Diammineplatinum(II) nitrite

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

No reliable genotoxicity data for diammineplatinum dinitrite were identified. Cis-diammineplatinum (II) nitrite [it is unclear whether this is the registered form of diammineplatinum (II) nitrite] was non-mutagenic, with and without S9, in a limited published assay in bacteria (Uno and Morita, 1993). In an unpublished study, diammineplatinum (II) nitrite was non-mutagenic in mouse lymphoma cells (Sandhu, 1979).

Link to relevant study records

Reference

Endpoint:

in vitro gene mutation study in bacteria

Remarks:

Type of genotoxicity: gene mutation

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

disregarded due to major methodological deficiencies

Study period:

not stated

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Not to current international guidelines. For example only two strains of bacteria used (should be five including Salmonella TA102 or E. coli according to OECD), no dose-response data reported, no controls used.

Principles of method if other than guideline:

Mutagenicity was tested using the Ames test, modified by the pre-incubation procedure.

Type of assay:

bacterial reverse mutation assay

Species / strain / cell type:

S. typhimurium TA 98

Species / strain / cell type:

S. typhimurium TA 100

Metabolic activation:

with and without

Metabolic activation system:

Liver S9 from Aroclor-1254 treated rats

Test concentrations with justification for top dose:

0.8-100 nmol/plate

Vehicle / solvent:

Distilled water

Untreated negative controls:

not specified

Positive controls:

not specified

Details on test system and experimental conditions:

The number of revertants per nmol was calculated from the number of revertants per plate and the molecular weight of the compound.

Tests were performed in triplicate.

Evaluation criteria:

By Ames' criteria a chemical will be considered mutagenic if, at the maximum non-inhibitory level, it more than doubles the number of spontaeous revertants

Species / strain:

S. typhimurium TA 98

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Species / strain:

S. typhimurium TA 100

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Additional information on results:

The frequency of revertants per nmol was not reported if a negative result was concluded by the authors.

Conclusions:

Cis-dinitrodiammineplatinum (II) was non-mutagenic in a limited Ames test in two strains (TA98 and TA100) of Salmonella typhimurium, with and without S9

Executive summary:

In a limited published Ames test, the mutagenicity of cis-dinitrodiammineplatinum (II) was assessed in two strains (TA98 and TA100) only of Salmonella typhimurium bacteria, both in the presence and absence of S9 liver metabolic activation mix from Aroclor-1254 treated rats. The experiments were conducted in triplicate, at 0.8 - 100 nmol/plate. No control was used.

The test substance gave no evidence of mutagenicity, according to the investigators, in TA98 or TA100 when tested in the presence or absence of S9; the dose(s) tested was not clear.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Genetic toxicity in vivo

Description of key information

No data identified.

Endpoint conclusion

Endpoint conclusion:

no study available

Mode of Action Analysis / Human Relevance Framework

No data identified.

Additional information

Additional information from genetic toxicity in vitro:

No reliable genotoxicity data for diammineplatinum dinitrite were identified.

Cis-diammineplatinum (II) nitrite [it is unclear whether this is the registered form of diammineplatinum (II) nitrite] was non-mutagenic, with and without S9, in a limited Ames test in two strains (TA98 and TA100) of Salmonella typhimurium [the actual doses tested are unclear] (Uno and Morita, 1993). In an unpublished study, diammineplatinum (II) nitrite was found to lack mutagenicity in mouse lymphoma cells (Sandhu, 1979).

However several Expert Groups have assessed the toxicity profile of platinum, and various platinum compounds, including CMR properties in their assessment. All reviews have indicated that platinum compounds have been reported to be mutagenic in a range of in vitro studies (DECOS, 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 (DECOS, 2008). Limited experimental data on reproductive toxicity and carcinogenicity for other platinum compounds give no evidence of activity that would meet classification criteria (DECOS, 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.

 

References

DECOS (2008). Dutch Expert Committee on Occupational Standards. Platinum and Platinum Compounds. Health-based recommended occupational exposure limit. Gezondheidsraad, 2008/12OSH. https://www.gezondheidsraad.nl/en/publications/gezonde-arbeidsomstandigheden/platinum-and-platinum-compounds-health-based-recommended

 

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

 

Sandhu S (1979). Evaluation of the mutagenic potentials of platinum compounds. Office of Research and Development, Health Effects Research Laboratory, Research Triangle Park, NC. EPA/600/1-79/033.

 

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

Justification for selection of genetic toxicity endpoint
The only genetic toxicity study available.

Justification for classification or non-classification

Based on the existing data set, diammineplatinum (II) nitrite does not currently meet the criteria for classification as a germ cell mutagen (category 1A or 1B). However, this conclusion should be revisited when the results of the planned in vivo studies are available.