Thiosemicarbazide

Endpoint summary

Description of key information

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, NOAEL value was considered to be 2 mg/kg/day for thiosemicarbazide.

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

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

other: publication

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data is from authoritative database: Japan Chemicals Collaborative Knowledge 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

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

M: 42days
F: 42 - 50 days (from 14 days before mating to day 4 of lactation)

Frequency of treatment:

Daily

Remarks:

Doses / Concentrations:
0, 0.4, 2, 10 mg/kg/day
Basis:
nominal in water

No. of animals per sex per dose:

Total: 136
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: 10 male, 10 female
10 mg/kg/day: 10 male, 10 female

Control animals:

yes, concurrent vehicle

Details on study design:

Rationale for selecting satellite groups: 10 male and 10 female rat for control and recovery group
- Post-exposure recovery period in satellite groups: 14 days

Observations and examinations performed and frequency:

Cage side observations were performed

Other examinations:

Organ weight:
Absolute and relative Liver, kidney and thymus weight were recorded.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Mortality: One female rat died at 10 mg/kg/day dose group as compared to control. Clinical signs: 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.

Mortality:

mortality observed, treatment-related

Description (incidence):

Mortality: One female rat died at 10 mg/kg/day dose group as compared to control. Clinical signs: 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 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):

Food consumption: No effect was observed on food consumption of treated rats as compared to control. Compound intake: No data available

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

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

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Increase in T-Cho level was observed in male rats in 10 mg/kg/day as compared to control.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

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

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Increase absolute and relative liver and kidney weight and Decrease in absolute and relative thymus weight were observed in male rats at 10 mg/kg/day does group as compared to control.

Gross pathological findings:

not specified

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 does group as compared to control.

Details on results:

NOAEL value was considered to be 2 mg/kg/day for thiosemicarbazide in Crj:CD (SD) male and female rats.

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

Critical effects observed:

not specified

NOAEL value was considered to be 2 mg/kg/day for thiosemicarbazide in Crj:CD (SD) male and female rats.

Conclusions:

NOAEL value was considered to be 2 mg/kg/day for thiosemicarbazide in Crj:CD (SD) male and female rats.

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). No effect 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 T-Cho 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. Therefore, NOAEL was considered to be 2 mg/kg/day when Crj:CD (SD) male and female rats were treated withHydrazinecarbothioamide orally by gavage.

Endpoint conclusion

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: Japan Chemicals Collaborative Knowledge Database

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

Repeated dose toxicity: Oral

Studies for repeated dose toxicity: oral route from reliable sources having Klimisch rating 2 were reviewed for the target substance.

The summary of the results are presented below:

Sr. No	End point	Value	Species	Route	Duration	Effects	Remarks
1.	NOAEL	2 mg/ kg bw/ d	Rat	Oral: gavage	50 days	No adverse effect on survival, clinical sign, body weight, food consumption, urinalysis, haematology, clinical chemistry, organ weight and histopathology.	Experimental data for target chemical
2.	NOAEL         NOAEL	1 mg/ kg bw/ d (male)     5 mg/ kg bw/ d (female)	Rat	Oral: gavage	42-50 days	No adverse effect on clinical sign, body weight, food consumption, haematology, clinical chemistry, organ weight and histopathology	Experimental data for target chemical

 

Based on the studies summarized in the above table it can be observed that NOAEL value varies from 1-5 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

 

Since no effective dose value (NOAEL) is 5 mg/Kg bw/d thus based on this value it can be concluded that substance is considered to be not toxic to repeated dose via oral route for the above mentioned dose.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
NOAEL value was considered to be 2 mg/kg/day for thiosemicarbazide in Crj:CD (SD) male and female rats.