3α,7α-dihydroxy-12-oxo-5β-cholan-24-oic acid

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

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.

Data source

Reference

Reference Type:

publication

Title:

Modified One-Generation Reproduction Study Of Ursodeoxycholic Acid In Rats And Its Subchronic Toxicity In The F1 Offspring

Author:

Stìtinová V et al.

Year:

2003

Bibliographic source:

Toxicol Lett,144, (1), S109

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Modified One-Generation Reproduction Study

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Ursodeoxycholic acid

EC Number:

204-879-3

EC Name:

Ursodeoxycholic acid

Cas Number:

128-13-2

IUPAC Name:

3,7-dihydroxycholan-24-oic acid

Test animals

Species:

rat

Strain:

not specified

Administration / exposure

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

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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.

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

no data

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

no data

Basis for effect level:

other: developmental toxicity

Results (fetuses)

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.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

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.