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Toxicological information

Genetic toxicity: in vivo

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Administrative data

Endpoint:
in vivo mammalian cell study: DNA damage and/or repair
Type of information:
experimental study planned (based on read-across)
Study period:
Following ECHA approval
Justification for type of information:
TESTING PROPOSAL ON VERTEBRATE ANIMALS – genetic toxicity in vivo

NON-CONFIDENTIAL NAME OF SUBSTANCE: dihydrogen hexahydroxyplatinate(IV)
- Name of the substance on which testing is proposed to be carried out: dihydrogen hexahydroxyplatinate(IV), compound with 2-aminoethanol (1:2)
- Name of the substance for which the testing proposal will be used [if different from tested substance]: dihydrogen hexahydroxyplatinate(IV)

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION [please address all points below]:
- List of all substance-specific available GLP and non-GLP studies considered for this test proposal:
McGarry (2013). Ames test; According to OECD guideline 471; GLP compliant; positive with and without metabolic activation.
Lloyd (2014). Mammalian cell micronucleus assay; According to OECD guideline 487; GLP compliant; positive with metabolic activation (weak positive without metabolic activation).
No substance-specific in vivo genotoxicity studies were identified.
- Historical human data: No substance-specific data identified.
- (Q)SAR: It is acknowledged that the results of QSAR modelling are of very limited applicability for inorganic substances (e.g. metals) and organometallics.
- In vitro methods: The available in vitro methods have been considered as part of the tiered approach to testing (see “List of substance-specific available GLP and non-GLP studies considered for this test proposal” above for details). Further in vitro testing, for mammalian cell mutagenicity, is considered unnecessary given the available in vitro positive results.
- Grouping and read-across: No critical supplementary read-across data were identified.
- Weight of evidence (summary of key data): Dihydrogen hexahydroxyplatinate(IV) was assessed in a bacterial reverse mutation (Ames) assay using five Salmonella typhimurium strains (TA98, TA100, TA102, TA1535 and TA1537), in both the presence and absence of metabolic activation (S9). Mutagenic activity was observed in this Ames assay. In addition, the compound induced micronuclei in CHO cells, indicating a genotoxic (clastogenic) effect. No in vivo genotoxicity studies were identified for any hexahydroxyplatinate(IV) substances.

CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- The substance is not classified for carcinogenicity or mutagenicity therefore genetic toxicity testing cannot be waived. As outlined in the Integrated Testing Strategy (ITS) for mutagenicity (ECHA, 2015), “if there is a positive result in any of the in vitro studies from Annex VII or VIII and there are no appropriate results available from an in vivo study already, an appropriate in vivo somatic cell genotoxicity study should be proposed.” No in vivo genotoxicity data were identified for this substance. Moreover, there are no adaptations for in vivo somatic cell genotoxicity testing according to Column 2 of the REACH Annexes on information requirements (EC, 2014). Hence, the observation of mutagenic activity in bacteria and clastogenic activity in mammalian cells necessitates the consideration of further in vivo testing “as a last resort” (ECHA, 2016).

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Details on study design / methodology proposed: In order to assess the potential to induce genotoxicity in vivo, an alkaline comet assay (OECD Test Guideline 489), with a concomitant micronucleus assay and combined toxicokinetic assessment is proposed. The purpose of the comet assay is to identify substances that cause DNA damage, by detecting single and double stranded breaks. “These strand breaks may be repaired, resulting in no persistent effect, may be lethal to the cell, or may be fixed into a mutation resulting in a permanent viable change. They may also lead to chromosomal damage which is also associated with many human diseases including cancer” (OECD, 2016). It is proposed that comet measurements should be taken in both the duodenum (site-of-contact tissue) and liver (due to the apparent influence of S9 metabolic activation in vitro), in rats following oral dosing. Bone marrow is selected as the target tissue for micronuclei assessment. Inclusion of a parallel toxicokinetic study is proposed for the purpose of demonstrating that adequate target tissue exposure to the test substance has been achieved.
It is proposed to test dihydrogen hexahydroxyplatinate(IV), compound with 2-aminoethanol (1:2) in rats by the oral gavage route, with the results being applied for read-across to dihydrogen hexahydroxyplatinate(IV) [CAS RN 51850-20-5] (cfr. read-across justification report for mutagenicity (IUCLID section 13)).

References:
ECHA (2015). European Chemicals Agency. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.7a: Endpoint specific guidance. Version 4.1. October 2015. https://echa.europa.eu/documents/10162/13632/information_requirements_r7a_en.pdf

ECHA (2016). European Chemicals Agency. How to prepare registration and PPORD dossiers. Version 1.0. April 2016. https://echa.europa.eu/documents/10162/22308542/manual_regis_and_ppord_en.pdf

EC (2014). European Commission. C1 Regulation (EC) No 1907/2006 of the European parliament and of the council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94 as well as Council Directive 76/769/EEC and Commission Directives 91. http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:02006R1907-20140822

OECD (2016). Organisation for Economic Cooperation and Development. OECD guideline for the testing of chemicals. In Vivo Mammalian Alkaline Comet Assay. TG 489. Adopted: 29 July 2016. http://www.oecd-ilibrary.org/docserver/download/9716431e.pdf?expires=1475142425&id=id&accname=guest&checksum=151E9EE218B896F623F1DAE23EB3667F

Data source

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 489 (In vivo Mammalian Alkaline Comet Assay)
Deviations:
no
GLP compliance:
yes
Type of assay:
mammalian comet assay

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Applicant's summary and conclusion