Sodium chromate

Endpoint summary

Additional information

Genotoxicity in vitro

Bacterial mutation

The results of a large number of (mainly non-standard) bacterial reverse mutation assays performed with water-soluble hexavalent chromium compounds have been reviewed by the UK HSE (1989), UK IOH (1997) and in the EU RAR. Findings in these studies are largely positive. In addition, an NTP Ames test (non-standard protocol) performed with sodium dichromate dihydrate was positive. Although no guideline and GLP-compliant Ames tests are available, further testing is not required based on the weight of evidence from the large number of existing studies.

Chromosomal aberration

The results of a large number of (mainly non-standard) cytogenicity / clastogenicity / chromosomal aberration assays performed with water-soluble hexavalent chromium compounds have been reviewed by the UK HSE (1989), UK IOH (1997) and in the EU RAR. Findings in these studies are largely positive. Although no guideline and GLP-compliant studies are available, further testing is not required based on the weight of evidence from the large number of existing studies. Additonally, reliable in vivo data are available.

Mammalian cell mutation

The results of a large number of (mainly non-standard) mammalian cell mutation assays performed with water-soluble hexavalent chromium compounds have been reviewed by the UK HSE (1989), UK IOH (1997) and in the EU RAR. Findings in these studies are largely positive. Although no guideline and GLP-compliant tests are available, further testing is not required based on the weight of evidence from the large number of existing studies.

Additional investigations

The reuslts of a large number of non-standard study types using different test systems and endpoints are also reviewed by the UK HSE (1989), UK IOH (1997) and in the EU RAR (2005). These results of these studies are largely positive, indicating that water-soluble hexavelnt chromium compounds have the potential to cause DNA damage, mutagenicity and chromosomal damage in vitro. These additional studies therefore further support the conclusion that teh water-soluble hexavelnt chromium compounds are genotoxic in vitro.

Genotoxicity in vivo

In an NTP peripheral blood erythrocyte micronucleus study, sodium dichromate administered in drinking water for 90 days to mice was found to cause a significant positive response in a transgenic strain, but not in standard strains of mice. No proprietary studies of genotoxicity performed using the water-soluble chromium (VI) compounds in this group are available. The genotoxicity of chromium (VI) trioxide and other chromium (VI) salts have been extensively reviewed by the UK Health and Safety Executive (HSE, 1989); the UK Institute of Occupational Health (IOH, 1997) and most recently in the EU RAR (2005). The resulte of studies using parenteral administration are generally positive. The results of studies using oral administration are less clearly positive, however the low gastrointestinal absorption and rapid reduction of Cr (VI) to Cr (III) in the gastrointestinal tract and plasma act to reduce systemic exposure to Cr (VI).

The EU RAR concluded that '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.

The genotoxicity of Cr (VI) compounds in vivo has been less extensively studied. 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.

Given the available database on the genotoxicity of chromium (VI) compounds and the conclusion that this group of compounds is mutagenic, it is considered that further testing (specifically in guideline and GLP-compliant studies is not required.

Mechanism of genotoxicity

Cr (VI) readily enters cells, in contrast to Cr (III) which cannot easily pass through the cell membrane. Because it has been shown to be relatively nonreactive, Cr (VI) is believed to exert its genotoxic effects, at least in part, through the generation of oxygen radicals during metabolic transformation from the hexavalent form through the more reactive Cr (V) and Cr (IV) valences to Cr (III). In studies with laboratory animals, administration of radical scavengers simultaneously with or prior to administration of Cr (VI) salts reduced clastogenic potency, thus providing support for the oxygen radical mechanism of action. The results of in vitro mammalian cell studies of Cr (VI)-induced DNA damage in the presence of a variety of oxygen radical scavengers and reducing agents provides additional support for this mechanism. Cr (III), the product of intracellular reduction of Cr (VI), has been shown to interact directly with DNA and other macromolecules to induce chromosomal alterations and mutational changes in DNA.

Reviews of chromium genotoxicity

An additional comprehenisive review of the genotoxicity of chromium compounds by De Flora et al, (Mut. Res. 238 (1990) 99 -172) discusses the results of approximately 130 studies performed with 32 different compounds. For the water-soluble hexavalent chromium compounds, the authors conclude that the results of genotoxicity studies in cellular systems are consistently positive. It is noted that an 'impressive' number' of bacterial mutagenicity studies are positive due to the induction of both frane-shift and substitution mutation. Compounds were also found to cause unscheduled DNA synthesis, DNA damage, forward mutation, sister chromatid exchanges, micronuclei and chromosomal aberrations in cultured mammalian cells. Several endpoints of genotoxicity including

sister chromatid exchanges, micronuclei and chromosomal aberrations are reported to have been observed in studies in vivo. The authors conclude, however, that the evidence for a dominant lethal effect in mice was 'conflicting'.

Short description of key information:

No proprietary studies are available, however there is a very large body of evidence available in the published literature for various water soluble hexavalent chromium compounds.  This comprehensive dataset indicates that the Cr(VI) compounds in this group are mutagenic in vitro and in vivo.  It is noted that the compounds in this group are classified as Category 2 mutagens.

Endpoint Conclusion: Adverse effect observed (positive)

Justification for classification or non-classification

Chromium trioxide, sodium chromate, sodium dichromate and potassium dichromate are listed on Annex I of Directive 67/548/EEC and are classified as a Category 2 mutagen (R46): 'May cause heritable genetic damage'. This classification is consistent with the data available in the literature and reviewed in the EU RAR. No change to this classification is proposed.