Ursodeoxycholic acid

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Link to relevant study records

Reference

Endpoint:

in vitro gene mutation study in bacteria

Remarks:

Type of genotoxicity: other: QSAR prediction

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Mutagenicity was estimated employing three powerful QSAR predictors (ACD/ToxSuite, Leadscope, CAESAR) and one decision rule system (Toxtree), in order to apply a consensus approach and improve the reliability of the predictions. Moreover, experimental results cited in the Australian Public Assessment Report for Ursodeoxycholic acid (2010) support the lack of mutagenicity of the biliary acid.

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Principles of method if other than guideline:

ACD/ToxSuite genotoxicity predictions are provided together with a reliability index which assesses the degree of confidence of the prediction. The reliability index (RI) takes into account the similarity of the tested compound with the training set compounds and the consistency of experimental values for similar compounds.
Leadscope FDA Model Applier considers a Positive Prediction Probability under 0.5 to be negative and a probability greater than or equal to 0.5 to be positive. The reliability of the prediction is evaluated by two parameters: “Model Fragment Count” (which verifies that the test compound contains a significant number of fragments that are present in the prediction model. The prediction is reliable if at least one model fragment is present in the test compound) and “30% Similarity Training Neighbours” Count (which verifies the number of compound structurally similar to the test compound).
CAESAR assesses the reliability of the mutagenicity prediction according to many parameters, e.g. descriptor ranges, chemical similarity index, fragments similarity, …
The mutagenicity of ursodeoxycholic acid was also evaluated according to the Benigni/Bossa rulebase for mutagenicity implemented in Toxtree. The positive or negative mutagenicity is predicted according to decision rules based on the identification of Structural Alerts (SA) for mutagenicity, i.e. molecular functional groups or substructures known to be linked to the mutagenicity activity of chemicals.

GLP compliance:

not specified

Type of assay:

bacterial reverse mutation assay

Species / strain:

S. typhimurium, other: uspecified

Metabolic activation:

not specified

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Vehicle controls validity:

not specified

Untreated negative controls validity:

not specified

Positive controls validity:

not specified

Remarks on result:

other: other: unspecified

Remarks:

Migrated from field 'Test system'.

Conclusions:

Interpretation of results (migrated information):
other: not mutagen

A consensus approach was applied which led to the conclusion that ursodeoxycholic acid is NOT MUTAGEN.

Executive summary:

ACD/Tox Suite predictions for Ursodeoxycholic Acid UDCA and Chenodeoxycholic Acid - CDCA were inconclusive; the predictions for 7 Keto-Lithocholic Acid - 7K-LCA and 12 Keto-Chenodeoxycholic Acid - 12K-CDCA were NOT reliable, while Cholic Acid – CA was predicted borderline, with a positive prediction probability equal to 0.61.

Leadscope predicted all the five biliary acids NEGATIVE.

All CAESAR predictions were reliable and predicted the five biliary acids NEGATIVE.

Toxtree predicted the biliary acids NEGATIVE.

A consensus approach was applied which led to the conclusion that the five biliary acids are NOT MUTAGENS.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Additional information

Additional information from genetic toxicity in vitro:

ACD/Tox Suite, Leadscope, CAESAR and Toxtree led to the conclusion that the five biliary acids are NOT MUTAGEN. Results are supported by the experimental results (Ames test, gene mutation assay at the TK locus in mouse lymphoma L5178Y cells, assay of sister chromatid exchanges in cultured human lymphocytes and micronucleus test in hamsters) cited in the Australian Public Assessment Report for Ursodeoxycholic acid (2010).

Justification for selection of genetic toxicity endpoint
Mutagenicity was estimated employing three powerful QSAR predictors (ACD/ToxSuite, Leadscope, CAESAR) and one decision rule system (Toxtree), in order to apply a consensus approach and improve the reliability of the predictions. Moreover, experimental results cited in the Australian Public Assessment Report for Ursodeoxycholic acid (2010) support the lack of mutagenicity of the biliary acid.

Justification for classification or non-classification

According to regulation 1272/2008/EC, ursodeoxycholic acid is not classified for the mutagenicity.