Chromium trioxide

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The EU RAR and other reviews contain summaries of literature studies performed to various designs and reoprted to different standards. However the information as a whole is consistent and is considered to provide adequate information to illustrate the basic toxicokinetics of Cr (VI) compounds.

Objective of study:

other: The reviewed studies cover all aspects of toxicokinetics

Qualifier:

no guideline followed

Principles of method if other than guideline:

The EU RAR summarises the results of a number of studies performed to various designs. Studies were performed to investigate all aspects of the toxicokinetics of CR (VI) compounds in various species.

GLP compliance:

not specified

Remarks:

Older published studies: assumed not to be GLP compliant

Radiolabelling:

other: Radiolabelling was used in some of the reviewed studies

Species:

other: Various species were used

Strain:

other: Various strains were used

Sex:

male/female

Details on test animals or test system and environmental conditions:

Various studies are reviewed

Route of administration:

other: Various routes were used

Vehicle:

water

Duration and frequency of treatment / exposure:

The RAR includes summaries of studies of various designs.

Remarks:

Doses / Concentrations:
The RAR includes summaries of studies of various designs.

No. of animals per sex per dose / concentration:

The RAR includes summaries of studies of various designs.

Control animals:

not specified

Preliminary studies:

A number of the reviewed studies could be considered to be preliminary in nature (i.e. non GLP- or guideline compliant), however these are summarised in the relevant sections below.

Details on absorption:

The available data show that the water-soluble hexavalent chromium compounds in this group are relativley poorly absorbed (~1-3%) following oral administration. This is likely to be due to the rapid and extensive reduction of Cr (VI) to Cr (III) in the gastrointestinal tract. Guinea pig studies indiate low dermal absorption (<4%). Absorption following inhalation exposure or intratracheal instillation is more extensive (20-30%).

Details on distribution in tissues:

Once absorbed, Cr (VI) appears to be widely distributed. There may be accumulation in the erythrocyte and spleen due to irreversible binding to haemoglobin following glutathione-mediated reduction of Cr (VI) to Cr (III). Repeated daily exposure to highly water-soluble Cr (VI) compounds by inhalation, oral or subcutaneous administration produced accumulation of chromium in many organs and tissues. In the case of the inhalation route, high levels have been found in lungs, spleen, duodenum, kidneys, liver and testes.

Details on excretion:

Inhaled Cr (VI) is excreted in similar amounts in the urine and faeces. Following oral administration, excretion is largely in the faeces due to poor bioavailability. 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.

Metabolites identified:

yes

Details on metabolites:

Cr (VI) is rapidly reduced in the gastrointestinal tract, in the plasma and intracellularly to Cr (III) by reaction with ascorbic acid, glutathione and by cytochrome P450. Follwoing exposure to Cr (VI), chromium is excreted in the form of Cr (III) complexes with glutathione.

Information on the toxicokinetics of Cr (VI) compounds is available from numerous published studies in rats, mice, guinea pigs and rabbits and has been reviewed in the EU RAR. The RAR (2005) also incorporates studies previously reviewed by the UK Health & Safety Executive (1989) and the UK Institute of Health (1997).

Absorption

Following inhalation or intratracheal instillation of highly water-soluble Cr (VI) compounds, approximately 20-30% of the administered chromium was rapidly absorbed into the bloodstream, apparently much of this still in the hexavalent state. Some chromium was also removed from the lung by mucociliary clearance into the gastrointestinal tract. The residual chromium remaining in the lung was cleared much more slowly, with significant amounts remaining in the lung for several weeks. In animals, gastrointestinal uptake of chromium following oral administration of highly-soluble Cr (VI) was generally poor due to reduction of Cr (VI) to Cr (III) in the stomach. When food was given ad libitum, only 1-3% of the orally administered Cr (VI) was absorbed in rats and mice; the amount was increased if food had been withdrawn for 16-48 hours previously. In contrast, one study reported at least 18% absorption in unstarved guinea pigs receiving potassium chromate orally. It has additionally been reported that insulin-dependent diabetic patients absorbed significantly more chromium-51 than non-diabetic subjects. Dermal absorption of highly water-soluble Cr (VI) compounds in guinea pigs varied between 1% and 4% of the applied aqueous dose, depending on the chromium concentration.

The available human data (volunteer studies) are consistent with the animal data and indicate that only poor absorption of Cr (VI) occurs from 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; findings are likely to be due to the essentiality of Cr and its role in glucose homeostasis. 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 watersoluble Cr (VI) through intact skin is limited in humans.

Distribution

Once absorbed into the bloodstream, a substantial proportion of Cr (VI) is initially taken up by the erythrocytes via a specific transport mechanism. Inside the erythrocyte, Cr (VI) is rapidly reduced to Cr (III) by glutathione, becoming irreversibly bound to haemoglobin for the lifespan of the cell. Cr (VI) is also reduced to Cr (III) in plasma. Ascorbic acid, cysteine and cytochrome P450 enzymes can also reduce Cr (VI): extracellular reduction to Cr (III) prevents cellular uptake. Chromium is cleared rapidly from the plasma but persists in the erythrocytes for several weeks until senescence and removal from the circulation by the spleen). Systemically absorbed chromium is distributed very widely and rapidly, with only a small proportion initally remaining in the hexavalent state. In experimental animal studies, the level of chromium in most tissues decreased gradually from the first day post-exposure. However, the chromium content of the spleen showed a time-dependent increase over several weeks, due to the clearance of senescent chromium-laden erythrocytes. Parenteral administration studies in pregnant rats (intravenous, intraperitoneal, subcutaneous) and mice (intravenous) using water-soluble Cr-51 (VI) compounds have shown that radioactivity in the bloodstream can cross the placenta and be distributed within the embryo.

Excretion

Inhaled or intratracheal instilled Cr (VI) is excreted in urine and faeces in similar amounts. When orally administered, most appears in faeces due to poor gastrointestinal tract absorption. Chromium in urine and faeces is in the form of Cr (III) complexes, with glutathione for example. 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. Repeated daily exposure to highly water-soluble Cr (VI) compounds by inhalation, oral or subcutaneous administration produces accumulation of chromium in many organs and tissues. In the case of the inhalation route, high levels were found in lungs, spleen, duodenum, kidneys, liver and testes. In terms of the available human data, results from 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 in humans

Conclusions:

Interpretation of results: bioaccumulation potential cannot be judged based on study results
The comprehensive review of the available toxicokinetics studies in experimental animals and in humans adequately illustrates the basic toxicokinetics of Cr (VI) from water-soluble compounds.

Executive summary:

There is a good database available on the toxicokinetics of the Cr (VI) compounds under review, although there are relatively few human data. The available data indicate that the water-soluble Cr (VI) compounds covered are likely to behave in a similar manner in respect of toxicokinetics, and that the kinetic behaviour of these substances would be similar in those species studied, including humans. Following inhalation exposure, animal studies have shown that 20-30% of the administered Cr (VI) is absorbed via the respiratory tract. Highly water-soluble Cr (VI) is poorly absorbed via the gastrointestinal tract (only 2-9% of the dose was absorbed in human studies) due to reduction to the relatively poorly absorbed Cr (III). Only limited dermal absorption takes place through intact skin, with 1-4% Cr (VI) from an aqueous solution crossing the skin in guinea pig studies. According to the results of animal testing, chromium derived from these compounds can remain in the lungs for several weeks after inhalation exposure and also becomes bound to haemoglobin in erythrocytes for the lifespan of the cells. Cr(VI) becomes reduced to Cr(III) after entering the body due to the influence of reducing agents, for example glutathione. Distribution is widespread even after a single dose and includes transfer of absorbed Cr (VI) across the placenta. Excretion occurs in urine and faeces. Repeated exposure leads to accumulation of chromium in several tissues, particularly the spleen because of the uptake of senescent erythrocytes.

Reference 2

Endpoint:

dermal absorption in vivo

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The reviews contain summaries of largely non-standard investigative studies that together are considered to be sufficiently reliable.

Qualifier:

no guideline followed

Principles of method if other than guideline:

The reviews report a number of older investigative studies performed using non-standard methods.

GLP compliance:

no

Remarks:

Older, literature studies

Radiolabelling:

yes

Remarks:

51Cr

Species:

guinea pig

Strain:

not specified

Sex:

not specified

Type of coverage:

not specified

Vehicle:

water

Duration of exposure:

Five hours

Doses:

The test material was administered at concentrations of between 0.48 mM to 4.87 M.

No. of animals per group:

Not reported

Control animals:

no

Remarks:

Not required

Total recovery:

Generally less than 1% of the dose was absorbed when animals were exposed to concentrations of between 0.48 mM and 4.87 M for 5 hours. At concentrations of 0.261 M and 0.398 M, 4% and 2.8% of the applied dose was absorbed, respectively.

Conversion factor human vs. animal skin:

Not relevant

The results of the reviewed studies indicate that the dermal absorption of chromate from water soluble Cr (VI) compounds is likely to be low. Dermal absorption values of 1 -4% were found in guinea-pig studies, however these are likely to be over-estimates.

Conclusions:

The dermal absorption of chromate from water-soluble Cr (VI) compounds is likely to be low in occupationally-exposed humans. It is possible that local irritant/corrosive effects may enhance dermal penetration.

Executive summary:

The dermal absorption of Cr (VI) has been studied in guinea pigs following the application of aqueous solutions of 51Cr-labelled chromate. Generally less than 1% of the dose was absorbed when animals were exposed to concentrations of between 0.48 mM and 4.87 M for 5 hours. At concentrations of 0.261 M and 0.398 M, 4% and 2.8% of the applied dose was absorbed, respectively. The UK IOH review cautions that, as dermal absorption was deteremined by measuring the disappearance of radiolabel from the applied dose, the reported figures include material residual in the skin at study termination. The reported dermal absorption figures may therefore be overestimates as material in the skin may not be systemically available.

An additional guinea pig study reported absorption (radioactivity in the carcass and excreta) of 1.4% after 24 hours; the findings of this study are therefore consistent with the earlier studies. Based on considerations of the comparative structure of human and guinea-pig skin, it can be concluded that the dermal absorption of water-soluble hexavalent chromium compounds in occupationally-exposed humans is likley to be negligible.

Description of key information

The available data indicate that the water-soluble Cr (VI) compounds covered are likely to behave in a similar manner in respect of toxicokinetics, and that the kinetic behaviour of these substances would be similar in those species studied, including humans. There is a good database available on the toxicokinetics of the Cr (VI) compounds under review, although there are relatively few human data.

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, absorbedCr (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.

Key value for chemical safety assessment

Bioaccumulation potential:

high bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100