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In vitro:

Three Ames test are available. Although different strains and/or protocols were followed in the three available Ames tests, the overall conclusions are comparable. One Ames test was performed in 4 strains of S.Typhimurium (TA98, TA100, TA1535, TA1537) without metabolic activation, showing positive results in three strains (TA98, TA100, TA1535). In an additional limited Ames test in only 2 strains of S.Typhimurium (TA100 and TA1535), with and without metabolic activation, this positive result is confirmed. Although the first Ames test was performed at the IBT Laboratories, the results were confirmed in a second Ames test performed in another laboratory (TNO). Both studies were performed in the 70's. In a recently performed dose range finding Ames test, S.Typhimurium TA100 and E.Coli WP2uvrA tested both positive in the presence of metabolic activation, while the E.Coli strain also showed positive effects in the absence of metabolic activation. As these results confirmed the results from the earlier studies, subsequently no full Ames test was performed.

An in vitro chromosome aberration study is known to exist via the public domain (TSCA), and the Lead Registrant does not want to withhold the outcome of this study (positive), however as in vivo studies are available for this endpoint, the in vitro chromosome aberration study was not required and thus not accessed.

The substance is positive in the in vitro Ames tests, therefore additional in vitro testing is not considered necessary.

In vivo:

Three in vivo micronucleus tests in mice were performed.

In one study reported in 1978, mice were dosed twice by gavage (1150 -4600 mg/kg bw/dose), showing evidence of a weak mutagenic potential at the highest dose (4600 mg/kg bw/dose) with no dose response and a small but significant increase in the presence of severe toxic effects.

In another micronucleus study reported in 2002, performed according to OECD test guidelines and GLP principles, also some deviations were present (three dose levels were used giving minimal toxicity, one dose level (16x higher) was then used showing severe toxicity + decreased ratio of polychromatic to normochromatic erythrocytes. Only 4 animals of highest dose were analyzable). The study is disregarded as the Lead Registrant will not be using this study as a key study. However, as the study is known in the public domain (via TSCA), the Lead Registrant does not want to withhold it from the dossier. Mice were intraperitoneally dosed twice (1.25 -80 mg/kg bw), a clastogenic effect was observed with the highest dose tested, while at the next lower dose, 5 mg/kg bw, no effect was observed.

An additional study was performed in 2011, according to OECD 474. This study was performed because in time the production process of the substance has changed significantly over the years and the result was used for an updated risk assessment for workers. In addition due to the unknown genetic toxicity status of the substance more information was required for CLP classification. Next to that, possible alternatives with different molecular weights were tested in a development project. In that project this substance was also tested as a reference.

In this study mice were dosed intraperitoneally once (25, 50 and 100 mg/kg bw). At 100 mg/kg bw no evidence of a mutagenic potential as shown, toxicity was shown by some clinical signs (hunched posture, rough coat, closed eyes), while a decrease in the ratio of polychromatic to normochromatic erythrocytes confirmed exposure of the target tissue.

The in vivo micronucleus study results are not consistent: the reasons for these clear different results are not clearly known (yet). Therefore, it is important to be able to explain the reason of the positive result.

- One of the possibilities is thatthe composition of the BAYER sample being (somewhat) different from the DSM sample might cause the differences in the outcome of the in vivo micronucleus studies. Performing an in vivo micronucleus study with a DSM and a BAYER sample is not possible, as the BAYER sample is not produced anymore.

- In addition, based on thein vivomicronucleus studies, one could also draw the conclusion that only when severe systemic toxicity is observed, the substance shows a positive mutagenic potential.

- Furthermore, over the years the production process has been changed significantly, especially the amount of propyleneimine (PI) being present has decreased significantly (first >100 ppm, then <100 ppm due to PI classification, nowadays usually <10 ppm).

Based on the positive Ames tests, further in vivo testing is warranted to be able to draw a conclusion on the mutagenicity of the substance. However, classification with Muta Cat.2 was included previously (in MSDS) and is for safety reasons still included for this substance. Therefore, it is considered not necessary to include a testing proposal for this endpoint.


Short description of key information:
In vitro Ames tests are available, all being positive. In addition, in vivo micronucleus studies are present instead of an in vitro chromosome aberration test, showing different outcomes. As the Ames test is positive no further in vitro study is performed, however an in vivo study is proposed.

Endpoint Conclusion:

Justification for classification or non-classification

The substance is still self classified as Muta Cat.2, H341 'Suspected of causing genetic defects' according to the CLP Regulation (EC) No. 1272/2008, as this represents the current used MSDSs and no further testing is proposed.