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

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

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.

Objective of study:

distribution

toxicokinetics

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPP 85-1 (Metabolism and Pharmacokinetics)

GLP compliance:

yes (incl. QA statement)

Radiolabelling:

yes

Remarks:

14 C

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

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).

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.

Type:

absorption

Results:

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

Type:

distribution

Results:

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

Type:

distribution

Results:

liver and kidneys exhibited the highest concentrations

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

Type:

excretion

Results:

66 % via kidney after iv administration

Type:

excretion

Results:

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

Type:

excretion

Results:

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

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.

Metabolites identified:

no

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.

Reference 2

Endpoint:

dermal absorption in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

March 1992

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: This study was approved by an independent ethical committee (Institutional Review Board) operating in accordance with the guidelines of the FDA. All phases of the clinical trial have been audited by the quality assurance unit.

Principles of method if other than guideline:

The skin penetrating potential of phenylbenzimidazole sulfonic acid was investigated in humans using 14C-radiolabelled test item. Six healthy male volunteers (age: 51 – 63 years) were used for this single dose dermal application study. One gram of a gel containing 80 mg of the radiolabelled test item (1.86 MBq) was applied on 333 cm2 on one upper arm of each participant using a spatula. The skin was protected with a non-occlusive cover, not being in contact with the gel. After 6 hours the remaining gel on the skin was removed by skin washings with cotton wool plugs soaked with ether. Thereafter, the whole area of treated skin was stripped 10 times with adhesive films (Scotch® 3M). Blood samples were taken up to 120 hours after gel application. Urine and feces were collected up to 5 days after treatment. Plasma samples, urine, feces, methanol extracts of the cotton wool plugs, and adhesive films were analyzed for total radioactivity using Liquid Scintillation Counting (LSC).

GLP compliance:

no

Remarks:

in compliance with Good Clinical Practice (GCP) Guidelines for trials on medicinal products in the EU

Radiolabelling:

yes

Species:

human

Sex:

male

Type of coverage:

occlusive

Vehicle:

other: creme

Doses:

80 mg per person

Total recovery:

- Total recovery:
- Recovery of applied dose acceptable: yes

Key result

Dose:

80 mg

Parameter:

percentage

Absorption:

ca. 0.2 %

Remarks on result:

other: after five days

Conclusions:

From the results of this study the author concluded that no noticeable absorption had taken place after the dermal application of Phenylbenzimidazole sulfonic acid. The low amount of radioactivity excreted in urine and feces within 5 days is in good agreement with the data from plasma measurements, which were always lower than two times the background radioactivity value, thus, confirming the fact that nearly no percutaneous absorption occurred.

Executive summary:

Study Design

The skin penetrating potential of phenylbenzimidazole sulfonic acid was investigated in humans using 14C-radiolabelled test item. Six healthy male volunteers (age: 51 – 63 years) were used for this single dose dermal application study. One gram of a gel containing 80 mg of the radiolabelled test item (1.86 MBq) was applied on 333 cm2 on one upper arm of each participant using a spatula. The skin was protected with a non-occlusive cover, not being in contact with the gel. After 6 hours the remaining gel on the skin was removed by skin washings with cotton wool plugs soaked with ether. Thereafter, the whole area of treated skin was stripped 10 times with adhesive films (Scotch® 3M). Blood samples were taken up to 120 hours after gel application. Urine and feces were collected up to 5 days after treatment. Plasma samples, urine, feces, methanol extracts of the cotton wool plugs, and adhesive films were analyzed for total radioactivity using Liquid Scintillation Counting (LSC).

Results

In general, no maximal plasma levels of total radioactivity were reached. The plasma radioactivity values were below 0.01 µg eq/mL and always lower than two times the background value. In most of the volunteers no noticeable plasma levels of radioactivity were observed, indicating no penetration. Therefore, pharmacokinetic parameters could not be calculated. The recoveries are summarized in the following table:

Medium	Recoveries (of dose applied)
Skin washing with cotton plugs	43.409 – 70.587 %
Skin stripping 6 hrs after application	10.472 – 35.637 %
Skin stripping 5 days after appl.	0.023 – 0.370 %
Fecal excretion	0.028 – 0.046 %
Renal excretion	0.068 – 0.217 %
Total excretion	0.107 – 0.259 %

Conclusion

From the results of this study the author concluded that no noticeable absorption had taken place after the dermal application of Phenylbenzimidazole sulfonic acid. The low amount of radioactivity excreted in urine and feces within 5 days is in good agreement with the data from plasma measurements, which were always lower than two times the background radioactivity value, thus, confirming the fact that nearly no percutaneous absorption occurred.

Description of key information

It is expected that 2-Phenylbenzimidazole-5-sulfonic acid (PBSA) is barely absorbed via oral (<5 % absorption assumed) and dermal exposure (<0.5 % absorption assumed). The absorption via inhalation is considered irrelevant due to negligible exposure (i.e. low vapour pressure). There was no evidence for accumulation in any of the organs investigated based on the available studies.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

5

Absorption rate - dermal (%):

0.5

Additional information

Considering the physico-chemical properties and its use of PBSA, absorption of PBSA is expected to mainly occur via dermal route though actually the dermal absorption is poor. Based on above information, it is expected that PBSA is barely absorbed via oral (<5 % absorption assumed) and dermal exposure (<0.5 % absorption assumed). The absorption via inhalation is considered irrelevant due to negligible exposure (i.e. low vapour pressure). Following absorption, PBSA is rapidly distributed mainly in plasma, liver and kidney, and trace amounts of PBSA were found in brain and fetuses after i.v. application; however, nothing was found in these organs via oral administration, which indicated that PBSA will not pass through neither blood/brain nor placental barriers. In addition, the elimination of PBSA virtually completed by a maximum of 72 hours via urine and feces only in the forms of parent compounds or metabolites as conjugations with enzyme. There was no evidence for accumulation in any of the organs investigated based on the available studies.