Sulpiride

Carcinogenicity

Description of key information

Levosulpiride was not found to be carcinogen in both rats and mice.

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:

key study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Guideline:

other: not specified

GLP compliance:

not specified

The oncogenic/carcinogenic toxicity of levosulpiride was tested in 600 Wistar rats and NMRI mice by long-term oral administration. 200 further rats and 200 further mice served as controls. Levosulpiride was given over 104 weeks in rats and 100 weeks in mice in daily dosage of 12.5, 25.0 and 50.0 mg/kg/day in the food. The control rats and mice remained untreated. The final mortality was significantly higher, in respect to controls, in rats and mice treated with levosulpiride at the dose of 50.0 mg/kg/day and it was similar or identic to controls in the groups treated with levosulpiride at doses of 12.5 and 25.0 mg/kg/day. The researches in rats showed that the lowest and medium tested dosage of levosulpiride (12.5 and 25.0 mg/kg/day in the food) were in the range of the estimated good tolerated doses and did not influence the behaviour, the external appearance, the faeces, the mortality, the food and drinking water consumption, the haematological and urinary profiles, the body weight development, the weight of examinated organs, sight, hearing, dentition and the number of palpable masses. The highest dose of levosulpiride (50.0 mg/kg/day in the food) did not modify the behaviour, the external appearance, faeces, the drinking water consumption, the haematological and urinary profiles, sight, hearing, dentition or the number of palpable masses, but it induced a significant decrease of food consumption, of body weight development and organ weights, and a significant increase in SGOT and SGPT. Moreover, in rats of both sexes treated with levosulpiride at all tested doses a significant increase of plasma prolactin and a moderate increase of corticosterone and aldosterone were shown. Macroscopically and microscopically there were no signs of oncogenic properties with all the doses of levosulpiride tested. At histopathologic examinations benign neoplasms of skin (epithelial and connectival turnours), soft tissues (lipomas, angiomas, leiomiomas), thyroid gland (follicular adenomas), ovaries (thecagranulosa cell tumours), liver (adenomas) and adrenal medulla (phaeochromocytomas) were observed. Microscopic alterations of liver were observed only with the highest dose of levosulpiride (50.0 mg/kg/day). With levosulpiride at all doses tested microscopic aspect of hyperactivity of mammary and pituitary glands has been observed. Moreover, in control and treated rats of both sexes aspecific alterations of lungs, kidneys, heart, spleen and liver were documented. Similar results dropped out from the trials on mice by using the same doses of levosulpiride (12.5, 25.0 and 50.0 mg/kg/day in the food).

Conclusions:

Levosulpiride was not found to be carcinogen in both rats and mice.

Executive summary:

The oncogenic/carcinogenic toxicity of levosulpiride was tested in 600 Wistar rats and NMRI mice by long-term oral administration. 200 further rats and 200 further mice served as controls. Levosulpiride was given over 104 weeks in rats and 100 weeks in mice in daily dosage of 12.5, 25.0 and 50.0 mg/kg/day in the food. The control rats and mice remained untreated. The final mortality was significantly higher, in respect to controls, in rats and mice treated with levosulpiride at the dose of 50.0 mg/kg/day and it was similar or identic to controls in the groups treated with levosulpiride at doses of 12.5 and 25.0 mg/kg/day. The researches in rats showed that the lowest and medium tested dosage of levosulpiride (12.5 and 25.0 mg/kg/day in the food) were in the range of the estimated good tolerated doses and did not influence the behaviour, the external appearance, the faeces, the mortality, the food and drinking water consumption, the haematological and urinary profiles, the body weight development, the weight of examinated organs, sight, hearing, dentition and the number of palpable masses. The highest dose of levosulpiride (50.0 mg/kg/day in the food) did not modify the behaviour, the external appearance, faeces, the drinking water consumption, the haematological and urinary profiles, sight, hearing, dentition or the number of palpable masses, but it induced a significant decrease of food consumption, of body weight development and organ weights, and a significant increase in SGOT and SGPT. Moreover, in rats of both sexes treated with levosulpiride at all tested doses a significant increase of plasma prolactin and a moderate increase of corticosterone and aldosterone were shown. Macroscopically and microscopically there were no signs of oncogenic properties with all the doses of levosulpiride tested. At histopathologic examinations benign neoplasms of skin (epithelial and connectival turnours), soft tissues (lipomas, angiomas, leiomiomas), thyroid gland (follicular adenomas), ovaries (thecagranulosa cell tumours), liver (adenomas) and adrenal medulla (phaeochromocytomas) were observed. Microscopic alterations of liver were observed only with the highest dose of levosulpiride (50.0 mg/kg/day). With levosulpiride at all doses tested microscopic aspect of hyperactivity of mammary and pituitary glands has been observed. Moreover, in control and treated rats of both sexes aspecific alterations of lungs, kidneys, heart, spleen and liver were documented. Similar results dropped out from the trials on mice by using the same doses of levosulpiride (12.5, 25.0 and 50.0 mg/kg/day in the food).

Endpoint conclusion

Quality of whole database:

The quality of database is limited as the reliability of the studies cannot be assigned.

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

Overall, data available are conclusive but not sufficient for classification.