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EC number: 240-979-3 | CAS number: 16921-30-5
Dipotassium hexachloroplatinate was mutagenic in a bacterial reverse mutation (Ames) assay using four Salmonella typhimurium strains (TA97a, TA98, TA100 and TA102) when tested in the presence and absence of a rat liver metabolic activation (S9) system (Bunger et al., 1996).
In a well-conducted in vitro mammalian gene mutation test using CHO cells, dipotassium hexachloroplatinate was weakly mutagenic when tested up to cytotoxic concentrations, in the absence of metabolic activation (Taylor et al., 1979).
Dipotassium hexachloroplatinate did not induce micronuclei in the cytokinesis-block micronucleus test with human lymphocytes, when tested at up to cytotoxic concentrations (Gebel et al., 1997).
High doses of the metal compounds proved toxic to the tester strains", resulting in a thinning of the background bacterial lawn. Although no actual data provided for potassium hexachloroplatinate, the minimum toxic dose for the platinum salts was apparently 100 ug/plate.
Dipotassium hexachloroplatinate was assessed for mutagenic activity in a bacterial reverse mutation (Ames) assay, similar to OECD Test Guideline 471, using Salmonella typhimurium strains TA97a, TA98, TA100 and TA102 and tested at up to 500 μg/plate in both the presence and absence of a metabolic activation system (S9) derived from phenobarbital and beta-naphthoflavone induced rat livers.
Mutagenic effects were seen in all four strains in the presence of metabolic activation and in all but strain TA97a in its absence. Although no cytotoxicity data were provided for the test material, the minimum toxic dose for the platinum salts was apparently 100 μg/plate.
No in vivo genotoxicity data were identified.
The observation of mutagenic activity in bacterial (Bunger et al., 1996; Suraikina et al., 1979) and mammalian cells (Taylor et al., 1979) necessitates the consideration of further in vivo testing. Related platinum compounds have also demonstrated a general tendency to induce genotoxicity in vitro, though the available, if somewhat limited, dataset suggests that such findings might not be relevant in vivo and hence a similar lack of classification for mutagenicity is proposed for these compounds. Additional in vivo testing of certain related platinates has been proposed to further elucidate the in vivo relevance of the in vitro findings. The conclusion not to classify dipotassium hexachloroplatinate as a germ cell mutagen should be revisited when the results of the planned in vivo studies (see testing proposals) are available.
No data identified.
Dipotassium hexachloroplatinate was assessed for mutagenic activity in a bacterial reverse mutation
(Ames) assay, similar to OECD Test Guideline 471, using Salmonella typhimurium strains TA97a, TA98, TA100 and TA102 and tested at up to 500 μg/plate in the presence and absence of a metabolic activation system (S9) derived from phenobarbital- and beta-naphthoflavone-induced rat livers. (It is not clear whether the di- or mono-ammonium form was used; the recommended strain TA1535 was omitted.) Mutagenic effects were seen in all four strains in the presence of metabolic activation and in all but strain TA97a in its absence. Although no cytotoxicity data were provided for the test material, the minimum toxic dose for the platinum salts was apparently 100 μg/plate (Bunger et al., 1996). This study conforms to OECD guidelines, aside from the lack of inclusion of a fifth tester strain.
In a limited Ames assay involving two strains (TA98 and TA100) of S. typhimurium bacteria, dipotassium hexachloroplatinate was tested at up to 1 mg/plate in the absence of S9. A weak mutagenic effect was reported for strain TA98; there was no evidence of mutagenicity in strain TA100 (Suraikina et al., 1979).
Dipotassium hexachloroplatinate was tested for genotoxicity in an in vitro mammalian gene mutation test using Chinese Hamster Ovary (CHO) cells deficient in HPRT (hypoxanthine-guanine phosphoribosyl transferase). Cells were tested only in the absence of a metabolic activation system. A 2-3-fold increase in the 8-AGR mutant frequency versus the spontaneous control was seen upon repeated subculture [prolonged exposure] with a non-cytotoxic concentration of 10 μM. This increase was apparent after 10 population doublings; the trend towards it was observed at 5 population doublings. Dipotassium hexachloroplatinate was determined to be weakly mutagenic to mammalian cells in the absence of metabolic activation under the conditions of the test (Taylor et al., 1979).
In a well-conducted study, similar to that described by OECD Test Guideline 487, the ability of dipotassium hexachloroplatinate to induce micronuclei in human peripheral mononuclear blood cells (lymphocytes) was assessed, in the absence of a metabolic activation system. The mean numbers of micronuclei in binucleate cells were 4, 5.5, 7.5 and 4 at test concentrations of 0, 5, 10 and 20 µM, respectively; there was no statistically significant change compared to the negative control. Severe cytotoxicity was observed at 40 µM. In conclusion, the test substance did not cause chromosome damage (micronuclei) in the cytokinesis-block micronucleus test with human lymphocytes (Gebel et al., 1997).
Dipotassium hexachloroplatinate did not cause DNA damage in a bacterial SOS chromotest, when tested at up to cytotoxic concentrations in the absence of metabolic activation (Gebel et al., 1997; Lantzsch and Gebel, 1997).
Several Expert Groups have assessed the toxicity profile of platinum, and various platinum compounds, including the assessment of CMR properties. All reviews have indicated that platinum compounds have been reported to be mutagenic in a range of in vitro studies (HCN, 2008; EMA, 2008; SCOEL, 2011; WHO, 1991). Cisplatin and related compounds are known DNA-reactive carcinogens and, as these compounds are better investigated due to their pharmaceutical properties, this has been confirmed in vivo. As cisplatin-type substances differ in chemical reactivity (liability of ligands, number of active sites etc.) it is reasonable to expect that not all forms of platinum are carcinogenic (HCN, 2008). Limited experimental data on carcinogenicity for other platinum compounds give no evidence of activity that would meet classification criteria (HCN, 2008; SCOEL, 2011).
Despite the generally positive in vitro results identified for the platinum compounds in various bacterial/mammalian cell mutagenicity assays (supported by some mammalian cell cytogenicity tests), the in vivo relevance of these in vitro findings remains unclear. Indeed, the available in vivo data returned mostly negative results. However, some of the identified studies might not be considered sufficiently robust (according to ECHA standards) to override the in vitro mutagenicity findings (e.g. a sex-linked recessive lethal test in Drosophila melanogaster (OECD TG 477, performed with dipotassium tetrachloroplatinate) and a liver unscheduled DNA synthesis assay (OECD TG 486, performed with tetraammineplatinum hydrogen carbonate)). Indeed, further in vivo testing of certain platinum compounds has been proposed to further elucidate the in vivo relevance of the in vitro findings.
EMA (2008). European Medicines Agency. Guideline on the specification limits for residues of metal catalysts or metal reagents. Committee for Medicinal Products for Human Use (CHMP). EMEA/CHMP/SWP/4446/2000. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003586.pdf
HCN (2008). Health Council of the Netherlands (DECOS). Platinum and platinum compounds. Health based recommended occupational exposure limit. https://www.gezondheidsraad.nl/sites/default/files/200812OSH_1.pdf
SCOEL (2011). Recommendation from the Scientific Committee on Occupational Exposure Limits for platinum and platinum compounds. SCOEL/SUM/150. http://ec.europa.eu/social/BlobServlet?docId=7303&langId=en
WHO (1991). World Health Organization. Platinum. International Programme on Chemical Safety. Environmental Health Criteria 125. http://www.inchem.org/documents/ehc/ehc/ehc125.htm#SectionNumber:7.4
Based on the existing data set, dipotassium hexachloroplatinate does not currently meet the criteria for classification as a germ cell mutagen (category 1A or 1B) under EU CLP criteria (EC 1272/2008). However, this conclusion should be revisited when the results of the planned in vivo studies are available.
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