Registration Dossier

Administrative data

Key value for chemical safety assessment

Additional information

Gene mutation (bacterial)

Currently, existing Ames data in the form of the GLP conducted key study (Herbold, 1995) confirms under the conditions of a 4 strain salmonella typhimurium test (TA98, TA100, TA1535 and TA1537) amicarbazone returned a negative result in the absence and presence of metabolic activation (S9) up to a maximum recommended dose of 5000 ug/plate. This study report is not fully compliant with current guidelines in the respect that no E.coli strain (usually WP2uvrA) was used.

 

Mammalian chromosome aberration (in vitro)

The availablein vitromammalian CHO chromosomal aberration studies conducted on amicarbazone returned a negative results following two independent tests up to maximum dose of 3000 ug/mL in the initial treatment in the presence and absence of S9 where cells were treated for 4 hours, with 14 hour recovery. In the confirmatory chromosome aberrations were assessed at a single dose level of 3000 ug/mL, where little / no toxicity was observed following a 4 hour treatment with a 26 hour recovery. The maximum dose of 3000 ug/mL is equivalent to ~12 mM, which is in excess of the current maximum recommended dose of 10 mM.

 

Mammalian gene mutation (in vitro)

The mammalian gene mutation study conducted (Bendler-Schwaab, 1997) confirmed that amicarbazone was negative in both the absence and presence of S9, following a 5 hour treatment when tested up to a concentration of 4000 ug/mL (which resulted in precipitation), with little or no toxicity. Whilst the result was confirmed in an independent test, the guidance states that at least one of the parameters used (S9 concentration, dose level selection, exposure time) should be altered for the confirmatory test. This was not the case, with a direct repeat of the initial treatment being undertaken. The maximum dose of 4000 ug/mL is equivalent to ~16.6 mM, whilst precipitation was observed the maximum dose tested was in excess of the current maximum recommended dose of 10 mM

 

In vivo bone marrow micronucleus

The mouse bone marrow micronucleus study on amicarbazone (Herbold, 1995) a single administration of the test material was undertaken with the bone marrow sampled at time points of 16, 24 and 48 hours post dosing. Data from the 16 hour sample time has not been reported in this submission as such a time point is considered too early for any effects to be detected in the proliferating bone marrow. Data from the 24 and 48 hour sample time were in line with the guideline requirements. A negative result was obtained from this study, with a dose level considered to be the MTD by the Study Director at the time, however the deaths observed confirmed that the MTD was exceeded. However of note, only a single test material dose group was used, which is not in line with the current guidance where at least 3 dose groups should be used (the only exception is when a limit dose is used).

 

Genetic Toxicology Summary

Individually these studies do not fully comply with the current guidelines, however together they provide a weight of evidence showing that amicarbazone is not mutagenic in vitro (to bacteria or mammalian cells) or in vivo, this view is strengthened considerably by the negative carcinogenicity data in both rat and mouse studies.

 

Under REACH for the registration of above 1000 tons/annum the minimum requirements for the genetic toxicology endpoint are bacterial gene mutation assay, in vitro mammalian gene mutation and chromosome aberration assays and in vivo assay. The available data, irrespective of the endpoint examined all returned negative results. The overall conclusion from these data confirm under the requirements of this registration the genetic endpoint has been adequately addressed and this chemicals which is devoid of genetic potential under the testing protocols used.

Short description of key information:
7.6.1 Genetic toxicity in vitro: KS - Ames. Herbold, 1995. KS.2. -ve; KS - Chrom abs. Herbold, 1997. KS.2. -ve; KS - Gene mut [HPRT]. Brendler-Schwaabb, 1997. KS.2. -ve
7.6.2 Genetic toxicity in vivo: KS - MMT. Herbold, 1997. KS.2. -ve

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Amicarbazone is not genotoxic, and therefore classification is not required.