Registration Dossier

Administrative data

Key value for chemical safety assessment

Additional information

- in vitro

bacterial gene mutation:

One fully reliable study is available (Sokolowski (2010) Genetic toxicity in vitro)) conducted according to OECD TG 471 and GLP (3, 10, 33, 100, 333, 1000, 2500 and 5000 µg/plate; two independent experiments both with and without liver microsomal activation). No toxic effects, evident as a reduction in the number of revertants (below the indication factor of 0.5), occurred in almost all strains with and without metabolic activation. A minor reduction in the number of revertants (below the indication factor of 0.5), occurred in strain TA 1537 and TA 98. No substantial increase in revertant colony numbers of any of the five tester strains was observed following treatment with FAT 40849/A TE at any dose level, neither in the presence nor absence of metabolic activation (S9 mix). There was also no tendency of higher mutation rates with increasing concentrations in the range below the generally acknowledged border of biological relevance.

 

mammalian gene mutation:

no data available to date

 

mammalian chromosome aberration:

One fully reliable study is available (Hall (2010) Genetic toxicity in vitro - Chromosome abberation) conducted according to OECD TG 473 and GLP (experiment I :19.5 - 5000.0 μg/mL 4 h exposure and 14 h recovery ith and without activation; experiment II: 2.4 – 625 µg/mL without activation in experiment II (18 h exposure), 9.8 – 312.5 µg/mL with activation in experiment II (4 h exposure + 14 h incubation)).

The following test results were reported: positive (a statistically significant increase in the number of aberrant cells excluding gaps (5.3 %) at the highest valuable concentration of 78.1 µg/mL) for Chinese hamster lung fibroblasts (V79) with activation. Cytotoxicity occurred at 78.1 to 156.3 µg/mL under all conditions. The results can be summarised in that FAT 40849/A TE is negative forin vitromammalian chromosome aberration without metabolic activation, but positive with metabolic activation.

 

- in vivo

mammalian chromosome aberration:

One fully reliable study is available (Merker (2010) Genetic toxicity in vivo - chromosome aberration - micronucleus assay) conducted according to OECD TG 474 and GLP (male NMRI mice; doses: 500, 1000, 2000 mg/kg bw, dissolved in 1% (w/v) carboxymethylcellulose (CMC) in water; collection of cells 24 and 48 h post administration).

As estimated by pre-experiments 2000 mg FAT 40849/A TE per kg b.w. (the maximum guideline-recommended dose) was suitable.

The mean number of polychromatic erythrocytes was not decreased after treatment with the test item as compared to the mean value of PCEs of the vehicle control indicating that FAT 40849/A TE did not have any cytotoxic properties in the bone marrow. However, the animals showed discoloured urine after treatment with at least 1000 mg/kg bw indicating the bioavailability of the test item.

In comparison to the corresponding vehicle controls there was no statistically significant or biologically relevant enhancement in the frequency of the detected micronuclei at any preparation interval and dose level after administration of the test item. The mean values of micronuclei observed after treatment with FAT 40849/A TE were near to the value of the vehicle control group. Additionally the values of all test item treated animals were within the range of the historical vehicle control data.

The results can be summarised in that FAT 40849/A TE is negative forin vivomammalian chromosome aberration while being bioavailable.

The negative result in thein vivocytogenetic assay overrules the positive result from the respectivein vitrotest. Therefore it can be concluded that FAT 40849/A TE is not clastogenic or aneugenic.

 

General:

According to ECHA Helpdesk the conducted tests are sufficient to fulfil the data requirements for genotoxicity:

“– The registrant will have fulfilled the data requirements by providing the following information: a negative resultin vitrogene mutation test in bacteria (as required in Annex VII, Section 8.4.1), a positive resultin vitromicro-nucleus test in mammalian cells (as required in Annex VIII, Section 8.4.2) and a negative findingin vivomicro-nucleus study (as required in Annex VIII, Section 8.4, Column 2). Anin vitrogene mutation study in mammalian cells (Annex VIII, Section 8.4.3) are only required if the firstin vitrocytogenetic study (Annex VIII, Section 8.4.2) produce a negative result.”

 

Accordingly it can be concluded that FAT 40849/A TE is not genotoxic.


Short description of key information:
- genetic toxicity in vitro: ambiguous; 1 study negative (Sokolowski (2010) Genetic toxicity in vitro), Ames Test; 1 study positive (Hall (2010) Genetic toxicity in vitro - Chromosome aberration),
- genetic toxicity in vivo: negative, 1 study negative (Merker (2010) Genetic toxicity in vivo - chromosome aberration - micronucleus assay)

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Based on the above stated assessment of the genotoxic potential FAT 40849/A TE (Ames test negative, in vitro mammalian chromosome aberration test positive, in vivo mammalian micronucleus test in bone marrow cells negative) the substance is deemed non-genotoxic and accordingly does not need to be classified according to Council Directive 2001/59/EC (28th ATP of Directive 67/548/EEC) and according to CLP (REGULATION (EC) No 1272/2008 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL) as implementation of UN-GHS in the EU.