1,3-dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: well documented and scientifically acceptable

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:

Sakemi K, Ito R, Umemura T, Ohno Y, Tsuda M

Year:

2002

Bibliographic source:

Arch Toxicol 76, 682-691

Materials and methods

Objective of study:

toxicokinetics

Principles of method if other than guideline:

MBI (2-Mercaptobenzimidazole) and the MMBIs [4-methylated MBI (4-MMBI) and 5-methylated MBI (5-MMBI), and a 1:1 mixture of these 4- and 5-methylated isomers (MMBI mix)] suspended in corn oil were repeatedly administered (at 0.3–0.6 mmol/ kg) to male Wistar rats by gavage once daily for 2 weeks. After the first and last administrations, blood and urine samples were collected, and the levels of unchanged compounds and their desulfurated metabolites were determined by high performance liquid chromatography.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

1,3-dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione

EC Number:

258-904-8

EC Name:

1,3-dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione

Cas Number:

53988-10-6

Molecular formula:

C8H8N2S

IUPAC Name:

1,3-dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione

Constituent 2

Reference substance name:

1,3-dihydro-4-methyl-2H-benzimidazole-2-thione

Cas Number:

27231-33-0

Molecular formula:

C8H8N2S

IUPAC Name:

1,3-dihydro-4-methyl-2H-benzimidazole-2-thione

Constituent 3

Reference substance name:

1,3-dihydro-5-methyl-2H-benzimidazole-2-thione

EC Number:

248-350-5

EC Name:

1,3-dihydro-5-methyl-2H-benzimidazole-2-thione

Cas Number:

27231-36-3

Molecular formula:

C8H8N2S

IUPAC Name:

5-methyl-1,3-dihydro-2H-benzimidazole-2-thione

Constituent 4

Reference substance name:

Benzimidazole-2-thiol

EC Number:

209-502-6

EC Name:

Benzimidazole-2-thiol

Cas Number:

583-39-1

Molecular formula:

C7H6N2S

IUPAC Name:

1H-benzimidazole-2-thiol

Details on test material:

MBI (2-mercaptobenzimidazole) = 583-39-1
MMBI (mixture of methyl isomers) = 53988-10-6
4-MMBI (2-mercapto-4-methylbenzimidazole) = CAS 27231-33-0
5-MMBI (2-mercapto-5-methylbenzimidazole) = CAS 27231-36-3

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Duration and frequency of treatment / exposure:

2 weeks

Doses / concentrations

Remarks:

Doses / Concentrations:
0.3-0.6 mmol/kg = ca. 49.27 - 98.54 mg/kg MMBI

No. of animals per sex per dose / concentration:

4-6 rats/group

Control animals:

yes, concurrent vehicle

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

After repeated oral administration (roa), the Cmax and area under concentration-time curve (AUC) of MBI were markedly increased, while the MMBIs essentially were cleared from the blood within 10 h. After roa, the Cmax and AUC of 4-MMBI decreased markedly, suggesting metabolic enzyme induction. However, the toxicokinetic parameters of 5-MMBI were not markedly altered by roa.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

desulfurated metabolites:
desulfurated metabolite (4-MeBI = 4-methylbenzimidazole) of 4-MMBI
desulfurated metabolite (5-MeBI = 5-methylbenzimidazole) of 5-MMBI

Any other information on results incl. tables

Toxicokinetics of MBI and the MMBIs

Serum concentration profiles of unchanged compounds for single (day 1) and repeated (day 14 or 15) oral administration of the MMBI mix (0.3 and 0.6 mmol/kg), 4-MMBI (0.6 mmol/kg) and 5-MMBI (0.6 mmol/kg) to male rats are compared. Serum concentration profiles of these thioureylene compounds were strongly influenced by roa of both MBI and the MMBIs but in apparently different manners. The AUCs of MBI on days 8 and 15 were increased 2- to 2.6-fold compared with that on day 1.

The MMBIs were eliminated from the blood faster than MBI and were essentially cleared from the blood within 10 h. With roa of the MMBI mix (0.6 mmol/kg), the Cmax and AUC for the sum of the isomers were not changed markedly between days 1 and 15. Although the MMBI mix is a 1:1 mixture of 4-MMBI and 5-MMBI, the AUC of 4-MMBI was much greater than that of 5-MMBI.. The AUC0–10 h of 5-MMBI did not change with roa. In contrast, that of 4-MMBI seemed to be increased. The absorption rate of these compounds seemed to be delayed upon roa. The Tmax of the 5-MMBI and that of the sum of 4-MMBI and 5-MMBI changed from 1 to 4 h. Serum concentrations of 4-MMBI at 0.25 and 1 h after administration of the mixture were much lower on day 15 than those on day 1.

We administered each isomer was administered to rats in order to distinguish the effects of each isomer. After roa of 5-MMBI

(0.6 mmol/kg), the Cmax and AUC0–10 h of 5-MMBI were not changed markedly between days 1 and 14. However, the Tmax in serum was delayed from 0.5 to 6 h. On the other hand, the TK parameters and the serum concentration profiles of 4-MMBI (0.6 mmol/kg) after roa were markedly changed between days 1 and 14, suggesting metabolic enzyme induction. The AUC of 4-MMBI was reduced to about one-third by roa. The Tmax was delayed also from 2 to 8 h.

Urinary excretion of MBI and the MMBIs and their metabolites

The amount of MBI excreted in the urine on day 1 was similar to that of the corresponding desulfurated metabolite, BI. 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.

After roa of 0.6 mmol/kg of the MMBI mix, urinary excretion of unchanged compounds, 4-MMBI and 5-MMBI, on day 15 increased markedly (7-fold and 2-fold of those amounts on day 1, respectively). In contrast, the urinary excretion of their desulfurated

metabolites was not altered significantly. Roa of the lower dose (0.3 mmol/kg) did not affect urinary excretion patterns. The sum of the urinary excretions of unchanged compounds and their desulfurated metabolites during the 24 h following oral administration of

these thioureylene compounds was less than 10% of the administered amounts. When administered each isomer separately, urinary excretion of the desulfurated metabolite, 4-MeBI, on day 14 was increased 2-fold (P<0.01) by roa of 4-MMBI compared

with that on day 1. However, in the case of 5-MMBI, urinary excretion of both the unchanged compound and the desulfurated metabolite, 5-MeBI, were not altered by roa.

Applicant's summary and conclusion

Conclusions:

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

Executive summary:

Method:

MBI (2-Mercaptobenzimidazole) and the MMBIs [4-methylated MBI (4-MMBI) and 5-methylated MBI (5-MMBI), and a 1:1 mixture of these 4- and 5-methylated isomers (MMBI mix)] suspended in corn oil were repeatedly administered (at 0.3–0.6 mmol/ kg) to male Wistar rats by gavage once daily for 2 weeks. After the first and last administrations, blood and urine samples were collected, and the levels of unchanged compounds and their desulfurated metabolites were determined by high performance liquid chromatography.

Toxicokinetics of MBI and the MMBIs

Serum concentration profiles of unchanged compounds for single (day 1) and repeated (day 14 or 15) oral administration of the MMBI mix (0.3 and 0.6 mmol/kg), 4-MMBI (0.6 mmol/kg) and 5-MMBI (0.6 mmol/kg) to male rats are compared. Serum concentration profiles of these thioureylene compounds were strongly influenced by roa of both MBI and the MMBIs but in apparently different manners. The AUCs of MBI on days 8 and 15 were increased 2- to 2.6-fold compared with that on day 1.

The MMBIs were eliminated from the blood faster than MBI and were essentially cleared from the blood within 10 h. With roa of the MMBI mix (0.6 mmol/kg), the Cmax and AUC for the sum of the isomers were not changed markedly between days 1 and 15. Although the MMBI mix is a 1:1 mixture of 4-MMBI and 5-MMBI, the AUC of 4-MMBI was much greater than that of 5-MMBI.. The AUC0–10 h of 5-MMBI did not change with roa. In contrast, that of 4-MMBI seemed to be increased. The absorption rate of these compounds seemed to be delayed upon roa. The Tmax of the 5-MMBI and that of the sum of 4-MMBI and 5-MMBI changed from 1 to 4 h. Serum concentrations of 4-MMBI at 0.25 and 1 h after administration of the mixture were much lower on day 15 than those on day 1.

We administered each isomer was administered to rats in order to distinguish the effects of each isomer. After roa of 5-MMBI

(0.6 mmol/kg), the Cmax and AUC0–10 h of 5-MMBI were not changed markedly between days 1 and 14. However, the Tmax in serum was delayed from 0.5 to 6 h. On the other hand, the TK parameters and the serum concentration profiles of 4-MMBI (0.6 mmol/kg) after roa were markedly changed between days 1 and 14, suggesting metabolic enzyme induction. The AUC of 4-MMBI was reduced to about one-third by roa. The Tmax was delayed also from 2 to 8 h.

Urinary excretion of MBI and the MMBIs and their metabolites

The amount of MBI excreted in the urine on day 1 was similar to that of the corresponding desulfurated metabolite, BI. 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.

After roa of 0.6 mmol/kg of the MMBI mix, urinary excretion of unchanged compounds, 4-MMBI and 5-MMBI, on day 15 increased markedly (7-fold and 2-fold of those amounts on day 1, respectively). In contrast, the urinary excretion of their desulfurated

metabolites was not altered significantly. Roa of the lower dose (0.3 mmol/kg) did not affect urinary excretion patterns. The sum of the urinary excretions of unchanged compounds and their desulfurated metabolites during the 24 h following oral administration of

these thioureylene compounds was less than 10% of the administered amounts. Then, we administered each isomer separately. Urinary excretion of the desulfurated metabolite, 4-MeBI, on day 14 was increased 2-fold (P<0.01) by roa of 4-MMBI compared

with that on day 1. However, in the case of 5-MMBI, urinary excretion of both the unchanged compound and the desulfurated metabolite, 5-MeBI, were not altered by roa.