Registration Dossier

MB2 (2-mercaptomethylbenzimidazole, CAS n° 53988 -10 -6):
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 a histopathological examination was conducted.

No repeated dose studies for inhalation and dermal toxicity are available

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The most reliable study for the determinatin of a NOAEL was used as key study and for classification

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: sufficient documented and scientifically acceptable

Reason / purpose for cross-reference:

reference to same study

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

Species:

rat

Strain:

Wistar

Sex:

male/female

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

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

Dose descriptor:

NOAEL

Effect level:

20 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

organ weights and organ / body weight ratios

Dose descriptor:

NOAEL

Effect level:

20 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

organ weights and organ / body weight ratios

Critical effects observed:

yes

Lowest effective dose / conc.:

100 mg/kg bw/day (nominal)

System:

other: organ weights and organ/body weight ratios of liver and thyroid.

Organ:

kidney

liver

thyroid gland

Treatment related:

yes

Dose response relationship:

yes

In a subacute oral toxicity study with MB2 (2-mercaptomethylbenzimidazole; also named MMBI; 1:1 mixture of 4-ethyl and 5-methyl isomers) male and female rats were treated by gavage at doses of 0 (corn oil), 4, 20 and 100 mg/kg bw/day 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 haematological parameters including clotting times, and micronuclei induction in bone marrow erytropoetic cells, and histopathology were examined (Saitoh et al., 1999).

“Relative organ weights of lung, liver and kidney, and serum cholesterol and phospholipid significantly increased in male rats treated with MMBIs at doses of 20 and 100 mg/kg. Males rats administered 100 mg/kg MMBIs exhibited a 1.8 fold increase in thyroid weight associated with histopathological changes but not altered serum thyroid hormone levels. Female rats administered 100 mg MMBIs/kg exhibited significant increases of liver and kidney weights, and serum cholesterol level. No-observed-effect levels for male and female rats were found to be 4 and 20 mg/kg, respectively, in this subacute oral toxicity study”.

Relative lung, liver and kidney weights were significantly increased in male rats treated with 20 mg/kg bw/day. However, absolute lung, liver and kidney weights in male rats were not increased significantly in male rats treated with 20 mg/kg bw/day. The increase in relative organ weights is slight and not evident in the recovery groups at 100 mg/kg bw/day. There is no correlate with histopathology finding in lung, liver and kidneys up to the highest dose of 100 mg/kg bw/day. The effects seen in relative organ weights at 20 mg/kg bw/day are regarded as secondary effects due to the slightly (2.4%) decreased body weight.

Taking the above information into account, the relative organ weight effects at 20 mg/kg bw/day are not considered adverse and the NOAEL for male rats is concluded to be 20 mg/kg bw/day.

In female rats relative and absolute organ weights of lung, liver and kidney were not increased at a dose of 20 mg/kg bw/day.

Therefore, the NOAEL for males and females is 20 mg/kg bw/day.

The PL (phospholipid) level was statistically increased in male rats only at 100 mg/kg bw/day and no effect was observed in female rats at any dose.

A slight but significant higher T-CHO (total cholesterol) level was observed in male rats at doses of 20 mg/kg bw/day and 100 mg/kg bw/day. The increase was approx. 25% and 50 %, respectively. In female rats the T-CHO level was increased at 100 mg/kg bw/day (approx. 25%) only andno significant increase in T-CHO level was observed in female rats at 20 mg/kg bw/day and below.Increased cholesterol levels in this study are accompanied by an increase of liver weights in male and female rats. The increase of cholesterol is interconnected with an increase of the liver weights. The increase of the liver weights is dose dependent and a result of the exposure of the rats to the test substance. Liver weight changes in repeated dose studies in mammalians are often caused by liver enzyme induction. An important function of the liver is to produce and clear cholesterol in the body. If the liver is not working properly, it can cause cholesterol to build up in the body.

In the subacute study by Saitoh et al. (1999), the T-CHO values were only slightly increased in male rats at 20 mg/kg bw/day. The effect was reversible in the recovery group at 100 mg/kg bw/day; the T-CHO values in the control and the 100 mg/kg bw/day groups were similar and there were no significant differences in liver or thyroid weights in the control and the 100 mg/kg bw/day groups. These data indicate, that the elevated cholesterol levels at 20 mg/kg bw/day are adaptive and should be considered non-adverse.

Conclusions:

The NOEL (no-observed-effect level) for male and female rats are 4 and 20 mg/kg bw/day, respectively. The NOAEL (no-observed-adverse-effect level) for male and female rats are concluded to be 20 mg/kg bw/day.

Executive summary:

In a subacute oral toxicity study with MB2 (2-mercaptomethylbenzimidazole; also named MMBI; 1:1 mixture of 4-ethyl and 5-methyl isomers) male and female rats were treated by gavage at doses of 0 (corn oil), 4, 20 and 100 mg/kg bw/day 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 haematological parameters including clotting times, and micronuclei induction in bone marrow erytropoetic cells, and histopathology were examined (Saitoh et al., 1999).

“Relative organ weights of lung, liver and kidney, and serum cholesterol and phospholipid significantly increased in male rats treated with MMBIs at doses of 20 and 100 mg/kg. Males rats administered 100 mg/kg MMBIs exhibited a 1.8 fold increase in thyroid weight associated with histopathological changes but not altered serum thyroid hormone levels. Female rats administered 100 mg MMBIs/kg exhibited significant increases of liver and kidney weights, and serum cholesterol level. No-observed-effect levels for male and female rats were found to be 4 and 20 mg/kg, respectively, in this subacute oral toxicity study”.

Relative lung, liver and kidney weights were significantly increased in male rats treated with 20 mg/kg bw/day. However, absolute lung, liver and kidney weights in male rats were not increased significantly in male rats treated with 20 mg/kg bw/day. The increase in relative organ weights is slight and not evident in the recovery groups at 100 mg/kg bw/day. There is no correlate with histopathology finding in lung, liver and kidneys up to the highest dose of 100 mg/kg bw/day. The effects seen in relative organ weights at 20 mg/kg bw/day are regarded as secondary effects due to the slightly (2.4%) decreased body weight.

Taking the above information into account, the relative organ weight effects at 20 mg/kg bw/day are not considered adverse and the NOAEL for male rats is concluded to be 20 mg/kg bw/day.

In female rats relative and absolute organ weights of lung, liver and kidney were not increased at a dose of 20 mg/kg bw/day.

Therefore, the NOAEL for males and females is 20 mg/kg bw/day.

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

20 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The materials/methods and results are described in detail und are sufficient for evaluation

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

MB2 (2-mercaptomethylbenzimidazole, CAS n° 53988 -10 -6):