Dichromium tris(chromate)

Endpoint summary

Additional information

Genetic toxicity in vitro - dichromium tris(chromate)

The mutagenic potential of dichromium tris(chromate) was evaluated in the bacterial reverse mutation assay according to GLP and OECD 471 (Ágh, 2010). Salmonella typhimurium strains TA98, TA100, TA1535 and TA1537 and Escherichia coli strain WP2 uvrA were tested, with and without metabolic activation (S9 mix), up to a maximum concentration of 500 µg active ingredient/plate. Dose-related increases in revertant colonies were observed in all tester species/strains, with and without metabolic activation. A high degree of cytotoxicity was observed at the highest concentrations. It was therefore concluded that Dichromium tris(chromate) was mutagenic to the five tester species/strains, under the conditions of the study.

Genetic toxicity - read across

There are no other in vitro or in vivo genotoxicity studies conducted with dichromium tris(chromate). A read across to other Cr (VI) salts is appropriate, and the positive result obtained in the Ames test (Ágh, 2010) confirms that these compounds are similar toxicologically. Further testing is not required based on the weight of evidence from the large number of existing studies.

The ATSDR (2008 - draft report for public comment) review also supports the read-across argument. The studies summarised demonstrate that Cr (VI) compounds are genotoxic in vitro and in vivo, whereas Cr (III) compounds are less genotoxic in intact cell systems because of the relative inability of Cr (III) to cross cell membranes: Cr (VI) compounds rapidly enter cells (within seconds to minutes) by facilitated diffusion, Cr (III) compounds enter much more slowly (within days) by simple diffusion. The ATSDR therefore concludes that Cr (VI) compounds are of greater concern than Cr (III) compounds with regard to health effects.

In vitro

The EU RAR (2005) comprehensively reviews the available data for several Cr (VI) compounds, and reaches the following conclusion: 'There is a very large body of evidence indicating that the Cr (VI) ion in solution is directly mutagenic in in vitro systems. Extensive in vitro testing of highly water-soluble Cr (VI) compounds has produced positive results for point mutations and DNA damage in bacteria, point mutations, mitotic crossing-over, gene conversion, disomy and diploid in yeasts, and gene mutation, DNA damage, chromosome aberrations, sister chromatid exchanges and unscheduled DNA synthesis in mammalian cells. The in vitro genotoxicity of Cr (VI) was diminished considerably by the presence of reducing agents, in the form of tissue S9 or S12 fractions, gastric juice or reducing agents such as glutathione, ascorbate or sulphite. These all serve to reduce Cr (VI) to Cr (III) outside the cell therefore greatly reducing entry of chromium into the cell.'

In vivo

The potential of sodium dichromate to induce micronuclei in the peripheral blood erythrocytes of mice was investigated in a GLP study conducted by the National Toxicology Progam (NTP, 2007). Sodium dichromate was administered to three strains of mice in the drinking water for 3 months. A significant increase in the frequency of micronuclei was seen in the transgenic am3 -C57/BL6 strain, however similar findings were not apparent in B6C3F1 or BALB/c mice. The results of this study were considered equivocal.

The ATSDR (2008 - draft report for public comment) reviews the available literature regarding the in vivo genotoxicity of trivalent and hexavalent chromium compounds. Mostly positive results were reported in rodents and Drosophila exposed to Cr (VI) compounds in vivo, indicating that Cr (VI) compounds are genotoxic. Mostly negative results were reported in in vivo rodent studies with Cr (III) compounds.

The EU RAR (2005) summarises the results of a number of in vivo genotoxicity studies of various designs and reliability. It is concluded, based on the weight of evidence, that water-soluble Cr (VI) compounds are genotoxic in vivo in somatic cells and in germ cells. The following is taken directly from the EU RAR:

'Parenteral administration of sodium or potassium dichromate or potassium chromate to rats or mice resulted in significant increases in chromosome aberrations and micronucleated cells in the bone marrow and DNA single-strand breaks, interstrand cross-links and DNA-protein cross-links in the liver, kidneys and lung. A mouse spot test involving intraperitoneal injection of potassium chromate gave positive results. Oral studies have been negative but these employed lower dose levels and absorption is known to be poor by the oral route. Overall, water soluble Cr (VI) compounds are in vivo somatic cell mutagens in animal studies. A significant increase in post-implantation deaths in a dominant lethal assay was reported in mice following intraperitoneal injection of potassium dichromate. Toxicokinetic data for water soluble Cr(VI) compounds indicate that chromium will reach the germ cells following inhalation exposure (a relevant route of exposure for humans). Therefore taking these two observations together, it can be concluded that water-soluble Cr(VI) compounds have the potential to produce germ cell mutagenicity.

A few studies have been conducted in which circulating lymphocytes have been isolated from chromium-exposed workers and examined for chromosome aberrations, micronuclei, SCE and changes in chromosome numbers. In general, the results from the better-conducted and reported studies including chromium plating workers in Japan and SS-MMA welders in Scandinavia have been negative. Evidence of genotoxicity has been reported in several other studies of chromate production workers in Eastern Europe and chromium plating workers in Italy. However the manner in which these were conducted and reported precludes full assessment of the significance of the findings.'

Potassium dichromate did not affect the frequency of micronucleated polychromatic erythrocytes when administered orally to male mice (De Flora et al, 2006). However intraperitoneal administration resulted in a significant increase in the frequency of micronucleated polychromatic erythrocytes. The authors concluded that orally administered Cr (VI) is adequately detoxified in the gastrointestinal tract before it exerts genotoxic effects, however bypassing the detoxification mechanisms (intraperitoneal route of exposure) results in positive mutagenic responses.

Short description of key information:
Dichromium tris(chromate) was found to be mutagenic to four Salmonella typhimurium strains and one Escherichia coli strain in a GLP Ames test (Ágh, 2010). Sodium dichromate was found to be genotoxic in an in vivo micronucleus study in 1 out of 3 mouse strains tested, leading to an overall equivocal conclusion (NTP, 2007). Potassium dichromate was genotoxic in vivo when administered intraperitoneally, but not when administered orally. Read-across data taken from published reviews (EU RAR, ATSDR) demonstrates that Cr (VI) compounds are genotoxic both in vitro and in vivo.

Endpoint Conclusion: Adverse effect observed (positive)

Justification for classification or non-classification

Chromium trioxide, sodium dichromate, sodium chromate and potassium dichromate are classified as 'Mutagen Category 1B' according to Regulation (EC) No 1272/2008. Dichromium tris(chromate) is not currently classified. It is proposed, based on the positive result achieved in the in vitro bacterial reverse mutation assay and the large body of data indicating that Cr (VI) compounds are genotoxic, that dichromium tris(chromate) should be classified as 'Mutagen Category 2' in accordance with Regulation (EC) No 1272/2008.