5-(aminosulphonyl)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-methoxybenzamide monohydrochloride

Endpoint summary

Description of key information

No adverse effects were observed after subacute and subchronic levosulpiride administration.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Guideline:

other: not specified

GLP compliance:

not specified

Rats, rabbits and dogs were used for subacute toxicity trials. Haematology and blood chemistry analyses have been selected to have an overall picture of the treatment effects on metabolism, on liver and renal functions and on complete blood count. The necropsy was carried out on major organs and apparatuses. This was performed on each animal, while each organ was subjected to histologic examination (See Figure). The subacute oral administration of levosulpiride in rats at 150-300 mg/kg for 12 weeks is well tolerated as shown by the haematology, blood chemistry and urine analysis, and does not significantly differ from controls. There are, however, a slight reduction in body weight and food consumption and some variations in liver function at the highest dosage (300 mg/kg) The subacute administration of levosulpiride by subcutaneous route in rats at 12.5-25 mg/kg/day for 12 weeks is well-tolerated as shown by laboratory analysis. A slight drop in body weight and variations in liver functions were documented with highest dosage (50 mg/kg/day). Similar results were obtained by studying the effects of the subacute oral (125-250 mg/kg/day for 12 weeks) or intramuscular (6.25-12.5 mg/kg/day) administration of levosulpiride in rabbits. In another trial the subacute oral administration of levosulpiride in rats for 13 weeks at 25, 150 and 900 mg/kg/day and racemic sulpiride at 50, 300 and 1800 mg/kg/day, no toxic effect was identified for either compound. However, findings obtained for both tested compounds, notably clinical signs, clinical pathology and mammary gland/vaginal changes are considered to be related to the exaggerated pharmacological action of the compounds. The only toxic effect noted was mortality among females receiving the highest treatment level of racemic sulpiride. In particular, two females receiving the highest dose of racemic sulpiride died during the course of the study. These deaths as a result of treatment cannot be excluded. Clinical signs of somnolence were noted among rats of the highest dose groups of either test substance, but they were predominant among females, particularly those treated with racemic sulpiride. Blood chemistry investigations showed a decrease in creatinine kinase among males receiving racemic sulpiride after 13 weeks of treatment. This decrease was still apparent at the end of the recovery phase, particularly in males receiving the middle and highest dose levels. Indeed, females receiving racemic sulpiride and rats of both sexes receiving levosulpiride were not affected. Several minor differences were noted between control and treated rats in pituitary and adrenal gland weights, vagina/mammary gland hyperplasia and vaginal mucification. It is considered that these changes, which show a marked degree of consistency for both L- and racemic sulpiride, reflect a physiological response to treatment. These changes could be originated from an increase in circulating prolactin concentration. It is known that treatment with dopamine D2 receptor antagonist (such as L- or racemic sulpiride) may cause a blockade of the tubero-infundibular pathway, in which dopamine is believed to act physiologically, via D2-receptors, as an inhibitor of prolactin secretion. The result of this blockade is responsible for an increase in circulating prolactin. It could be considered that an increased circulating level of this hormone could promote the observed vagina/mammary gland hyperplasia and vaginal mucification and may also give rise to the slight changes in pituitary and adrenal gland weights. L- and racemic sulpiride were administered orally (25-200 mg/kg), as capsules, to pure-bred beagle dogs for a period of 13 weeks. The study consisted of six groups, each containing three male and three female or five male and five female dogs. An additional group including five male and five female dogs served as control. Mortality did not occur in any experimental group. Initiation of treatment with L- or racemic sulpiride was associated in most dogs with the following clinical signs: decreased activity, tremor, abnormal gait, stereotyped behaviour, erythema of the mucous membranes of the buccal cavity, and salivation. Treatment with either compound at 200 mg/kg was associated in some dogs with collapse, ptosis, deep respiration and/or bradypnea. Vomiting was also recorded in some dogs treated with either compound; however, in view of the incidence and distribution throughout the groups, no definite association with treatment could be made. In view of the persistence of several of these signs and since animals from all treatment groups were affected, a decision was made to reduce the daily dose of each group by half from day 7. With the exception of salivation, decreased activity and ptosis (L- or racemic sulpiride, 100-200 mg/kg only), the clinical signs described above disappear within 1 or 2 weeks of reducing the dose levels. From the beginning of week 3 slight to moderate mammary development is detected in females receiving either L- or racemic sulpiride. The degree of development is similar for both compounds and shows no relationship to dose. There were also documented: a transient reduction in food consumption during week 1 (levosulpiride or racemic sulpiride, 100 or 200 mg/kg); a slight, transient loss in body weight during week 1 (levosulpiride 200 mg/kg, racemic sulpiride 100-200 mg/kg); increases in plasma cholesterol and phospholipid concentrations during weeks 7 and/or 13, without any relationship to dose. No treatment related change was documented in haematology or urine profiles. A clear reduction in prostate weight is apparent in males treated with L- or racemic sulpiride at all dose. The microscopic study documented hyperplasia and active secretion of the mammary glands of treated females, and atrophy of the prostate glands of treated males.

Conclusions:

Although treatment related effects can be observed after oral sulpiride administration, they do not support the classification as STOT RE in accordance with Regulation (EC) 1272/2008.

Executive summary:

Rats, rabbits and dogs were used for subacute toxicity trials. Haematology and blood chemistry analyses have been selected to have an overall picture of the treatment effects on metabolism, on liver and renal functions and on complete blood count. The necropsy was carried out on major organs and apparatuses. This was performed on each animal, while each organ was subjected to histologic examination (See Figure). The subacute oral administration of levosulpiride in rats at 150-300 mg/kg for 12 weeks is well tolerated as shown by the haematology, blood chemistry and urine analysis, and does not significantly differ from controls. There are, however, a slight reduction in body weight and food consumption and some variations in liver function at the highest dosage (300 mg/kg) The subacute administration of levosulpiride by subcutaneous route in rats at 12.5-25 mg/kg/day for 12 weeks is well-tolerated as shown by laboratory analysis. A slight drop in body weight and variations in liver functions were documented with highest dosage (50 mg/kg/day). Similar results were obtained by studying the effects of the subacute oral (125-250 mg/kg/day for 12 weeks) or intramuscular (6.25-12.5 mg/kg/day) administration of levosulpiride in rabbits. In another trial the subacute oral administration of levosulpiride in rats for 13 weeks at 25, 150 and 900 mg/kg/day and racemic sulpiride at 50, 300 and 1800 mg/kg/day, no toxic effect was identified for either compound. However, findings obtained for both tested compounds, notably clinical signs, clinical pathology and mammary gland/vaginal changes are considered to be related to the exaggerated pharmacological action of the compounds. The only toxic effect noted was mortality among females receiving the highest treatment level of racemic sulpiride. In particular, two females receiving the highest dose of racemic sulpiride died during the course of the study. These deaths as a result of treatment cannot be excluded. Clinical signs of somnolence were noted among rats of the highest dose groups of either test substance, but they were predominant among females, particularly those treated with racemic sulpiride. Blood chemistry investigations showed a decrease in creatinine kinase among males receiving racemic sulpiride after 13 weeks of treatment. This decrease was still apparent at the end of the recovery phase, particularly in males receiving the middle and highest dose levels. Indeed, females receiving racemic sulpiride and rats of both sexes receiving levosulpiride were not affected. Several minor differences were noted between control and treated rats in pituitary and adrenal gland weights, vagina/mammary gland hyperplasia and vaginal mucification. It is considered that these changes, which show a marked degree of consistency for both L- and racemic sulpiride, reflect a physiological response to treatment. These changes could be originated from an increase in circulating prolactin concentration. It is known that treatment with dopamine D2 receptor antagonist (such as L- or racemic sulpiride) may cause a blockade of the tubero-infundibular pathway, in which dopamine is believed to act physiologically, via D2-receptors, as an inhibitor of prolactin secretion. The result of this blockade is responsible for an increase in circulating prolactin. It could be considered that an increased circulating level of this hormone could promote the observed vagina/mammary gland hyperplasia and vaginal mucification and may also give rise to the slight changes in pituitary and adrenal gland weights. L- and racemic sulpiride were administered orally (25-200 mg/kg), as capsules, to pure-bred beagle dogs for a period of 13 weeks. The study consisted of six groups, each containing three male and three female or five male and five female dogs. An additional group including five male and five female dogs served as control. Mortality did not occur in any experimental group. Initiation of treatment with L- or racemic sulpiride was associated in most dogs with the following clinical signs: decreased activity, tremor, abnormal gait, stereotyped behaviour, erythema of the mucous membranes of the buccal cavity, and salivation. Treatment with either compound at 200 mg/kg was associated in some dogs with collapse, ptosis, deep respiration and/or bradypnea. Vomiting was also recorded in some dogs treated with either compound; however, in view of the incidence and distribution throughout the groups, no definite association with treatment could be made. In view of the persistence of several of these signs and since animals from all treatment groups were affected, a decision was made to reduce the daily dose of each group by half from day 7. With the exception of salivation, decreased activity and ptosis (L- or racemic sulpiride, 100-200 mg/kg only), the clinical signs described above disappear within 1 or 2 weeks of reducing the dose levels. From the beginning of week 3 slight to moderate mammary development is detected in females receiving either L- or racemic sulpiride. The degree of development is similar for both compounds and shows no relationship to dose. There were also documented: a transient reduction in food consumption during week 1 (levosulpiride or racemic sulpiride, 100 or 200 mg/kg); a slight, transient loss in body weight during week 1 (levosulpiride 200 mg/kg, racemic sulpiride 100-200 mg/kg); increases in plasma cholesterol and phospholipid concentrations during weeks 7 and/or 13, without any relationship to dose. No treatment related change was documented in haematology or urine profiles. A clear reduction in prostate weight is apparent in males treated with L- or racemic sulpiride at all dose. The microscopic study documented hyperplasia and active secretion of the mammary glands of treated females, and atrophy of the prostate glands of treated males.

Reference 2

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Guideline:

other: not specified

GLP compliance:

not specified

Chronic toxicity trials were carried out in rats, rabbits and dogs for 180 days. Analyses regarding haematology and blood chemistry were selected to have an overall picture, within limits of the effects from treatment on metabolism, on liver function, on renal function, and on complete blood count. The necroscopy was carried out on major organs and apparatuses and was performed on each animal and on each organ by microscopy. The doses used were 10, 20 or 30 mg/kg/day subcutaneously or 50 or 100 mg/kg/day orally for rats, 5, 10 or 15 mg/kg/day intramuscularly for rabbits, and 50 or 100 mg/kg/day orally for dogs. In the study on 120 rats six animals died during the trials. The necroptic exam revealed that all six animals had bronchopulmonary complications affecting both lungs. This was unrelated to the drug administration. Only in the group of rats treated with the dose of 30 mg/kg/day by subcutaneous route there was a mild reduction in weight gain with a slight decrease in food consumption. The haematology and blood chemistry analyses have shown that treatment with levosulpiride subcutaneously at 10-20 mg/kg/day for 190 days is well tolerated in rats. The findings of the pathologic and histopathologic exams in the treated animals were unremarkable (See Figure). In the study carried out on rats treated for 180 days with 50-100 mg/kg/day of levosulpiride by oral route, the general health of all animals in all groups remained normal. From a behavioural point of view there was no difference between the groups treated with levosulpiride and the control group. No change in urine analyses were noted in spite of a weight gain trend. This shows that levosulpiride neither determines renal damage, nor influences weight gain after chronic use. The white cell count and the complete blood count, as well as the weight, necroptic and histologic examinations of internal organs carried out in treated animals and in controls, excluded any damage caused by levosulpiride. In trials carried out in rabbits there was a mild, not statistically significant decline in growth compared to controls in the group with the highest dosage (15 mg/kg/day). Haematology, blood chemistry analyses and gross pathologic, histopathologic analyses have shown that treatment with levosulpiride at 5, 10 or 15 mg/kg/day by intramuscular route for 180 days is well tolerated in rabbits. In the study carried out on dogs treated for 180 days with 50-100 mg/kg/day of levosulpiride by oral route, none of the treated animals had behavioural modifications worth noting. Even in the group receiving the highest dose provoked no episode of gastrointestinal intolerance, or symptoms linked to neurotoxicity. No change in blood cell count, blood chemistry, urine composition and body weight, which could be linked to levosulpiride use, was documented. The necroptic and histologic evaluations showed no gross anatomical or microscopic pathologies in the major organs.

Conclusions:

Although treatment related effects can be observed after oral sulpiride administration, they do not support the classification as STOT RE in accordance with Regulation (EC) 1272/2008.

Executive summary:

Chronic toxicity trials were carried out in rats, rabbits and dogs for 180 days. Analyses regarding haematology and blood chemistry were selected to have an overall picture, within limits of the effects from treatment on metabolism, on liver function, on renal function, and on complete blood count. The necroscopy was carried out on major organs and apparatuses and was performed on each animal and on each organ by microscopy. The doses used were 10, 20 or 30 mg/kg/day subcutaneously or 50 or 100 mg/kg/day orally for rats, 5, 10 or 15 mg/kg/day intramuscularly for rabbits, and 50 or 100 mg/kg/day orally for dogs. In the study on 120 rats six animals died during the trials. The necroptic exam revealed that all six animals had bronchopulmonary complications affecting both lungs. This was unrelated to the drug administration. Only in the group of rats treated with the dose of 30 mg/kg/day by subcutaneous route there was a mild reduction in weight gain with a slight decrease in food consumption. The haematology and blood chemistry analyses have shown that treatment with levosulpiride subcutaneously at 10-20 mg/kg/day for 190 days is well tolerated in rats. The findings of the pathologic and histopathologic exams in the treated animals were unremarkable (See Figure). In the study carried out on rats treated for 180 days with 50-100 mg/kg/day of levosulpiride by oral route, the general health of all animals in all groups remained normal. From a behavioural point of view there was no difference between the groups treated with levosulpiride and the control group. No change in urine analyses were noted in spite of a weight gain trend. This shows that levosulpiride neither determines renal damage, nor influences weight gain after chronic use. The white cell count and the complete blood count, as well as the weight, necroptic and histologic examinations of internal organs carried out in treated animals and in controls, excluded any damage caused by levosulpiride. In trials carried out in rabbits there was a mild, not statistically significant decline in growth compared to controls in the group with the highest dosage (15 mg/kg/day). Haematology, blood chemistry analyses and gross pathologic, histopathologic analyses have shown that treatment with levosulpiride at 5, 10 or 15 mg/kg/day by intramuscular route for 180 days is well tolerated in rabbits. In the study carried out on dogs treated for 180 days with 50-100 mg/kg/day of levosulpiride by oral route, none of the treated animals had behavioural modifications worth noting. Even in the group receiving the highest dose provoked no episode of gastrointestinal intolerance, or symptoms linked to neurotoxicity. No change in blood cell count, blood chemistry, urine composition and body weight, which could be linked to levosulpiride use, was documented. The necroptic and histologic evaluations showed no gross anatomical or microscopic pathologies in the major organs.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

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

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

Justification for classification or non-classification

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