Sulpiride

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Levosulpiride does not cause any adverse effect to reproduction. Other studies suggest that sulpiride can alter reproductive function in female offspring rats and may impact the reproductive development of male rats: the testes seem to be the main target organ at adulthood.

Link to relevant study records

Reference

Reference 1

Endpoint:

fertility, other

Remarks:

reproductive development of female offspring

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

abstract

Qualifier:

no guideline followed

Principles of method if other than guideline:

The aim of the study was to investigate whether maternal exposure to Sulpiride during lactation could impair reproductive development of female offspring.

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

Sulpiride and sulpiride HCl are expected to be similar for this endpoint.

Species:

rat

Strain:

not specified

Sex:

female

Route of administration:

oral: gavage

Vehicle:

water

Duration of treatment / exposure:

The dams were treated throughout the lactation period.

Frequency of treatment:

Daily.

Dose / conc.:

2.5 mg/kg bw/day (nominal)

Remarks:

SUL 2.5mg group

Dose / conc.:

25 mg/kg bw/day (nominal)

Remarks:

SUL 25mg group

Control animals:

yes, concurrent vehicle

Litter observations:

During early life, body weight, anogenital distance, and vaginal opening were analyzed on the female offspring. In adulthood, estrous cycle, sexual behavior, estrogen levels as well as the weight of the reproductive organs were evaluated.

Details on results:

There were no differences regarding body weight, anogenital distance, puberty onset, frequency and duration of the estrous cycle and estradiol levels on female offspring. Nonetheless, there were changes in sexual behavior. There was an increase in the number of observations in reflex magnitude 0 (absence of lordosis) and reflex magnitude 2 as well as a reduction of reflex magnitude 3 in the rats of SUL 25mg group in relation to the Control group, suggesting a decrease in sexual receptivity of these animals.

Conclusions:

Study results suggest that maternal exposure to Sulpiride can alter reproductive function in female offspring rats.

Executive summary:

The dams were treated daily by gavage with Sulpiride doses of 2.5mg/Kg (SUL 2.5mg group) and 25mg/Kg (SUL 25mg group), or distilled water (Control group) throughout the lactation period. During early life, body weight, anogenital distance, and vaginal opening were analyzed on the female offspring. In adulthood, estrous cycle, sexual behavior, estrogen levels as well as the weight of the reproductive organs were evaluated. There were no differences regarding body weight, anogenital distance, puberty onset, frequency and duration of the estrous cycle and estradiol levels on female offspring. Nonetheless, there were changes in sexual behavior. There was an increase in the number of observations in reflex magnitude 0 (absence of lordosis) and reflex magnitude 2 as well as a reduction of reflex magnitude 3 in the rats of SUL 25mg group in relation to the Control group, suggesting a decrease in sexual receptivity of these animals. These results demonstrate that maternal exposure to Sulpiride can alter reproductive function in female offspring rats.

Reference 2

Endpoint:

fertility, other

Remarks:

male offspring reproductive development

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

abstract

Qualifier:

no guideline followed

Principles of method if other than guideline:

The aim of the study was to evaluate if maternal exposure to sulpiride during lactation could disrupt maternal care and/or male offspring reproductive development.

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

Sulpiride and sulpiride HCl are expected to be similar for this endpoint.

Species:

rat

Strain:

Wistar

Sex:

female

Route of administration:

oral: gavage

Vehicle:

water

Duration of treatment / exposure:

The dams were treated during lactation.

Frequency of treatment:

Daily

Dose / conc.:

2.5 mg/kg bw/day (nominal)

Dose / conc.:

25 mg/kg bw/day (nominal)

No. of animals per sex per dose:

20 dams/dose level

Control animals:

yes, concurrent vehicle

Parental animals: Observations and examinations:

Maternal behavior was analyzed on lactational days 5 and 10.

Litter observations:

Reproductive and behavioral parameters were analyzed at different time points.

Body weight, food intake and general activity in the open-field (data not shown) of dams during lactation were unaffected by sulpiride treatment. Sulpiride treatment did not impair maternal care.

At postnatal day 90, a reduction in testis weight, volume of seminiferous tubule and histopathological alterations such as an increased percentage of abnormal seminiferous tubules were observed.

Conclusions:

Study results show that maternal exposure to sulpiride during lactation may impact the reproductive development of male rats and the testes seem to be the main target organ at adulthood.

Executive summary:

The dams were treated daily (gavage) with Sulpiride (SUL) 2.5mg/kg or 25mg/kg during lactation. Maternal behavior was analyzed on lactational days 5 and 10. In offspring, reproductive and behavioral parameters were analyzed at different time points. SUL treatment did not impair maternal care, but caused testicular damage in male offspring. At postnatal day 90, a reduction in testis weight, volume of seminiferous tubule and histopathological alterations such as an increased percentage of abnormal seminiferous tubules were observed. Data shows that maternal exposure to SUL during lactation may impact the reproductive development of male rats and the testes seem to be the main target organ at adulthood.

Reference 3

Endpoint:

screening for reproductive / developmental toxicity

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

The oral administration of levosulpiride in rats at 75, 150 or 300 mg/kg/day is without direct effect on fertility, reproduction or organogenesis; more specifically, the administration of levosulpiride before coupling and 13 days after coupling showed that fertility in rats was unchanged, neither time periods nor sequence of gestation modified, newborn vitality was unaffected, no apparent damage to suckling occurred, and either preimplant or post-implant loss remained unchanged. Moreover, in the second generation coming from the zero generation treated with levosulpiride the newborn vitality overlapped with controls. The oral administration of levosulpiride at 10-25 mg/kg/day in rats and 25-50 mg/kg/day in rabbits during organogenesis caused no statistically significant change in weight gain by pregnant animals, in the number of foetal implants, in the number of dead or undeveloped foetuses, and in the weight of foetal offspring from animals treated compared to controls. In addition, some malformations were observed in treated rats and rabbits as well as in controls. Therefore, there is no substantial difference between control groups and treated animals. Teratogenic process in the two tested animal species can be excluded. Levosulpiride administered at dose of 75, 150 or 300 mg/kg/day by oral route in the final period of gestation and during the 21 days of suckling in rats neither changes fertility or gestation indices, nor modify newborn vitality indices. However, all treated groups have suckling indices somewhat lower than controls. The finding does not mean that there is decreased milk production following treatment. On the contrary, there is an increase in production that leads to better nutrition when there are many young and appearance of breast disease (congestion, inflammation) or when the young are few. These findings may be explained by the fact that levosulpiride under the right endocrine conditions and particularly at the end of pregnancy, induces an increase in milk production.

Conclusions:

Study results show that levosulpiride does not cause any adverse effect to reproduction. An increase of milk production was observed following treatment.

Executive summary:

The oral administration of levosulpiride in rats at 75, 150 or 300 mg/kg/day is without direct effect on fertility, reproduction or organogenesis; more specifically, the administration of levosulpiride before coupling and 13 days after coupling showed that fertility in rats was unchanged, neither time periods nor sequence of gestation modified, newborn vitality was unaffected, no apparent damage to suckling occurred, and either preimplant or post-implant loss remained unchanged. Moreover, in the second generation coming from the zero generation treated with levosulpiride the newborn vitality overlapped with controls. The oral administration of levosulpiride at 10-25 mg/kg/day in rats and 25-50 mg/kg/day in rabbits during organogenesis caused no statistically significant change in weight gain by pregnant animals, in the number of foetal implants, in the number of dead or undeveloped foetuses, and in the weight of foetal offspring from animals treated compared to controls. In addition, some malformations were observed in treated rats and rabbits as well as in controls. Therefore, there is no substantial difference between control groups and treated animals. Teratogenic process in the two tested animal species can be excluded. Levosulpiride administered at dose of 75, 150 or 300 mg/kg/day by oral route in the final period of gestation and during the 21 days of suckling in rats neither changes fertility or gestation indices, nor modify newborn vitality indices. However, all treated groups have suckling indices somewhat lower than controls. The finding does not mean that there is decreased milk production following treatment. On the contrary, there is an increase in production that leads to better nutrition when there are many young and appearance of breast disease (congestion, inflammation) or when the young are few. These findings may be explained by the fact that levosulpiride under the right endocrine conditions and particularly at the end of pregnancy, induces an increase in milk production.

Effect on fertility: via oral route

Quality of whole database:

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

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

Levosulpiride does not cause any adverse effect to development.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

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

Species:

rat

Strain:

not specified

The oral administration of levosulpiride in rats at 75, 150 or 300 mg/kg/day is without direct effect on fertility, reproduction or organogenesis; more specifically, the administration of levosulpiride before coupling and 13 days after coupling showed that fertility in rats was unchanged, neither time periods nor sequence of gestation modified, newborn vitality was unaffected, no apparent damage to suckling occurred, and either preimplant or post-implant loss remained unchanged. Moreover, in the second generation coming from the zero generation treated with levosulpiride the newborn vitality overlapped with controls. The oral administration of levosulpiride at 10-25 mg/kg/day in rats and 25-50 mg/kg/day in rabbits during organogenesis caused no statistically significant change in weight gain by pregnant animals, in the number of foetal implants, in the number of dead or undeveloped foetuses, and in the weight of foetal offspring from animals treated compared to controls. In addition, some malformations were observed in treated rats and rabbits as well as in controls. Therefore, there is no substantial difference between control groups and treated animals. Teratogenic process in the two tested animal species can be excluded. Levosulpiride administered at dose of 75, 150 or 300 mg/kg/day by oral route in the final period of gestation and during the 21 days of suckling in rats neither changes fertility or gestation indices, nor modify newborn vitality indices. However, all treated groups have suckling indices somewhat lower than controls. The finding does not mean that there is decreased milk production following treatment. On the contrary, there is an increase in production that leads to better nutrition when there are many young and appearance of breast disease (congestion, inflammation) or when the young are few. These findings may be explained by the fact that levosulpiride under the right endocrine conditions and particularly at the end of pregnancy, induces an increase in milk production.

Conclusions:

Study results show that levosulpiride does not cause any adverse effect to development.

Executive summary:

The oral administration of levosulpiride in rats at 75, 150 or 300 mg/kg/day is without direct effect on fertility, reproduction or organogenesis; more specifically, the administration of levosulpiride before coupling and 13 days after coupling showed that fertility in rats was unchanged, neither time periods nor sequence of gestation modified, newborn vitality was unaffected, no apparent damage to suckling occurred, and either preimplant or post-implant loss remained unchanged. Moreover, in the second generation coming from the zero generation treated with levosulpiride the newborn vitality overlapped with controls. The oral administration of levosulpiride at 10-25 mg/kg/day in rats and 25-50 mg/kg/day in rabbits during organogenesis caused no statistically significant change in weight gain by pregnant animals, in the number of foetal implants, in the number of dead or undeveloped foetuses, and in the weight of foetal offspring from animals treated compared to controls. In addition, some malformations were observed in treated rats and rabbits as well as in controls. Therefore, there is no substantial difference between control groups and treated animals. Teratogenic process in the two tested animal species can be excluded. Levosulpiride administered at dose of 75, 150 or 300 mg/kg/day by oral route in the final period of gestation and during the 21 days of suckling in rats neither changes fertility or gestation indices, nor modify newborn vitality indices. However, all treated groups have suckling indices somewhat lower than controls. The finding does not mean that there is decreased milk production following treatment. On the contrary, there is an increase in production that leads to better nutrition when there are many young and appearance of breast disease (congestion, inflammation) or when the young are few. These findings may be explained by the fact that levosulpiride under the right endocrine conditions and particularly at the end of pregnancy, induces an increase in milk production.

Effect on developmental toxicity: via oral route

Quality of whole database:

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

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Overall, data available are deemed to be inconclusive for classification.