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Description of key information

Short description of key information on absorption rate: 
A number of non-guidline studies performed in the guinea pig in vivo have been summarised in published reviews. The results of these studies
indicate that the dermal absorption of chromium (VI) compounds is likley to be low. It is possible that dermal absorption may be higher at levels
producing local irritation or corrosion. Further testing of the dermal absorption of chromium (VI) trioxide (i.e. to a recognised modern guideline)
is not justified for animal welfare reasons.

Key value for chemical safety assessment

Additional information

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

Chromium (VI) trioxide, sodium (VI) dichromate, sodium (VI) chromate; potassium (VI) dichromate

The compounds in this group are considered to be toxicologically equivalent, 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 four 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 four of the compounds will readily dissolve in the aqueous environments within the body, to release chromate (CrO42 -) or dichromate (Cr2O72 -) ions. However it is importnat 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 UK Health and Safety Executive (UK HSE, 1988), the UK Institute of Occupational Health (UK IOH, 1997) and the EU RAR (2005). The EU RAR covers the studies discussed in the earlier reviews 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 toxicokinetcs. It is concluded that the dermal absorption of the water-soluble hexavelnt chromium compounds in humans is likely to be negligible.

Distribution

Systemically absorbed chromium (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.

Discussion on absorption rate:

The UK Institute of Occupational Health (IOH, 1997) 'Criteria Document for Hexavalent Chromium' reports the results of a number of non-guideline dermal absorption studies in the guinea pig in vivo. These studies are also referred to in the EU RAR (2005), albeit in less detail, which reports dermal absorption values of between 1-4%.

The IOH document reports dermal absorption of <1% of an aqueous solution of radiolabelled sodium chromate at concentrations of between 0.48 mM-4.87 M for 5 hours. Dermal absorption values of 4% and 2.8% were reported for concentrations of 0.261 M and 0.398 M, respectively. It is cautioned that dermal absorption may actually be much lower than the reported figures as these inlcude material residual in the skin at study termination which may not be systemically available. A further study reports a dermal absorption value of 1.4% (based on excretion and carcass radioactivity) after 24 hours.

Although the studies do not meet current regulatory guidelines, they indicate that the dermal absorption of Cr (VI) is likley to be limited. Low dermal absorption of chromate from water-soluble Cr (VI) compounds in occupationally-exposed humans is therefore predicted, however it is possible that the dermal absorption from chromium (VI) trioxide may be greater as a result of more severe local corrosive effects.