2H-Benzimidazole-2-thione, 1,3-dihydro-ar-methyl-, sodium salt (1:1)

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: sufficient documented and scientifically acceptable

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Toxicity study of a rubber antioxidant, mixture of 2-mercaptomethylbenzimidazoles, by repeated oral administration to rats

Author:

Saitoh M, Umemura T, Kawasaki Y, Momma Y, Matsushima Y, Sakemi K, Isama K, Kitajima S, Ogawa Y, Hasegawa R, Suzuki T, Hayashi M, Inoue T, Ohno Y, Sofuni T, Kurokawa Y, Tsuda M

Year:

1999

Bibliographic source:

Food Chem Toxicol 37, 777-787

Materials and methods

Principles of method if other than guideline:

Male and female rats were treated with MMBIs (2-mercaptomethylbenzimidazoles (a 1:1 mixture of 4-methyl and 5-methyl isomers, MMBIs) by gavage at doses 0 (corn oil), 4, 20 and 100 mg/kg for 28 consecutive days followed by a 2-week recovery period for the control and highest dose groups. Body weight and food consumption, clinical signs, organ weights, clinical biochemistry and hematological parameters including clotting times and micronuclei induction in bone marrow erythropoeitic cells were recorded and a histopathological examination was conducted.

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

Details on test material:

2-Methylmercaptobenzimidazoles (MMBIs, CAS no 53988-10-6, a 1:1 mixture of 2-mercapto-4-methylbenzimidazole, CAS no 27231-33-0 and 2-mercapto-5-methylbenzimidazole, 27231-36-3, mol.wt 164.23 were obtained from Ouchi Shinko Chemical Ind. Ltd (Osaka, Japan)

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

28 days

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 2, 10, 25, 50, 100, or 150 mg/kg
Basis:
other: nominal

No. of animals per sex per dose:

5 male and 5 female rats/group

Control animals:

yes, concurrent vehicle

Results and discussion

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

4 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: thyroid toxicity

2

Dose descriptor:

NOAEL

Effect level:

20 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: thyroid toxicity

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Relative organ weights of lung, liver, kidney, and serum cholesterol and phospholipid significantly increased in male rats treated with MMBIs at doses of 20 and 100 mg/kg bw/d. Male rats administered 100 mg/kg bw/d exhibited a 1.8 fold increase in thyroid weight associated with histopathological changes but not altered serum thyroid hormone levels. Haematology and urine analysis were uneffected. Female rats administered 100 mg/kg bw/d MMBIs exhibited significant increases of liver and kidney but not thyroid weights and serum cholesterol levels.

Reproductive organs of the rats were examined histopathologically. No adverse effects were reported from these organs. Based on these results there are no indications for specific adverse effects on the reproductive organs up to 100 mg/kg bw/day

Applicant's summary and conclusion

Executive summary:

Male and female rats were treated orally by gavage with 2-mercaptomethylbenzimidazole at doses of 0 (corn oil), 4, 20 and 100 mg/kg bw for 28 consecutive days. Clinical signs, body weight, food consumption, organ weights, clinical biochemistry and hematological parameters were recorded and autopsy was conducted.

Relative organ weights of lung, liver, kidney, and serum cholesterol and phospholipid significantly increased in male rats treated with MMBIs at doses of 20 and 100 mg/kg bw/d. Male rats administered 100 mg/kg bw/d exhibited a 1.8 fold increase in thyroid weight associated with histopathological changes but not altered serum thyroid hormone levels. Haematology and urine analysis were uneffected. Female rats administered 100 mg/kg bw/d MMBIs exhibited significant increases of liver and kidney but not thyroid weights and serum cholesterol levels.

Reproductive organs of the rats were examined histopathologically. No adverse effects were reported from these organs. Based on these results there are no indications for specific adverse effects on the reproductive organs up to 100 mg/kg bw/day.

The no-observed-effect levels for male and female rats were found to be 4 and 20 mg/kg bw/d, respectively