2-phenyl-1H-benzimidazole-5-sulphonic acid

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

11/1992 - 4/1993

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Remarks:

GLP Study with excellent study design and documentation.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1993

Report date:

1993

Materials and methods

Objective of study:

distribution

toxicokinetics

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPP 85-1 (Metabolism and Pharmacokinetics)

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

2-phenyl-1H-benzimidazole-5-sulphonic acid

EC Number:

248-502-0

EC Name:

2-phenyl-1H-benzimidazole-5-sulphonic acid

Cas Number:

27503-81-7

Molecular formula:

C13H10N2O3S

IUPAC Name:

2-phenyl-1H-benzimidazole-5-sulphonic acid

Radiolabelling:

yes

Remarks:

14 C

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
The test was performed in pregnant Wistar rats.
- Source: WINKELMANN, Borchen
- Age at study initiation: adult
- Weight at study initiation: 241- 296 g
- Fasting period before study: no
- Housing: conventionally in Makrolon cages type M III (WOETHO, Emmendingen)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least one week after delivery

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 22 °C
- Humidity (%): 50 - 60 %
- Photoperiod (hrs dark / hrs light): 12 / 12 hours

Administration / exposure

Route of administration:

other: iv and oral

Vehicle:

water

Details on exposure:

The chemical dose was 1 mg/kg for iv injection and 1000 mg/kg for po administration. The radioactive dose was 2 MBq/kg.

Duration and frequency of treatment / exposure:

The rats received the dissolved substance as a single dose both intravenously and orally. Iv injection was into one of the caudal veins, oral administration was by gavage using a stainless-steel infusion cannula (AKU-FIRM Cat. No. 1464/2).

Doses / concentrations

Remarks:

Doses / Concentrations:
The administration volume was 0.15 ml per 100 g body weight for both modes of administration.
single po: 1000 mg/kg
single iv: 1 mg/kg

No. of animals per sex per dose / concentration:

single po:
single iv: 1 mg/kg

Control animals:

no

Details on study design:

- Rationale for animal assignment (if not random): random

Details on dosing and sampling:

The rats received the dissolved substance as a single dose both intravenously and orally. Iv injection was into one of the caudal veins, oral administration was by gavage using a stainless-steel infusion cannula (AKU-FIRM Cat. No. 1464/2).
The administration volume was 0.15 ml per 100 g body weight for both modes of administration.

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

14C - peak concentration reached after 15 min after oral administration

Main ADME results 2

Type:

distribution

Results:

after iv administration, elimination from plasma: half-life 0.4 h

Main ADME results 3

Type:

distribution

Results:

liver and kidneys exhibited the highest concentrations

Main ADME results 4

Type:

distribution

Results:

lowest concentrations of all organs and tissues were measured in the fetuses, i.e. the placental barrier was very poorly penetrated by the test item

Main ADME results 5

Type:

excretion

Results:

66 % via kidney after iv administration

Main ADME results 6

Type:

excretion

Results:

after oral administration 2.5% of the dose was found in the urine within the collection period of 48 hours

Main ADME results 7

Type:

excretion

Results:

after both modes of administration, the dose had been excreted after 48 hours

Toxicokinetic / pharmacokinetic studies

Details on absorption:

After single iv injection, the 14C-radioactivity was eliminated from the plasma with an apparent half-life of 0.4 hours. After oral administration the peak 14C-concentrations were already reached after 15 min, indicating a rapid absorption from the gastrointestinal tract.

Details on distribution in tissues:

Both after iv and oral administration, liver and kidneys exhibited the highest concentrations. The lowest concentrations of all organs and tissues were measured in the foetuses, i.e. the placental barrier was very poorly penetrated by the test item.

Details on excretion:

The iv injected radioactivity was predominantly (about 66 %) excreted via the kidneys. After oral administration 2.5 % of the dose was found in the urine within the collection period of 48 hours. Since no radioactivity was present in the bodies of the rats (residual radioactivity) after both modes of administration, it can be inferred that the dose had been excreted completely during the interval 0 to 48 hours. Based on the comparison of the AUCs and the excretion data after iv and oral administration it can be concluded that 3 – 4 % of the dose had been absorbed from the gastrointestinal tract.

Metabolite characterisation studies

Metabolites identified:

no

Applicant's summary and conclusion

Conclusions:

Based on the results of this study it can be concluded that there is no bioaccumulation potential after oral and iv administration of the test item in rats.

Executive summary:

Study Design

The pharmacokinetics of ¹⁴C-labelled Phenylbenzimidazole sulfonic acid sodium salt was investigated after single iv injection (dose: 1 mg/kg bw) and oral administration (dose: 1000 mg/kg bw) in pregnant Wistar rats (day 18 of gestation).

Results

After single iv injection, the 14C-radioactivity was eliminated from the plasma with an apparent half-life of 0.4 hours. After oral administration the peak 14C-concentrations were already reached after 15 min, indicating a rapid absorption from the gastrointestinal tract.
Both after iv and oral administration, liver and kidneys exhibited the highest concentrations. The lowest concentrations of all organs and tissues were measured in the foetuses, i.e. the placental barrier was very poorly penetrated by the test item.
The iv injected radioactivity was predominantly (about 66 %) excreted via the kidneys. After oral administration 2.5 % of the dose was found in the urine within the collection period of 48 hours. Since no radioactivity was present in the bodies of the rats (residual radioactivity) after both modes of administration, it can be inferred that the dose had been excreted completely during the interval 0 to 48 hours. Based on the comparison of the AUCs and the excretion data after iv and oral administration it can be concluded that 3 – 4 % of the dose had been absorbed from the gastrointestinal tract.

Conclusion

Based on the results of this study it can be concluded that there is no bioaccumulation potential after oral and iv administration of the test item in rats.