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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
data from handbook or collection of data

Data source

Reference
Reference Type:
publication
Title:
Comparative toxicokinetic/toxicodynamic study of rubber antioxidants, 2-mercaptobenzimidazole and its methyl substituted derivatives, by repeated oral administration in rats
Author:
Kazue Sakemi
Year:
2002
Bibliographic source:
Arch Toxicol

Materials and methods

Objective of study:
absorption
distribution
excretion
Test guideline
Qualifier:
according to
Guideline:
other: As mention below
Principles of method if other than guideline:
Two-week repeated oral administration toxicity studies have been carried out to chekc the toxicokinetics of test substance specific pathogen-free 4 weeks old male Wistar rats .
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: SLC Co. (Shizuoka, Japan)
- Age at study initiation: 4 weeks old
- Weight at study initiation:
- Housing: three rats/cage
- Diet (e.g. ad libitum):ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period:1 week
-Type of food-basal pellet diet (MF

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 25±2C
- Humidity (%): 55±5%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12-h/12-h light/dark cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Repeated oral administration (ROA) toxicity studies of MBI in male rats (four to six rats/group) were conducted as follows: MBI (45.06mg/kg) suspended in corn oil, were orally administered to rats once daily by gavage in 5.0 ml per kg body weight for 15 days.
Blood and urine samples were collected on scheduled days. Control group rats were treated with corn oil similarly. Body weight was measured on days 1 (first day of administration), 4, 7, 10 and 14 (or 15), and the most recently obtained body weight values were used for the calculation of doses administered on a per kilogram body weight basis. Food and water consumption were measured once weekly.
Duration and frequency of treatment / exposure:
15 days
Doses / concentrations
Remarks:
Doses / Concentrations:
45.06mg/kg
No. of animals per sex per dose:
four to six rats/group
Control animals:
yes
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): urine, blood, plasma, serum
- Time and frequency of sampling: Blood samples for TK profiling studies (6–8 time points) were collected on days 1 and 14 (or 15) from the orbital plexus of the rats under ethyl ether anesthesia at the following time-points: 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24 h
- Other:For the TK monitoring study (ICH 1994), blood samples were collected on day 8 at the time-points of 1, 4, 10 and 24 h

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled (delete / add / specify): urine, and blood serum
- Time and frequency of sampling: After blood and 24-h urine sample collections on days 1, 8 and 14 (or 15).
- From how many animals: (samples pooled or not) :From each subgroup of rats (n=3), 24-h fasting urine samples from each individual
- Method type(s) for identification :HPLC LC-10A
- Limits of detection and quantification:
- Other:

TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable):
Statistics:
Student’s t-test was applied in this study

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
The absorption rate of Mercaptobenzimidazole (MBI) compounds seemed to be delayed upon ROA
Type:
distribution
Results:
: After absorption, MBI was distributed in the blood but cleared within 10 hours of administration
Type:
excretion
Results:
The amount of MBI excreted in the urine on day 1 was similar to that of the corresponding desulfurated metabolite, BI (benzimidazole). However, MBI was dominant in urine relative to BI on day 8.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The absorption rate of Mercaptobenzimidazole (MBI) compounds seemed to be delayed upon ROA
Details on distribution in tissues:
After absorption, MBI was distributed in the blood but cleared within 10 hours of administration
Details on excretion:
The amount of MBI excreted in the urine on day 1 was similar to that of the corresponding desulfurated metabolite, BI (benzimidazole). However, MBI was dominant in urine relative to BI on day 8. BI was not detected on day 15, suggesting inhibition of desulfuration metabolism by repeated dosing

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Test substance was dominant in urine relative to BI on day 8. BI was not detected on day 15, suggesting inhibition of desulfuration metabolism by repeated dosing.

Bioaccessibility

Bioaccessibility testing results:
Repeated oral administration increased serum levels of test substance and urinary excretion of test substance and it decreased urinary excretion of BI. These data suggest that the metabolic desulfuration of MBI was reduced by repeated dosing.

Any other information on results incl. tables

In one of the a 28-day roa toxicity study in rats, MBI induced a two- to three-fold increase in thyroid weight with apparent histopathologic changes at 10 mg (0.067 mmol)/kg per day.MBI increased thyroid weight in association with a decrease in circulating thyroid hormone levels and an increase in the TSH level, indicating a negative feedback mechanism by the pituitary gland to stimulate thyroid function. Typical histopathologic changes of the thyroid due to hypothyroidism induced by MBI have been demonstrated.

Applicant's summary and conclusion

Conclusions:
Since the unchanged test substance was dominant in urine relative to its metabolite BI on day 8 after administration, test substance is expected to exhibit low bio-accumulation potential based on study results.
Executive summary:

Repeated dose oral administration toxicity studies have been carried for two-weeks a to check the pharmacokinetics of test substance .Specific pathogen-free 4 weeks old male Wistar rats were selected for the study.Test substance (45.06mg/kg) suspended in corn oil, were orally administered to rats once daily by gavage in 5.0 ml per kg body weight for 15 days.Food and water were available add libitum.Rats were acclimitized for one week and the animal room was maintained at a temperature of 25±2C and 55±5% humidity with a 12-h/12-h light/dark cycle.Rats were kept in plastic cages (five rats/cage) on wood-chip bedding for the acclimatization period and were then housed either in the plastic cages (three rats/ cage) for the subacute toxicity study or individually in metabolism cages (stainless steel) for 24-h urine collection. Rats were weighed 1 day before initiation of the treatment and the rats were randomly allocated to the several experimental groups.

Test substance is found to exhibit thyroid toxicity, and Roa of 45.06mg/kg test substance for 8 days and 15 days resulted in 4.0 and 7.0-fold increase in relative thyroid weight, respectively. Relative liver weight also increased, by 27.4% and 31.6%, respectively.Since the unchanged test substance was dominant in urine relative to its metabolite benzimidazole (BI) on day 8 after administration, test substance is expected to exhibit low bio-accumulation potential based on study results.