radiolabelled test material (as cited in study report): [Sulfonylbenzamide-ring-UL-14C]AE 0001789
- Analytical purity: >99%
- Lot/batch No.: BECH 1557
Radiolabelling:
yes
Remarks:
14C labelled test substance (Sulfonylbenzamide-ring)

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan & Winkelmann Versuchstierzucht GmbH, Borchen, Germany
- Age at study initiation: 8 weeks
- Weight at study initiation: approx. 200 g
- Housing: Individually in Makrolon metabolism cages.
- Individual metabolism cages: Yes
- Diet: Rat/mice maintenance long life diet (no. 3883.0.15), supplied by Provimi Kliba AG, Switzerland; ad libitum
- Water: Tap water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-25
- Humidity (%): 50-67
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.5% aqueous Tragacanth
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
For the radiolabelled and non-radiolabelled test substance an adequate aliquot of the stock solution was taken and evaporated to near dryness under a gentle stream of nitrogen. The residue was suspended in 28 mL of 0.5% aqueous Tragacanth.
Duration and frequency of treatment / exposure:
single exposure
Doses / concentrations
Remarks:
Doses / Concentrations:
4.95 mg/kg bw (actual dose received)
No. of animals per sex per dose / concentration:
8 males
Control animals:
yes, concurrent vehicle
Positive control reference chemical:
no
Details on study design:
No. of control animals: 1
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, expired air
- Time and frequency of sampling: 1, 4, 8, 24, 48, 72, 96, 120, 144 and 168 h after dosing (The control animal was sacrificed after 4 h.)

Results and discussion

Preliminary studies:
no
Main ADME resultsopen allclose all
Type:
absorption
Results:
The test substance was quickly absorbed i.e. the maximum concentration of radioactivity in almost all organs and tissues was found 1 hour after administration.
Type:
distribution
Results:
At all time-points examined, high radioactivity was mainly observed in the excretory organs kidney and liver. The residues in all other organs and tissues were fairly evenly distributed and always lower than the residues observed in blood.
Type:
excretion
Results:
The test substance was rapidly eliminated from the body, predominantly via renal excretion. Excretion was almost complete 48 h after administration (90% excretion).

Toxicokinetic / pharmacokinetic studies

Details on absorption:
One hour after the administration of [Sulfonylbenzamide-ring-UL-14C]AE 0001789, the maximum concentration of radioactivity was observed in the contents of stomach and small intestine, which is an inherent result of the oral administration. High radioactivity was also observed in blood, indicating fast absorption and high bioavailability of AE 0001789.
Details on distribution in tissues:
A high concentration of radioactivity was mainly observed in the excretory organs liver and kidney, indicating commencing clearance of the compound immediately after absorption mainly by the renal route.
The highest radioactivity concentration (Cmax) in all organs and tissues was observed 1 hour after the administration. The radioactivity levels observed in blood decreased quickly to an intermediate minimum observed in the animal sacrificed 24 hours after the administration (0.189 µg/g), before they increased again to a second maximum 48 hours after the administration (0.234 µg/g). This effect can be attributed to an interruption of the fast absorption in the intestine resulting from the delayed gastric emptying which was observed between 4 and 48 hours after administration.
Overall, the equivalent concentrations in most organs and tissues were relatively low compared to the actual administered amount of 4.95 mg/kg bw. Only the dose normalised concentrations (CN) at Cmax for renal medulla was close to the equilibrium value of 1, which is an indication for the efficient depletion of the compound via kidney and urine. The CN-values for blood, liver and renal cortex were between 0.5 and 0.7. All other CN-values were well below 0.5.
Details on excretion:
The excretion of total radioactivity was almost complete 48 h after administration of 14C-AE 0001789. At this time more than 90% of the administered dose had been excreted via urine and faeces. The major part of the radioactivity administered was excreted by urine. The expiration of 14CO2 and other 14C-labelled volatiles could not be determined quantitatively due to a malfunction of the collection equipment. However, the volatile radioactivity was determined in the course of an autoradiography test with AE 0001789 labelled in the methoxybenzoyl moiety. This test demonstrated the high stability of the labelling position with regard to possible formation of volatile products (key, 2006, M-274337-01-1, rat, oral, metabolism, RL1). As no molecule cleavage was observed in the metabolism studies performed in rat (key, 2006, M-274975-01-2, rat, oral, metabolism, RL1; key, 2006, M-276053-01-2, rat, oral, metabolism, RL1) with both radiolabels, a repetition of the test for volatile radioactivity with the [sulfonylbenzamide-ring-UL-C]-label was not considered necessary.
Toxicokinetic parameters
Toxicokinetic parameters:
Cmax: 0.899 (normalised concentration at Cmax in renal medulla)

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

Table 1: Total radioactive residues (C and CN) in organs and tissues [µg a.s. equivalents per g wet weight]

Sacrifice

1 h

4 h

8 h

24 h

48 h

72 h

120 h

168 h

CN at Cmax

Blood

3.655

0.452

0.394

0.189

0.234

0.012

–

–

0.738

Liver

2.739

0.290

0.270

0.116

0.115

0.011

<LOQ

<LOQ

0.553

Renal cortex

2.386

0.231

0.190

0.072

0.168

–

–

–

0.482

Renal medulla

4.448

0.549

0.448

0.113

0.364

–

–

–

0.899

Brown fat

0.941

0.077

0.085

0.055

0.103

–

–

–

0.190

Perirenal fat

0.542

0.031

0.0262

0.018

0.031

–

–

–

0.110

Skeleton muscle

0.357

0.033

0.027

0.013

0.018

<LOD

–

–

0.072

Myocardium

1.537

0.145

0.150

0.055

0.074

<LOD

–

–

0.311

Lung

1.177

0.212

0.238

0.045

0.136

0.006

–

–

0.238

Spleen

0.462

0.068

0.066

–

0.039

<LOQ

–

–

0.093

Pancreas

0.495

0.048

0.058

–

0.028

<LOD

–

–

0.100

Bone marrow

0.606

0.088

0.118

0.072

0.055

<LOQ

–

–

0.122

Testes

0.417

0.153

0.049

0.021

0.026

<LOD

–

–

0.084

Brain

0.046

0.008

0.007

0.004

<LOQ

<LOD

–

–

0.009

Spinal cord

0.063

0.010

0.009

<LOQ

0.005

–

–

–

0.013

Pituitary gland

0.895

0.105

0.061

0.038

0.040

–

–

–

0.181

Pineal body

0.850

0.085

0.076

0.030

0.052

–

–

–

0.172

Adrenal gland

1.855

0.212

0.187

–

0.082

0.005

–

–

0.375

Thymus

0.379

0.035

0.035

0.020

0.023

<LOD

–

–

0.077

Thyroid gland

1.077

0.098

0.096

0.039

0.059

–

–

–

0.218

Salivary gland

0.858

0.103

0.100

0.043

0.059

–

–

–

0.173

Nasal mucosa

0.439

0.048

0.053

0.018

0.019

–

–

–

0.089

Skin

1.273

0.095

0.094

0.035

0.068

–

–

–

0.257

Vitreal body

0.093

<LOQ

0.009

<LOQ

0.007

–

–

–

0.019

 

C           Equivalent concentration

CN        Normalised concentration

<LOD    Below the limit of detection

<LOQ    Below the limit of quantification

–          Organ or tissue usually visible in the rat sections, but not discernible in the radioluminograms

xxx      Maximum values are shown in bold style.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results

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