Benzimidazole-2-thiol

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

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 peer- reviewed journal

Data source

Reference

Reference Type:

publication

Title:

The Adverse Effects of Oral test chemical on Pregnant Rats and Their Fetuses

Author:

Tetsuo Yamano,et.al

Year:

1995

Bibliographic source:

Fundamental and Applied Toxicology (1995)

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

The adverse effects of test chemical on pregnant Wistar rats were examined.

GLP compliance:

not specified

Limit test:

no

Justification for study design:

not specified

Test material

Test material information

Constituent 1

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:

- Name of test material : 2-Mercaptobenzimidazole
- Substance type: Organic
- Physical state: Solid

Test animals

Species:

rat

Strain:

Wistar

Details on species / strain selection:

not specified

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: CLEA Japan Inc. (Tokyo, Japan)
- Age at study initiation: Four-week-old
- Housing: Housed individually in stainless steel cages
- Diet (e.g. ad libitum): Feed (NMF, Oriental Yeast Co., Ltd., Tokyo, Japan) ; ad libitum
- Water (e.g. ad libitum): Tap water; ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2°C
- Humidity (%):60 ± 10%
- Photoperiod (hrs dark / hrs light): Dark period from 7:00 PM to 7:00 AM

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

olive oil

Details on exposure:

not specified

Details on mating procedure:

- Impregnation procedure: [artificial insemination / purchased timed pregnant / cohoused]: cohoused
- If cohoused:
- M/F ratio per cage: females were individually paired overnight with a male of similar age.
- Length of cohabitation: overnight
- Further matings after two unsuccessful attempts: no
- Verification of same strain and source of both sexes: no
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: The day upon which sperm was found in vaginal smears was designated as Day 0 of gestation.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

11 days

Frequency of treatment:

Daily

Details on study schedule:

20 days of gestation

Doses / concentrations

Doses / concentrations 1

Remarks:

0,2.5,5,10,20,40 and 60 mg/kg bw for dose finding study

Doses / concentrations 2

Remarks:

0.3.3,10,30 mg/kg bw for teratogenicity study

No. of animals per sex per dose:

Dose-finding study:
Mated (pregnant) rats were assigned to seven groups of five or six animals each.

Teratology study:
Mated (pregnant) rats were divided into four groups of 20 rats each.

Control animals:

yes

Details on study design:

Dose-finding study:
Mated rats were assigned to seven groups of five or six animals each. They were treated by gavage with 2-MBI in oIive oil at 0, 2.5, 5, 10, 20, 40, and 60 mg/kg/day in a volume of 5 ml/kg from Days 7 through 17 of gestation. The animals were weighed and food consumpiion was measured each day; general condition and behavior were also observed. On Day 20 of gestation, the animaIs were killed under diethylether anesthesia, laparotomy was performed, and the maternal thymus and the gravid uterus were weighed. The position and number of live and dead fetuses, including resorbed fetuses, and the number of corpora lutea were recorded. Live fetuses were weighed, sexed, and gross deformities noted. Only one dam treated with 60 mg/kg of test chemical survived; viscera ot the fetuses were examined.

Teratology study:
Dose levels of 0, 3.3, 10, and 30 mg/kg/day in a volume of 5 ml/kg were selected based upon the results of the dose-finding study.
The dose-finding study revealed that 60 mg/kg was toxic to both fetuses and dams when given throughout the period of organogenesis (Days 7-17 of gestation).Therefo re, when mated (pregnant) rats were dosed with 60 mg/kg of test chemical it was given upon 3 or 4 consecutive days at different periods during organogenesis (Days 7— 10, 11 —14, and I 5—17 of gestation). The other procedures were the same as described here.

Positive control:

not specified

Examinations

Parental animals: Observations and examinations:

BODY WEIGHT: Yes

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes

OTHER:
GENERAL CONDITION AND BEHAVIOUR: Yes

ORGAN WEIGHT:
Maternal thymus, thyroid gland, and gravid uterus were weighed.

Oestrous cyclicity (parental animals):

The uterine content was examined after termination: Yes
Examinations included:
- Number of early resorptions: Yes
- Number of corpora lutea were recorded.

Sperm parameters (parental animals):

not specified

Litter observations:

The position and number of live and dead fetuses, including resorbed fetuses were recorded. Live fetuses were weighed, sexed, and gross deformities noted.

Postmortem examinations (parental animals):

GROSS NECROPSY
- Uteri was examined grossly.

Postmortem examinations (offspring):

GROSS NECROPSY
- Fetuses were examined grossly.
- Gross necropsy consisted of Visceral and Skeletal observation.

Statistics:

Data from the dose-finding and teratology studies in which animals were treated with ≤30 mg/kg of test chemical were analyzed by Dunnett’s multiple comparison method in a parametric or nonpararnetric manner.

Reproductive indices:

not specified

Offspring viability indices:

not specified

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

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:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Details on results (P0)

Mortality:
Teratology study: All dams survived.
Dose-finding study: Four of five rats treated with 60 mg/kg dose and one of six rats treated with 40 mg/kg died.
Body weight:
Teratology study: Substantial decrease in body weight gain was observed in all three groups.
Dose-finding study: In pregnant rats, the maternal weight gain was decreased at a 40 and a 20 mg/kg of test chemical , respectively.
Food consumption:
Teratology study: Substantial decrease in food consumption was observed in all three groups.
Dose-finding study: In pregnant rats, the food consumption was decreased at a 40 and a 20 mg/kg of test chemical , respectively.
Organ weight: Thymus weight was decreased even at the lowest dose of 3.3 mg/kg whereas treatment with 10 and 30 mg/kg of test chemical resulted in increased thyroid weight.
Reproductive performance:
No effects on reproduction of treated female rats were observed

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

30 < mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

mortality

body weight and weight gain

food consumption and compound intake

reproductive performance

Remarks on result:

other: No effects on reproductive performance

Target system / organ toxicity (P0)

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

no mortality observed

Description (incidence and severity):

Live fetuses was observed.

Body weight and weight changes:

effects observed, treatment-related

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:

effects observed, treatment-related

Histopathological findings:

not specified

Other effects:

not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):

not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not specified

Details on results (F1)

Body weight:
Fetal body weights significantly decreased only in the litters of dams dosed with 10 mg/kg or higher dose
Gross pathology:
Visceral variations consisting of unilateral or bilateral kinked ureter and / or dilated renal pelvis were noted in 20.5% of fetuses at 10 mg/kg and in 47.6% of the fetuses at 30 mg/kg.
Skeletal variations, unilateral or bilateral rudimentary lumbar ribs, were observed in 22.2% of the fetuses at 30 mg/kg.
The degree of ossification was significantly reduced in the litters of dams treated with ≥ 10 mg/kg of test chemical
Dose-finding study
All fetuses from dams treated with daily doses upto 40 mg/kg body weight, all parameters with respect to fetuses were unaffected.
Only rudimentary lumbar ribs were observed when the treatment period with 60 mg/kg was shortened to Gestation days 7-10, while kinked ureter and dialated renal pelvis were observed only following treatment with 60 mg/kg on days 15-17. Finally , dilated lateral ventricles and cleft palate were observed only in the litters f dams treated with 60 mg/kg on Days 11-14; these anomalies were not observed at lower doses of the chemical.

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

30 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

viability

mortality

body weight and weight gain

gross pathology

other: No adverse effects observed on

Remarks on result:

other: Fetal body weights significantly decreased only in the litters of dams dosed with 10 mg/kg or higher dose

Target system / organ toxicity (F1)

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Overall reproductive toxicity

Reproductive effects observed:

not specified

Treatment related:

not specified

Applicant's summary and conclusion

Conclusions:

NOAEL was considered to be 30 mg/kg bw when Wistar female rat were treated with test chemical orally by gavage from day 7 to 17.

Executive summary:

In a reproductive toxicity study, Wistar female rat were treated with test chemical in the concentration of 0,2.5,5,10,20,40 and 60 mg/kg bw for dose finding study and 0.3.3,10,30 mg/kg bw for teratogenicity study orally by gavage in olive oil from day 7 to 17. Four of five rats treated with 60 mg/kg of test chemical and one of six rats treated with 40 mg/kg died in Dose-finding study and all dams survived in main study. The maternal weight gain was decreased at a 40 and a 20 mg/kg of test chemical respectively in dose-finding study Substantial decrease in body weight gain was observed in all three groups in Teratology study. Food consumption was decreased at a 40 and a 20 mg/kg of test chemical , respectively in dose-finding study and Substantial decrease in food consumption was observed in all three groups in teratology study. Thymus weight was decreased even at the lowest dose of 3.3 mg/kg whereas treatment with 10 and 30 mg/kg of test chemical resulted in increased thyroid weight. No effete on reproduction of treated female rats were observed as compared to control. In addition,All fetuses from dams treated with daily doses upto 40 mg/kg body weight, all parameters with respect to fetuses were unaffected in Dose-finding study. Only rudimentary lumbar ribs were observed when the treatment period with 60 mg/kg was shortened to Gestation days 7-10, while kinked ureter and dialated renal pelvis were observed only following treatment with 60 mg/kg on days 15-17. Finally, dilated lateral ventricles and cleft palate were observed only in the litters f dams treated with 60 mg/kg on Days 11-14; these anomalies were not observed at lower doses of the chemical. Significantly decreased only in the litters of dams dosed with 10 mg/kg or higher of test chemical . Visceral variations consisting of unilateral or bilateral kinked ureter and / or dilated renal pelvis were noted in 20.5% of fetuses at 10 mg/kg and in 47.6% of the fetuses at 30 mg/kg. Skeletal variations, unilateral or bilateral rudimentary lumbar ribs, were observed in 22.2% of the fetuses at 30 mg/kg were observed. The degree of ossification was significantly reduced in the litters of dams treated with ≥ 10 mg/kg of test chemical in main study. Therefore, NOAEL was considered to be 30 mg/kg bw when Wistar female rat were treated with test chemical orally by gavage from day 7 to 17.

 

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