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Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels (migrated information)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Published in authoritative database
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
Age at study initiation: 9 weeks old
Route of administration:
oral: gavage
Vehicle:
water
Details on mating procedure:
No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Male: 42 days
Female: 42 - 50 days (from 14 days before mating to day 4 of lactation)

Recovery period:
Males, 14 days
Females (satellite), 14 days
Frequency of treatment:
Daily
Details on study schedule:
No data available
Remarks:
Doses / Concentrations:
0, 0.4, 2, 10 mg/kg/day
Basis:

No. of animals per sex per dose:
Total: 116
0 mg/kg/day: 12 male, 12 female
0.04 mg/kg/day: 12 male, 12 female
2 mg/kg/day: 12 male, 12 female
10 mg/kg/day: 12 male, 12 female
For recovery group
0 mg/kg/day: 5 male
10 mg/kg/day: 5 male
Satellite group:
0 mg/kg/day: 5 female
10 mg/kg/day: 5 female
Control animals:
yes, concurrent vehicle
Parental animals: Observations and examinations:
Cage side observations to observe for mortality
Oestrous cyclicity (parental animals):
Any irregularity in Estrous cyclicity were observed
Implantations, gestation length and parturition were observed in female rats .
Litter observations:
Survival number of offspring or live
offspring at birth, sex ratio, clinical signs, external features and body weights were examined.
Postmortem examinations (parental animals):
Organ weight:
Absolute and relative Liver, kidney and thymus weight were recorded.

Gross pathology: Yes,
Female rats were observed for numbers of corpora lutea or
Implantations were examined.

HISTOPATHOLOGY: Yes
Postmortem examinations (offspring):
Postmortem examinations (offspring)
SACRIFICE: yes, Offspring, On day 4 after birth

GROSS NECROPSY: Yes
Gross abnormalities were examined.

HISTOPATHOLOGY / ORGAN WEIGTHS: Yes
Reproductive indices:
Copulation index, fertility index, delivery index, implantation index and gestation index were examined.
Offspring viability indices:
Viability on day 4 were observed.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
One female rat died at 10 mg/kg/day dose group as compared to control. Tonic convulsion in male and female rats and excessive response to touch or tail pinch were observed in male rats at 10 mg/kg/day dose group as compared to control
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Decrease tendency in the body weight and body weight gain was comparable to that of the control group from day 15 onwards were observed in treatment and recovery at 10 mg/kg/day dose group as compared to control.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Decrease tendency in the body weight and body weight gain was comparable to that of the control group from day 15 onwards were observed in treatment and recovery at 10 mg/kg/day dose group as compared to control.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Atrophy of the thymus in male rat and Pulmonary edama, increase in the karyorrhexis in the white pulp of the spleen, mandibular lymph node and mesenteric lymph node in dead female rats were observed in 10 mg/kg/day
Other effects:
not specified
Reproductive function: oestrous cycle:
effects observed, treatment-related
Description (incidence and severity):
No effect were observed on estrous cycle, copulation index, fertility index, delivery index, gestation length, numbers of corpora lutea or implantations, implantation index, gestation index, parturition and maternal behavior of treated female rats
Reproductive function: sperm measures:
not specified
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
Decrease in live birth index were observed in 10 mg/kg/day treeated female rats as compared to control.
Dose descriptor:
NOAEL
Effect level:
2 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effect on survival, clinical sign, body weight, food consumption, urinalysis, hematology, clinical chemistry, organ weight and histopathology
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Decreased in number of live offspring and viability on day 4 were observed at 10 mg/kg/day dose group as compared to control.
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
Decreased in number of live offspring and viability on day 4 were observed at 10 mg/kg/day dose group as compared to control.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
No changes were observed in body weight
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Jaundice was observed in 1 offspring each at 2 and 10 mg/kg/day. However, the relation to the test substance was not clear, since no similar changes were noted in any other offspring
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
2 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effect on viability index, live birth index and number of live pups
Reproductive effects observed:
not specified

Food consumption:

No effect was observed on food consumption of treated rats as compared to control.

 

Haematology:

No effect was observed on blood hematology of treated rats as compared to control.

 

Clinical chemistry:

Increase in total cholesterol level was observed in male rats in 10 mg/kg/day as compared to control.

 

Urinanalysis:

No effect was observed on urinanalysis of treated rats as compared to control.

Conclusions:
NOAEL was considered to be 2 mg/kg/day for F0 and F1 generation when Crj: CD (SD) male and female rats treated with Hydrazinecarbothioamide
Executive summary:

In a Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD TG422) was conducted. Crj:CD (SD) male and female rats were dosed orally at concentration 0, 0.4, 2, 10 mg/kg/day for 42days (male rats) & 42-50 days (Female-from 14 days before mating to day 4 of lactation). In F0 generation,No effects were observed on food consumption, urinalysis and hematology of treated rats. One female rat died,Tonic convulsion in male and female rat and Excessive response to touch or tail pinch were observed in male rat and Decrease tendency in the body weight were observed in treatment and recovery at10 mg/kg/day dose group trreated rats as compared to control. Similarly,Increase in total cholesterol level and Increase absolute and relative liver and kidney weight and Decrease in absolute and relativethymus weight were observed in male rats at 10 mg/kg/day does group as compared to control. Decrease in absolute and relativethymus weight was observed in male rats at 2 mg/kg/day does group. In addition, Atrophy of the thymus in male rat and Pulmonary edama, Increase in the karyorrhexis in the white pulp of the spleen, mandibular lymph node and mesenteric lymph node in dead female rats were observed in 10 mg/kg/day does group as compared to control.Decrease in live birth index were observed in 10 mg/kg/day treeated female rats as compared to control. In F1 generation, Decreased in number of live offspring and viability on day 4 were observed at 10 mg/kg/day dose group as compared to control. Therefore, NOAEL was considered to be 2 mg/kg/day for F0 and F1 generation when Crj: CD (SD) male and female rats treated with Hydrazinecarbothioamide. orally by gavage.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is from authoritative database
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Studies for reproductive toxicity from reliable sources having Klimisch rating 2 were reviewed

The summary of the results are presented below:

Sr. No

End point

Value

Species

Route

Effects

Remarks

1.     

NOAEL

2 mg/ kg bw/ d

Rat

Oral: gavage

No adverse effect on survival, clinical sign, body weight, food consumption, urinalysis, haematology, clinical chemistry, organ weight and histopathology of parents and No effect on viability index, live birth index and number of live pups

Experimental data for target chemical

2.     

 NOAEL

 

1 mg/ kg bw/ d

Rat

Oral: gavage

No adverse effect on clinical sign, body weight, food consumption, haematology, clinical chemistry, organ weight, gross pathology, histopathology and reproductive effect

Experimental data for target chemical

 

Based on the studies summarized in the above table it can be observed that NOAEL value varies from 1 to 2 mg/Kg bw/ d. in rats. The effects observed on these doses was listed as follows:

 

·        No adverse effect on survival, clinical sign, body weight, food consumption, urinalysis, haematology, clinical chemistry, organ weight and histopathology

·        No effect on viability index, live birth index and number of live pups

·        No adverse effect on clinical sign, body weight, food consumption, haematology, clinical chemistry, organ weight, gross pathology, histopathology and reproductive effect.

 

Since highest no effective dose value (NOAEL) is 2 mg/Kg bw/d thus based on this value it can be concluded that substance is considered to be not toxic to reproduction via oral route for the above mentioned dose.


Short description of key information:
NOAEL was considered to be 2 mg/kg/day for F0 and F1 generation when Crj: CD (SD) male and female rats treated with Hydrazinecarbothioamide

Justification for selection of Effect on fertility via oral route:
NOAEL was considered to be 2 mg/kg/day for F0 and F1 generation when Crj: CD (SD) male and female rats treated with Hydrazinecarbothioamide

Justification for classification or non-classification

On the basis of available information, the substanceThiosemicarbazide is not expected to be reprotoxic in nature.

Additional information