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General discussion on the grouping of the water-soluble hexavalent chromium compounds

Dichromium tris(chromate) contains both Cr (III) and Cr (VI) moieties. Cr (III) compounds are generally not classified for health effects; they are poorly absorbed into the body following oral, dermal and inhalation exposure and Cr (III) is an essential nutrient required for energy metabolism. It is predicted that toxic effects of the substance will be almost entirely due to Cr (VI), therefore a read-across is proposed to other water-soluble hexavalent chromium compounds.

The compounds in this group (e.g. chromium (VI) trioxide, sodium (VI) dichromate, potassium (VI) dichromate, sodium (VI) chromate) are considered to be toxicologically equivalent to each other and to dichromium tris(chromate), with the exception of the more severe local corrosivity caused by chromium (VI) trioxide. Chromium (VI) trioxide in aqueous solution produces the corrosive compound, chromic acid. Hence, of the water-soluble Cr (VI) compounds covered by this dossier, there are site-of-contact issues related to low pH that are a consideration for chromium (VI) trioxide but not for the others. Beyond this all of the compounds will readily dissolve in the aqueous environments within the body, to release chromate (CrO42 -) or dichromate (Cr2O72 -) ions. However it is important to note that these two ions will co-exist, in equilibrium, regardless of the particular Cr (VI) compound involved. The chromate/dichromate ions produced from all compounds will behave similarly in biological tissues and hence, other than the additional property of acidity and its potential influence on local toxic effects for chromium (VI) trioxide, they can be treated as a common group. Furthermore, toxicological observations made with other chromium (VI) compounds that can similarly readily dissociate to produce chromate/dichromate ions in solution can be legitimately made use of in predicting the toxicokinetics of these compounds.

Summary of the available data

The available toxicokinetic data in experimental animals (rats, mice, guinea-pigs and rabbits) and in humans for chromium (VI) compounds have been reviewed by the EU RAR (2005) and the ATSDR (2008, draft report for public comment). The EU RAR covers studies discussed in earlier published reviews (e.g. UK Health and Safety Executive, 1988) and concludes that the toxicokinetics of the water soluble chromium (VI) compounds covered by the RAR is likely to be similar and therefore the findings of studies with different compounds can be extrapolated. The toxicokinetic data on Cr (VI) taken from these authoritative and comprehensive reviews is summarised below. Although based on a large number of non-standard literature studies of variable reliability, findings are consistent and adequately illustrate the toxicokinetics of Cr (VI).

Absorption

The available data indicate that Cr (VI) is poorly absorbed following oral (2-9% in humans) and dermal exposure (1-4% in guinea pigs), but was more extensively absorbed following inhalation exposure (20-30% in animal studies). Gastrointestinal absorption is limited due to the reduction of Cr (VI) to Cr (III), but has been reported to be greater in insulin-dependent diabetics and in fasted animals. The dermal absorption of highly water-soluble Cr (VI) compounds in guinea pigs was found to vary between 1% and 4% of the applied aqueous dose, depending on the chromium concentration. It is likely that the dermal absorption of this group of compounds may be increased by local corrosive effects, this would particularly be the case for chromium trioxide. As discussed above, once systemically absorbed, the four compounds in this group are essentially identical in terms of toxicokinetics. It is concluded that the dermal absorption of the water-soluble hexavalent chromium compounds in humans is likely to be negligible.

Distribution

Systemically absorbed Cr (VI) is distributed rapidly and widely, with only a small proportion initially remaining in the Cr (VI) state. Following inhalation exposure, Cr (VI) is well distributed, but may accumulate in the lung, the red blood cell and spleen (due to haemoglobin binding), however accumulation in the lung is more marked for the less water-soluble Cr (VI) compounds. Once absorbed into the blood stream, Cr (VI) is absorbed into erythrocytes by a specific carrier, however extracellular reduction in the plasma to Cr (III) reduces cellular uptake. Parenteral administration studies in pregnant rats and mice using water-soluble Cr-51 (VI) compounds have shown that radioactivity in the bloodstream can cross the placenta and be distributed within the embryo. No data are available on potential excretion into milk.

In experimental animal studies, the level of chromium in most tissues decreases gradually from the first day post-exposure. However the chromium content of the spleen may show a time-dependent increase over several weeks due to the clearance of senescent chromium-laden erythrocytes. Repeated daily exposure to highly water-soluble Cr (VI) compounds by inhalation, oral or subcutaneous administration produces an accumulation of chromium in many organs and tissues. In studies of inhalation exposure, high levels of Cr(VI) have been found in lungs, spleen, duodenum, kidneys, liver and testes.

Metabolism

Cr (VI) is reduced to Cr (III) in the gastrointestinal tract, thereby markedly limiting its bioavailability. Studies in vitro have shown that this reduction is promoted by human saliva and gastric juice. Cr (III) is very poorly absorbed from the gastrointestinal tract. Once absorbed into the body, Cr (VI) is reduced to Cr (III) by glutathione and other endogenous molecules including ascorbate and cytochrome P450. In the bloodstream, absorbed Cr (VI) is also rapidly reduced to Cr (III) in the plasma. The glutathione-mediated reduction of Cr (VI) in the erythrocyte results in irreversible binding to haemoglobin for the lifespan of the cell.

Excretion

Chromium is rapidly cleared from the plasma and is excreted in urine and bile, but it may persist in erythrocytes for several weeks, as discussed above. Inhaled or intratracheally-instilled Cr (VI) is excreted in urine and faeces in similar amounts (in the range 20-70% of the administered dose). When orally administered, most of the dose appears in faeces, due to poor absorption from the gastrointestinal tract. Chromium excreted in the urine and faeces is in the form of Cr (III) complexes, typically with glutathione. During the first 7 days following parenteral administration of readily water-soluble chromates, 35-60% of the chromium was excreted in the urine and 14-28% in the faeces.

Human data

The results of volunteer studies indicate that only poor absorption occurs in the gastrointestinal tract (2-9%). However, it is known from the literature that diabetic patients may absorb up to 4 times more chromium from the gastrointestinal tract than healthy individuals. Workers in chromate production, chromium plating and SS-MMA welding with occupational exposure to highly water-soluble Cr (VI) compounds had elevated blood and urine chromium levels. In addition, chromate production workers (who also had exposure to poorly-soluble chromium) had very high levels of chromium in the lungs and higher than normal chromium levels in several other tissues; these increases were still apparent a considerable number of years after exposure ceased. The increased body burden in these studies was probably the result of absorption via the respiratory tract since absorption of highly water-soluble Cr (VI) through intact skin is limited.