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Effects on fertility

Description of key information

NOAEL was considered to be 53 mg/kg bw for P and F1 generation when pregnant female rat were treated with 1H-benzimidazole orally.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data is from handbook
Qualifier:
according to guideline
Guideline:
other: No data
Principles of method if other than guideline:
Reproductive toxicity study of 1H-benzimidazole in rats was evaluated.
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
- Name of test material: Benzimidazole
- IUPAC name: 1H-benzimidazole
- Molecular formula: C7H6N2
- Molecular weight: 118.1384 g/mol
- Substance type: Organic
- Physical state: Solid
Species:
rat
Strain:
not specified
Details on species / strain selection:
No data
Sex:
female
Details on test animals or test system and environmental conditions:
No data
Route of administration:
not specified
Type of inhalation exposure (if applicable):
not specified
Vehicle:
not specified
Details on exposure:
No data
Details on mating procedure:
No data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
5 days (day 8 to day 12)
Frequency of treatment:
Daily
Details on study schedule:
no data
Dose / conc.:
53 mg/kg bw/day
Remarks:
upto
No. of animals per sex per dose:
No data
Control animals:
not specified
Details on study design:
No data
Positive control:
No data
Parental animals: Observations and examinations:
No data
Oestrous cyclicity (parental animals):
No data
Sperm parameters (parental animals):
No data
Litter observations:
Fetal weight were observed
Postmortem examinations (parental animals):
No data
Postmortem examinations (offspring):
Gross pathology were examined.
Statistics:
No data
Reproductive indices:
No data
Offspring viability indices:
No data
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Reproductive performance:
No effect on fetal growth were observed
Dose descriptor:
NOAEL
Effect level:
53 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
reproductive performance
Remarks on result:
other: No toxic effect were observed.
Critical effects observed:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings:
not specified
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Body weight:
No effect on fetal body weight were observed in treated rats upto 53 mg/kg bw

Gross pathology:
No malformations were observed in treated rats upto 53 mg/kg bw
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
53 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
gross pathology
Remarks on result:
other: No toxic effect were observed
Critical effects observed:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Reproductive effects observed:
no
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
NOAEL was considered to be 53 mg/kg bw for P and F1 generation when pregnant female rat were treated with 1H-benzimidazole orally.
Executive summary:

In a reproductive toxicity study 1H-benzimidazole was assessed for its possible reprotoxic nature.For this purpose pregnant female rat were treated with 1H-benzimidazole orally upto 53 mg/kg bw on day 8 through 12. The animals were observed for clinical sign, mortality, bodyweight, Food intake, gross and histopathology. The foetus  growth and malformation was observed. No significant effects were observed in treated female rats. No effect on fetal growth nor malformation were observed in treated female rats. Therefore, NOAEL was considered to be 53 mg/kg bw for P and F1 generation when pregnant female rat were treated with 1H-benzimidazole orally through 8-12 days of gestation.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
53 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
data for the target chemical from K2
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In various experimental studies, 1H-benzimidazole (51-17-2)has been investigated for reproductive toxicity to a greater or lesser extent. The studies are mention below

In a reproductive toxicity study 1H-benzimidazole was assessed for its possible reprotoxic nature. For this purpose pregnant female rat were treated with 1H-benzimidazole orally up to 53 mg/kg bw on day 8 through 12. The animals were observed for clinical sign, mortality, bodyweight, Food intake, gross and histopathology. The foetus  growth and malformation was observed. No significant effects were observed in treated female rats. No effect on fetal growth no malformation was observed in treated female rats. Therefore, NOAEL was considered to be 53 mg/kg bw for P and F1 generation when pregnant female rat were treated with 1H-benzimidazole orally through 8-12 days of gestation.

 

In a subacute toxicity study, Sprague-Dawley male and female rats were treated with test chemical in the concentration of 0, 250, 500 and 1000 mg/kg bw orally by gavage for 28 days. All the male and female animals from control and different dose groups up to 1000 mg/kg survived throughout the dosing period of 28 days and the recovery period of 14 days. At the end of the dosing period reduced body weight gain of 14.94% was observed in male animals from 1000 mg/kg dose group. All the male animals from control, 250, 500 and 1000 mg/kg reversal dose groups exhibited normal body weight gain throughout the dosing period of 28 days and the recovery period of 14 days. Female animals from control, 250, 500 and 1000 mg/kg dose groups exhibited normal body weight gain throughout the dosing period of 28 days. Reduced body weight gain of 11.36% was observed in female animals from 1000 mg/kg reversal group. Feed intake of animals from control and different dose groups was found to be comparable throughout the dosing period of 28 days and the recovery period of 14 days. No signs of toxicity were observed in male and female animals from 250 and 500 mg/kg dose groups during the dosing period of 28 days. Detailed clinical observations conducted at weekly interval did not reveal any abnormality in all male and female animals from control and different dose groups during the dosing period of 28 days and the recovery period of 14 days. No statistically significant changes in the values of various Haematological parameters were at the end of the dosing period on day 29. At the end of the recovery period on day 43, statistically significant decrease in the values of Total RBC and HCT at 1000 mg/kg in male. Statistically significant decrease in the values of Hb and HCT at 500 mg/kg and Total RBC at 250 and 500 mg/kg were observed in female rat. At the end of the recovery period on day 43, no statistically significant changes in the values of various parameters in female rats. The decrease in the values of various parameters was marginal and within the normal biological and laboratory limits. Clinical biochemistry analysis at the end of the dosing period on day 29, revealed statistically significant increase in the values of Globulin at 250 mg/kg in male rat. In addition statistically significant decrease was observed in the values of BUN and Urea Nitrogen at 250 mg/kg in male, BUN and Urea Nitrogen at 500 mg/kg in female rat, Alanine Aminotransferase at 250 and 500 mg/kg in female and Alkaline Phosphatase at 250 mg/kg in female rat. At the end of the recovery period on day 43 (Reversal groups) statistically significant increase was observed in the values of Bile Acid at 1000 mg/kg in female and statistically significant decrease was observed in the values of Calcium at 1000 mg/kg in male. The increase/decrease in the values of various parameters was marginal and within the normal biological and laboratory limits. Urine analysis conducted on male animals during 4thand 6thweek of study period (on day 23, 24 and 43), revealed no abnormality attributable to the treatment. Urine analysis conducted on female animals during 4thweek of study period (on day 24 and 26), higher volume of urine was observed in female at 1000 mg/kg dose group. During 6th week of study period (on day 43) revealed no abnormality attributable to the treatment. At termination of dosing on day 29, male animals from 1000 mg/kg dose group revealed increased relative weights of brain. In addition, increased relative weights of liver and kidneys were observed in male at 500 and 1000 mg/kg dose groups when compared with that of controls. Increased relative weights of spleen were observed in male at 250 and 1000 mg/kg as compared to controls. Increased relative weights of thymus were observed in male at 250 mg/kg as compared to controls. No effect on male organ weight sacrificed on day 43 from 1000 mg/kg as comparable to controls. At termination of dosing on day 29, at 1000 mg/kg increased relative weights of liver were observed in female as compared to controls. In addition, increased relative weights of kidneys were observed in female at 500 and 1000 mg/kg as compared to controls. At 500 mg/kg dose decreased relative weights of heart in female rats as compared to controls. Organ weight data of female animals sacrificed on day 43 at 1000 mg/kg increased relative weights of brain, liver, kidneys, spleen and uterus were observed in female as compared to controls. Although significant changes in the values of organ weight of brain, liver, spleen, thymus, heart and uterus were observed in male and female animals at 250 mg/kg and 500 mg/kg dose groups, no related gross pathological and histopathological findings were seen in reproductive organ, hence these findings were considered to be of no toxicological importance. Gross pathological examination did not reveal any abnormality attributable to the treatment. Histopathological examination revealed focal to diffuse, minimal to moderate tubular dilatation in kidneys in male (1/6) and female (6/6) animals from 1000 mg/kg dose group, in male (1/6) and female (6/6) animals from 500 mg/kg dose group and in male (0/6) and female (5/6) animals from 250 mg/kg dose group and in female (1/6) from 1000 mg/kg reversal dose group. Focal to multifocal, minimal mononuclear cells infiltration was observed in kidneys in male (1/6) and female (3/6) animals from 1000 mg/kg dose group and in female animals from 250 mg/kg (2/6) and 500 mg/kg (2/6) dose groups. All histopathological the changes observed in male animals were reversible during the recovery period of 14 days. The histopathological changes observed in female animals were evident in reversal group one animal, during the recovery period of 14 days in reproductive organ. Therefore, No Observed Adverse Effect Level (NOAEL) of test chemical in the Sprague Dawley rat via oral route, over a period of 28 days was found to be 1000 mg/kg body weight for male and female animals.

In a chronic study Male and female CD-1 mice were administered test chemical in diet at levels of 0 (control), 0.031, 0.125 and 0.5% (33.2, 146.3 and 605 mg/kg body weight per day in males and 40.0, 178.8 and 615 mg/kg body weight )for 78 weeks.The animals were observed for clinical sign,mortality,body weight ,food intake, hematology,gross and histopathology There were no significant differences in mortality between the control and treated groups. Mean body weights of high-dose groups showed significant decreases compared with the controls. The bladder weights of male and female mice of the 605 or 615 mg/kg/day group were significantly higher than those of the control mice. Gross findings in treated mice included the renal atrophy, hydronephrosis, calculi in renal pelvis and/or bladder and ovarian atrophy. Microscopic findings in the kidneys of treated mice included the nephrosis, hydronephrosis or hyperplasia of transitional epithelium of renal pelvis or papilla. In the bladder of treated mice, hyperplasia or squamous metaplasia of transitional epithelium and one transitional cell papilloma were observed. Dose-dependent decreases in the

incidence of spontaneous lesion in the male or female reproductive system were recognized. ThereforeNOAEL was considered to be 178 mg/kg/day for female 146.3 mg/kg/day for male respectivley .When test chemical was exposed to the Crj:CD-1 (ICR) male and female mice by oral feed for 78 weeks.

 

Based on the data available for the target chemical 1H-benzimidazole (51-17-2) does not exhibit reproductive toxic nature and hence is not likely to classify as per the criteria mentioned in CLP regulation.

 

Effects on developmental toxicity

Description of key information

NOAEL was considered to be 53 mg/kg bw for F1 generation when pregnant female rat were treated with 1H-benzimidazole orally.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data is from Handbook
Qualifier:
according to guideline
Guideline:
other: No data
Principles of method if other than guideline:
Developmental toxicity study of 1H-benzimidazole in rats
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
- Name of test material: Benzimidazole
- IUPAC name: 1H-benzimidazole
- Molecular formula: C7H6N2
- Molecular weight: 118.1384 g/mol
- Substance type: Organic
- Physical state: Solid
Species:
rat
Strain:
not specified
Details on test animals or test system and environmental conditions:
Sex: Female
Route of administration:
oral: unspecified
Type of inhalation exposure (if applicable):
not specified
Vehicle:
not specified
Details on exposure:
No data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Details on mating procedure:
pregnant female rat were used
Duration of treatment / exposure:
5 days
Frequency of treatment:
Daily
Duration of test:
day 8 through day 12
Dose / conc.:
53 mg/kg bw/day
Remarks:
upto
No. of animals per sex per dose:
No data
Control animals:
not specified
Maternal examinations:
No data
Ovaries and uterine content:
No data
Fetal examinations:
Fetal weight and gross pathology were examined.
Statistics:
No data
Indices:
No data
Historical control data:
No data
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Number of abortions:
not specified
Pre- and post-implantation loss:
not specified
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
not specified
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
not specified
Other effects:
no effects observed
Details on maternal toxic effects:
No effect on fetal growth were observed in trearted rats
Dose descriptor:
NOAEL
Effect level:
53 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: No effect on No effect on fetal growth
Remarks on result:
other: No toxic effect were observed
Abnormalities:
not specified
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
not specified
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Skeletal malformations:
not specified
Visceral malformations:
not specified
Other effects:
not specified
Dose descriptor:
NOAEL
Effect level:
53 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
external malformations
Remarks on result:
other: No toxic effect were observed
Abnormalities:
not specified
Developmental effects observed:
no
Treatment related:
no
Relation to maternal toxicity:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
NOAEL was considered to be 53 mg/kg bw for F1 generation when pregnant female rat were treated with 1H-benzimidazole orally.
Executive summary:

In a developmental toxicity study, pregnant female rat were treated with 1H-benzimidazole orally upto 53 mg/kg bw on day 8 through 12. No effect on fetal growth nor malformation were observed in treated female rats. Therefore, NOAEL was considered to be 53 mg/kg bw for F1 generation when pregnant female rat were treated with 1H-benzimidazole orally.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
53 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
data for the target chemical from K2
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Developmental toxicity

In a developmental toxicity study, pregnant female rat were treated with 1H-benzimidazole orally upto 53 mg/kg bw on day 8 through 12. No effect on fetal growth nor malformation were observed in treated female rats. Therefore, NOAEL was considered to be 53 mg/kg bw for F1 generation when pregnant female rat were treated with 1H-benzimidazole orally.

Based on the data available for the target chemical 1H-benzimidazole (51-17-2) does not exhibit teratogenic nature and hence is not likely to classify as per the criteria mentioned in CLP regulation

Justification for classification or non-classification

Thus based on the above annotation for the target chemical 1H-benzimidazole (51-17-2)does not exhibit reproductive toxic nature and hence is not likely to classify as per the criteria mentioned in CLP regulation.  

Additional information