Thiosemicarbazide

Carcinogenicity

Description of key information

The treatments with Thiocarbamylhydrazine resulted in no significantly increased tumor incidence relative to control incidence. The No observed Adverse Effect Level (NOAEL) for Thiocarbamylhydrazine is considered to be 0.0312% (44.57mg/kg bw/ day).

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data is from peer reviewed publication

Qualifier:

according to guideline

Guideline:

other: as below

Principles of method if other than guideline:

Carcinogenic effect of was studied for the lifelong administration of Thiocarbamylhydrazine in Mice

GLP compliance:

not specified

Species:

mouse

Strain:

Swiss

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Colony randomly bred since 1951
- Age at study initiation:
For conc. 0.0312%- 6 week (43 days) old
For conc. 0.0156%- 6 week (46 days) old
Control rats: 5 weeks
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: housed in plastic cages with granular cellulose bedding
- Diet (e.g. ad libitum): Wayne Lab-blox diet in regular pellets
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: No data available

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%):No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available

IN-LIFE DATES: From: To: No data available

Route of administration:

oral: drinking water

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): Solution were prepared 3 times weekly
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: The solutions were contained in brown bottles because of the possible light sensitivity of the chemicals.

VEHICLE
- Justification for use and choice of vehicle (if other than water): No data available
- Concentration in vehicle: 0, 0.0156 and 0.0312% (44.57 & 22.29 mg/Kg bw/day)
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Life time (130-140 weeks)

Frequency of treatment:

Daily

Post exposure period:

No data available

Remarks:

Doses / Concentrations:
0, 0.0156 and 0.0312% (44.57 & 22.29 mg/Kg bw/day)
Basis:
no data

No. of animals per sex per dose:

50/sex/dose
Total: 300
0 mg/Kg bw/day: 50 male and 50 female
22.29 mg/Kg bw/day: 50 male and 50 female
44.57 mg/Kg bw/day: 50 male and 50 female

Control animals:

yes

Details on study design:

- Dose selection rationale: Five dose levels of TCH 0.5, 0.25, 0.125, 0.0625 and 0.0312% were administered in the drinking water for 35 days to Swiss mice. By taking into account four parameters: survival rates, body weights, chemical consumption levels and histological changes, the 0.0312% doses for both chemicals were chosen for the lifelong treatments. These doses were, however, subsequently found to be
too toxic in the chronic studies, and additional lower doses of 0.0156% were started separately. This toxicity technique was developed in this laboratory.
- Rationale for animal assignment (if not random): Animals were separated according to sex
- Rationale for selecting satellite groups: No data available
- Post-exposure recovery period in satellite groups: No data available
- Section schedule rationale (if not random): No data available

Positive control:

No data available

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Weekly
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data available

DERMAL IRRITATION (if dermal study): No data available
- Time schedule for examinations: No data available

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: 3 times weekly

OPHTHALMOSCOPIC EXAMINATION: No data - Time schedule for examinations: No data
- Dose groups that were examined: No data

HAEMATOLOGY: No data
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined.

CLINICAL CHEMISTRY: No data
- Time schedule for collection of blood:
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined.

URINALYSIS: No data
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined.

NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data

OTHER:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, All organs were examined macroscopically and fixed in 10% buffered formalin.

HISTOPATHOLOGY: Yes, Histological studies were done on the liver, spleen, kidneys, bladder, thyroid, heart, pancreas, testes, ovaries, brain, nasal turbinals, at least 4 lobes of the lungs of each mouse, and on those organs with gross pathological changes. Sections from these tissues were stained with hematoxylin and eosin, and examined by light microscopy.

Statistics:

The statistical analysis was carried out by Fisher's exact probability test 2 X 2 tables

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Clinical signs: No data available Mortality: The treatments at the higher dose level of 0.0312% (44.57mg/kg) substantially shortened the survivals in both sexes.

Mortality:

mortality observed, treatment-related

Description (incidence):

Clinical signs: No data available Mortality: The treatments at the higher dose level of 0.0312% (44.57mg/kg) substantially shortened the survivals in both sexes.

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

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Dose descriptor:

NOAEL

Effect level:

44.57 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Conclusions:

The treatments with Thiocarbamylhydrazine resulted in no significantly increased tumor incidence relative to control incidence. The No observed Adverse Effect Level (NOAEL) for Thiocarbamylhydrazine is considered to be 0.0312% (44.57mg/kg bw/ day).

Executive summary:

Effects of Lifelong Administration of thiocarbamylhydrazine in were studied in mice.

 

Thiocarbamylhydrazine were separately administered as 0.0312 and 0.0156% (44.57 & 22.29mg/Kg bw/day) solutions in drinking water for life to randomly bred Swiss mice.

 

The consumption of the chemicals resulted in no detectable tumorigenic effects in the treated animals, and it is therefore concluded that these compounds are apparently noncarcinogenic under the present experimental conditions.

 

The treatments with Thiocarbamylhydrazine resulted in no significantly increased tumor incidence relative to control incidence. The No observed Adverse Effect Level (NOAEL) for Thiocarbamylhydrazine is considered to be0.0312% (44.57mg/kg bw/ day).

 

In accordance with the CLP classification, the test material Thiocarbamylhydrazine does not classify as a carcinogen.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

44.57 mg/kg bw/day

Study duration:

chronic

Species:

mouse

Quality of whole database:

Data is from peer reviewed publication

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

On the basis of available information, the substance Thiosemicarbazide is not expected to be carcinogenic in nature.

Additional information

Studies were reviewed for carcinogenicity from reliable sources having Klimisch rating 2

The summary of the results are presented below

Sr. No	End point	Value	Species	Route	Effects	Remarks
1.	NOAEL	44.57 mg/ kg bw/ d	Mouse	Oral: drinking water	No significantly increased tumor incidence.	Experimental data for target chemical
2.	NOAEL	3.75 mg/ kg bw/ d	Rat	Oral: feed	Ambiguous carcinogenic effect observed.	Experimental data for target chemical

Based on the studies summarized in the above table it can be observed that the substance is found to be non-carcinogenic in mice whereas it gives ambiguous results in rats.

Justification for selection of carcinogenicity via oral route endpoint:
The treatments with Thiocarbamylhydrazine resulted in no significantly increased tumor incidence relative to control incidence. The No observed Adverse Effect Level (NOAEL) for Thiocarbamylhydrazine is considered to be 0.0312% (44.57mg/kg bw/ day).