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Description of key information

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.
ZMB2 (1,3-dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione, zinc salt, CAS n° 61617 -00 -3):
In a combined repeated-dose reproductive/developmental toxicity study, 2-mercaptomethylbenzimidazole, zinc salt was administered orally in the diet to rats (10/sex/dose) at 1000, 2750 or 7500 ppm (ca. 50, 138 or 375 mg/kg bw/d). These dose levels were reduced to 900, 2500 or 6750 ppm (ca. 45, 125 or 338 mg/kg bw/d) on day 29. On study day 33 the high dose level was further reduced to 5500 ppm (ca. 275 mg/kg bw/d). Signs of systemic toxicity, body weight, food consumption, blood chemistry and hematological parameters, organ weights and histopathological examinations were recorded.
No repeated dose studies for inhalation and dermal toxicity are available

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
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:
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:
4 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:
not specified

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

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

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
4 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

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

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

In the 28 day repeated dose study the 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.

ZMB2 (1,3-dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione, zinc salt, CAS n° 61617 -00 -3):

In the combined repeated-dose reproductive/developmental toxicity study, nine female animals were killed in extremis in the high (1 animal) and middle (8 animals) dose groups, due to a possible impairment of parturition. All mortalities were associated with pregnant females particularily during late gestation at and around the time of parturation. Signs of systemic toxicity was evident in a dose related decrease of body weight gain and food consuption in all treatment groups; these signs were considered not to be indicative of behavioural or neurotoxic effect.

The findings from the blood chemistry evaluations showed alterations in plasma concentrations of phosphorus and chloride for both sexes plus increased plasma creatinines for males. These findings were not associated with any significant renal pathology. The observed blood chemistry changes together with an increase plasma cholesterol, reduced adrenal weights for both sexes plus histopathological changes to the liver and thyroid glands are symptomatic of altered metabolic state. This may well be a direct consequence of test material metabolism or as a consequence of the reductions in weight gain and food consumption. The splenic changes for males and females seen at histopathology and with the organ weight decrements does not appear to be associated with any significant haematological changes. The slight variations in clotting time and platlet count for males or females may be a consequence of potential alterations in hepatic or general metabolism that may have a secondary effect upon clotting factors.

At histopathology, the hypertrophy observed for the liver of both sexes may be indicative of enhanced metabolism from xenobiotic administration. The thyroid gland hypertophy may also be a consequence of a negative feedback via enhanced metabolism of circulating thyroid hormones. The histopathological changes tend to support the proposal of an altered metabolism being the principal sytemic effect seen following administration of test material. The splenic changes seen may be associated with the altered physiologic status of the animals from reductions in bodyweight and food consumption. Other treatment related histopathological changes to the salivary glands and pituitary are of note because of the treatment and dosage relationship but are not indicative of a specific toxic effect. Organ weight analysis showed decrements for a number of organs for males at termination, which were primarily a consequence of reduced bodyweight. Elevated relative liver weight was connected to their hypertrophy observed at histopathology, which may be a result of alterations in metabolic status.

The administration of the substance to male and female rats at dose levels up to 7500 ppm (adjusted to 6750 ppm and then to 5500 ppm), for a period of up to 47 days, resulted in treatment-related toxic effects upon adults. A No Observed Adverse Effect Level (NOAEL) was not established.

The lowest-observed-adverse-level LOAEL (systemic) was 45 -50 mg/kg bw/day (based on decreased body weight gain).


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

Justification for classification or non-classification

The no-observed-effect level (NOEL) of MMBls, under the conditions of the present subacutce toxicity study, was evaluated to be 4 mg/kg, based on the significant increases of relative liver and kidney weights and serum levels of T-CHO (total cholesterol) at doses of 20 mg/kg and above for male rats, and the NOEL for female rats was 20 mg/kg.

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

In the low dose level of the 28 day study effects were obvious, but these effects are regarded as adaptive effects and not as severe effects.At the termination of the 2-wk recovery period, changes in the absolute organ weights were no longer apparent.

ZMB2 (1,3-dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione, zinc salt, CAS n° 61617 -00 -3):

In the combined repeated-dose reproductive/developmental toxicity study, the administration of the substance to male and female rats

at dose levels up to 7500 ppm (adjusted to 6750 ppm and then to 5500 ppm ), for a period of up to 47 days, resulted in treatment-related toxic effects upon adults. A No Observed Adverse Effect Level (NOAEL) was not established.

The lowest-observed-adverse-level LOAEL (systemic) was 45 -50 mg/kg bw/day (based on decreased body weight gain).

Therefore based on the result of the oral 28 d repeated dose study (increased organ weights) and the combined repeat-dose reproductive/ developmental toxicity study which has similar results as the 28 d repeat dose study a classification as Xn; R48/22 (GHS: STOT Rep. 2; H373) is justified.