Registration Dossier

Administrative data

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:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Data have been obtained by a secondary source (RTECS database) and it was not possible to assess the quality of the original source.
Reference:
Composition 0
Qualifier:
no guideline available
Principles of method if other than guideline:
not specified.
GLP compliance:
not specified
Test material information:
Composition 1
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.
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.
Reference:
Composition 0
Qualifier:
no guideline available
Principles of method if other than guideline:
Modified One-Generation Reproduction Study
GLP compliance:
not specified
Test material information:
Composition 1
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.
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.