Registration Dossier

Administrative data

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

- Ames Test (OECD 471, pre-GLP, K, rel. 2): non mutagenic in S. typhimurium TA 98, , TA 100, TA 1535, TA1537 and E. coli WP2uvrA.

- QSAR prediction (DEREK, s, rel.2): no alerts for mutagenicity
- DNA Repair test (OECD 482, pre-GLP, K, rel.2): not mutagenic

- HL/CAT performed on an analogue substance (OECD 473, GLP, K, rel.1): not clastogenic and not aneugenic

- MLA performed on an analogue substance (OECD 476, GLP, K, rel. 1): not mutagenic

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Genetic toxicity in vivo

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Table 7.6.1/1: Summary of Genetic Toxicity Tests:

 

Test n°

Test guideline / reliability

Focus

Strains tested

Metabolic activation

Test concentration

Statement

1

(Safepharm, 2008)

Ames Test (OECD 471)

K, rel.1

Gene mutation

TA 98,

TA 100,

TA 1535,

TA 1537,

E. coli WP2 uvrA

-S9

+S9

Up to limit concentrations

-S9 / +S9 : non mutagenic

2

(DEREK, 2017)

QSAR prediction

S, rel.2

Gene mutation

bacteria

not applicable

not applicable

non mutagenic

3

(Huntingdon, 1981)

DNA repair Test

(OECD 482)

K, rel.2

Gene mutation

Chinese hamster lung fibroblasts (V79 cells)

-S9
+S9

Up to cytotoxic concentrations

-S9 / +S9: non mutagenic

 4
(Covance, 2005)
CAT
(OECD 473)
K, rel.1 
 chromosomal aberration  Human lymphocytes  -S9
+S9
 Up to limit concentrations  -S9 / +S9: Not clastogenic and not aneugenic

 5

(Covance, 2008)

MLA
(OECD 476)
K, rel.1 
 Gene mutation  mouse lymphoma L5178Y cells

 -S9

+S9

 up to limit concentrations  - S9 / + S9: Not mutagenic

Gene mutation Assays (Tests n° 1-2-3-5):

- A Bacterial Reverse mutation Assay (Ames test) was performed according to OECD guideline No. 471 with the substance on Salmonella strains (See Table 7.6/1). No significant increases in the frequency of revertant colonies were recorded for any of the bacterial strains under the test condition, with any dose of the substance, either in the presence or absence of metabolic activation. The substance does not induce gene mutations in bacteria whereas all positive control chemicals (with and without metabolic activation) induced significant increase of colonies. The substance is therefore considered as non-mutagenic according to the Ames test.

- QSAR predictions (Test n°2) showed also no alerts for mutagenicity of test substance in bacteria.

- Inability to produce gene mutation was confirmed in a DNA repair test in Chinese hamster lung fibroblasts (Test n°3). In the main test, no clear evidence of repair synthesis was observed.

- Moreover, in a mammalian cells using an in vitro forward mutation assay in Mouse lymphoma cells (L5178Y/tk test) (Test n°5), none of the dose levels up to the limit concentration with the analogue substance, either in the presence or absence of metabolic activation, induced significant mutant frequency increases in the initial or repeat tests. The analogue substance does not induce mutations at the tk locus in L5178Y cells under activation and non-activation conditions whereas both positive control chemicals (with and without metabolic activation) induced significant mutant frequency increases. Based on the available data on the analogue substance, the registered substance is therefore considered as negative for inducing mutations at the tk locus in L5178Y cells under activation and non-activation conditions used in this assay.

These results confirm the results of the Ames test and extends the non-mutagenic effect of the substance to mammalian cells.

Chromosomal aberration (test n°4)

The clastogenic and aneugenic potential of an analogue substance was determined using chromosome aberration test (Test n°4), which identifies substances that cause structural or numerical chromosome aberrations in human lymphocytes. The analogue substance did not induce any statistically significant increases in the frequency of cells with micronuclei, in either of the two experiments using a dose range which included a dose level which achieved approximately 50% reduction in cytokinesis block proliferation index (CBPI) in the 4 h exposure group in the presence of S9 and in the 20 h exposure group. The toxicity curve in the 4 h exposure group in the absence of S9 was very steep so that there was only a modest reduction in CBPI at the maximum dose scored although the test item was tested to toxic limits. The analogue substance did not induce structural or numerical chromosome aberrations in cultured human lymphocytes under activation and non-activation conditions used in this assay. The registered substance is therefore considered as non-clastogenic and non-aneugenic in vitro.

Justification for classification or non-classification

Harmonized classification:

The test material has no harmonized classification for human health according to the Regulation (EC) No. 1272/2008.

Self-classification:

Based on the available data on registered and analogue substances, no additional classification is proposed regarding genetic toxicity according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP).