Ursodeoxycholic acid

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

fertility, other

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Remarks:

RTECS database

Qualifier:

no guideline available

Principles of method if other than guideline:

not specified.

GLP compliance:

not specified

Species:

mouse

Strain:

not specified

Sex:

not specified

Route of administration:

oral: unspecified

Type of inhalation exposure (if applicable):

other: not applicable

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

From day 7 to day 12 of pregnancy.

Remarks on result:

not measured/tested

Dose descriptor:

other: TDLo

Generation:

F1

Effect level:

9 000 mg/kg bw (total dose)

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: Effects on Embryo or Fetus. Fetotoxicity (except fetal death) in presence of maternal effects. The numerical dose data is a cumulative amount over the duration of the study.

Reproductive effects observed:

not specified

Conclusions:

The TDLo for fetotoxicity of ursodeoxycholic acid is 9 g/kg bw (total dose).

Executive summary:

After oral administration of ursodeoxycholic acid to pregnant mice from day 7 to day 12 of pregnancy, the TDLo for fetotoxicity is 9 g/kg bw (total dose), in presence of maternal effects.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LOAEL

1 500 mg/kg bw/day

Species:

mouse

Quality of whole database:

No effects on fertility have been reported by repeated dose toxicity studies and the lack of toxicity on fertility is confirmed by the developmental studies and by the high doses at which negative effects have been generally observed. The results of the QSAR study, therefore, have been considered not reliable in a weight of evidence approach. In conclusion, the provided information is considered sufficient to assess the toxicity on fertility of the substance.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Quality of whole database:

Exposure via inhalation route is unlikely and not significant. The substance is solid with very low vapour pressure and it is only used at industrial sites by trained workers, under operative conditions not forming aerosols and dusts and under specific risk control measures (as described in the Exposure Scenarios).

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No effects on fertility have been reported by repeated dose toxicity studies and the lack of toxicity on fertility is confirmed by the developmental studies and by the high doses at which negative effects have been generally observed. The results of the QSAR study, therefore, have been considered not reliable in a weight of evidence approach.

Justification for selection of Effect on fertility via oral route:
Although the original report is not availbale, the toxicological database reporting the information is well recognized.

Justification for selection of Effect on fertility via dermal route:
Exposure of humans via dermal route is unlikely and not significant. The substance is only used at industrial sites by trained workers, wearing suitable protective gloves and clothes, under specific risk control measures (as described in the Exposure Scenarios).

Effects on developmental toxicity

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study is well documented, but no standard protocol have been observed.

Qualifier:

no guideline available

Principles of method if other than guideline:

Modified One-Generation Reproduction Study

GLP compliance:

not specified

Species:

rat

Strain:

not specified

Route of administration:

oral: unspecified

Type of inhalation exposure (if applicable):

other: not applicable

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

A dose of 1000 mg/kg bw was administered to mothers during pregnancy and lactation and to several groups of the F1 offspring (both sexes) for 1, 2 and 3 months while other groups of F1 offspring were treated with the vehicle (polyethylene glycol 400). Control groups received the vehicle (e.g. parental females and their offspring).

Frequency of treatment:

Orally daily doses.

Control animals:

yes

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
Fertility, gestation, maternal toxicity, number of live foetuses per litter and their clinical status were not changed after administration of ursodeoxycholic acid.

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

no data

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

no data

Basis for effect level:

other: developmental toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No evidence of embryolethal or teratogenic effects of ursodeoxycholic acid was found. In animals treated with ursodeoxycholic acid, the weight gain was significantly reduced during suckling period while water consumption was increased. Urine and hematological examinations were not changed. Clinical chemistry determination showed a slight increase in creatinine concentration and elevated plasma levels of ALT and AST. The weight of organs and gross necropsy did not show changes while histopathology showed only a slight higher frequency of single necrosis of hepatocytes in comparison with the control animals.

Remarks on result:

not determinable due to absence of adverse toxic effects

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

The NOAELs for maternal toxicity and developmental toxicity in rat can be estabished at 1000 mg/kg bw/day.

Executive summary:

In a modified one-generation reproduction study of ursodeoxycholic acid in rats, a daily oraldose of 1000 mg/kg bw was administered to mothers during pregnancy and lactation and to several groups of the F1 offspring (both sexes) for 1, 2 and 3 months while other groups of F1 offspring were treated with the vehicle (polyethylene glycol 400). Control groups received the vehicle (e.g. parental females and their offspring).

Fertility, gestation, maternal toxicity, number of live foetuses per litter and their clinical status were not changed after administration of ursodeoxycholic acid.

No evidence of embryolethal or teratogenic effects of ursodeoxycholic acid was found. In animals treated with ursodeoxycholic acid, the weight gain was significantly reduced during suckling period while water consumption was increased. Urine and hematological examinations were not changed. Clinical chemistry determination showed a slight increase in creatinine concentration and elevated plasma levels of ALT and AST. The weight of organs and gross necropsy did not show changes while histopathology showed only a slight higher frequency of single necrosis of hepatocytes in comparison with the control animals.

The NOAELs for maternal toxicity and developmental toxicity can be estabished at 1000 mg/kg bw/day.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Species:

rat

Quality of whole database:

The developmental effects of the substance have been observed only at high doses, with the exception of the effects on the offspring of rabbits, but condisering that this is the only species in which negative effects have been observed at 65 mg/kg bw/day and that the extent of the effects has not been reported, the TDLo value can be considered not relevat for the overall assessment. In conclusion, the provided information is considered sufficient to assess the developmental toxicity of the substance.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Quality of whole database:

Exposure to the substance by inhalation route is unlikely because the substance is for professional use only and suitable respiratory personal protective equipment are adopted to avoid workers exposure.

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Quality of whole database:

Exposure to the substance by dermal route is unlikely because the substance is for professional use only and suitable personal protective equipment are adopted to avoid workers exposure.

Additional information

The developmental effects of the substance have been observed only at high doses, with the exception of the effects on the offspring of rabbits, but considering that this is the only species in which negative effects have been observed at 65 mg/kg bw/day and that the extent of the effects has not been reported, the TDLo value can be considered not relevat for the overall assessment.

Justification for selection of Effect on developmental toxicity: via oral route:
The selected study provides the up-to-date and more completed information on developmental toxicity of the susbtance.

Toxicity to reproduction: other studies

Additional information

In conclusion, effects on fertility and development realted to ursodeoxycholic acid have been observed only at very high doses and, according to the study of Stìtinová V et al. (2003), the NOAELs for maternal toxicity and developmental toxicity can be established at 1000 mg/kg bw/day.

Justification for classification or non-classification

Basing on the overall data and according to Regulation 1272/2008/EC, ursodeoxycholic acid is not considered toxic to reproduction.