Registration Dossier

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
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
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Objective of study:
absorption
distribution
excretion
Qualifier:
according to
Guideline:
other: As mention below
Principles of method if other than guideline:
Weight of evidence prepared from various publication mention below
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
Radiolabelling:
no
Species:
other: 1,rat 2,guinea pig
Strain:
other: 1,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

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
Remarks:
Doses / Concentrations:
45.06mg/kg
Remarks:
Not specified
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
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.
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
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 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.

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.

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:

Based on the weight of evidence study available for test substance , given below are the summaries predicting the absorptio nmetabolism and exretion -

Author conducted a Metabolism studies in F344 rats indicated that the half-life for 2-mercaptobenzothiazole after administration by gavage was less than 8 hours and possibly as short as 4-6 hours. Absorption was rapid and unaffected by doses up to 55 mg/kg. The major products of metabolism were polar metabolites, a finding in agreement with those from earlier dermal absorption studies. Given the lack of data for the target chemical 1,3-dihydro-5-methoxy-2H-benzimidazole-2-thione, its bio-accumulation potential has been read across from analogue chemicals that have exhibited metabolism and rapid excretion out of the living system via the urinary route. Also, the predicted bio-concentration factor (BCF) value of the target chemical is 4.8 which is much less than the threshold value of 2000. Thus, bio-accumulation potential of 1,3-dihydro-5-methoxy-2H-benzimidazole-2-thione appears to be low.

As indicated in the study report(National Toxiclolgy Program (NTP) Technical Report Series Absorption, tissue distribution, and metabolism study of radiolabeled test substance in guinea pigs was for 48 hrs duration conducted.Based on the observation 90% of 2-mercaptobenzothiazole was metabolized and excreted in the urine 6 hours after injection, the chemical can be concluded as exhibiting low bio-accumulation potential based on study results

Description of key information

Using the weight of evidence approach; the bio-accumulation potential of 1,3-dihydro-5-methoxy-2H-benzimidazole-2-thione appears to be low as the 2 read across chemicals benzimidazole-2-thiol & benzothiazole-2-thiol exhibit low bio-accumulation potential based upon the information related to the absorption, distribution, metabolism and excretion (ADME).

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

Toxicokinetics-

Based on the weight of evidence study available for test substance , given below are the summaries predicting the absorptio nmetabolism and exretion -

Author conducted a Metabolism studies in F344 rats indicated that the half-life for 2-mercaptobenzothiazole after administration by gavage was less than 8 hours and possibly as short as 4-6 hours. Absorption was rapid and unaffected by doses up to 55 mg/kg. The major products of metabolism were polar metabolites, a finding in agreement with those from earlier dermal absorption studies. Given the lack of data for the target chemical 1,3-dihydro-5-methoxy-2H-benzimidazole-2-thione, its bio-accumulation potential has been read across from analogue chemicals that have exhibited metabolism and rapid excretion out of the living system via the urinary route. Also, the predicted bio-concentration factor (BCF) value of the target chemical is 4.8 which is much less than the threshold value of 2000. Thus, bio-accumulation potential of 1,3-dihydro-5-methoxy-2H-benzimidazole-2-thione appears to be low.

As indicated in the study report(National Toxiclolgy Program (NTP) Technical Report Series No 332 1988 )Absorption, tissue distribution, and metabolism study of radiolabeled test substance in guinea pigs was for 48 hrs duration conducted. Based on the observation 90% of 2-mercaptobenzothiazole was metabolized and excreted in the urine 6 hours after injection, the chemical can be concluded as exhibiting low bio-accumulation potential based on study results