Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
migrated 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 contains 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.

Data source

Referenceopen allclose all

Reference Type:
other: EU RAR
Title:
European Union Risk Assessment Report: chromium trioxide, sodium chromate, sodium dichromate, ammonium dichromate, potassium dichromate
Author:
European Chemicals Bureau
Year:
2005
Bibliographic source:
3rd Priority List; Volume 53
Reference Type:
review article or handbook
Title:
Criteria Document for Hexavalent Chromium
Author:
Cross HJ et al
Year:
1997
Bibliographic source:
Institute of Occupational Health
Reference Type:
review article or handbook
Title:
UK Health & Safety Executive Toxicity Review 21: The toxiicty of chromium and inorganic chromium compounds
Author:
Fairhurst S & Minty CA
Year:
1989
Bibliographic source:
HMSO

Materials and methods

Objective of study:
other: The reviewed studies cover all aspects of toxicokinetics
Test guideline
Qualifier:
no guideline followed
Deviations:
not applicable
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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
Various Cr (VI) compounds were used in the reviewed studies. Absorption into the body of the different water-soluble Cr (VI) salts is very similar, and once absorbed, dissociation in aqueous media means that the toxicokinetics of Cr(VI) in the different salts is essentially identical. Toxicokinetic data obtained experimentally using different water soluble Cr (VI) compounds can therefore be extrapolated to all compounds in this group.
Radiolabelling:
other: Radiolabelling was used in some of the reviewed studies

Test animals

Species:
other: Various species were used
Strain:
other: Various strains were used
Sex:
male/female
Details on test animals and environmental conditions:
Various studies are reviewed

Administration / exposure

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.
Doses / concentrations
Remarks:
Doses / Concentrations:
The RAR includes summaries of studies of various designs.
No. of animals per sex per dose:
The RAR includes summaries of studies of various designs.
Control animals:
not specified

Results and discussion

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.

Toxicokinetic / pharmacokinetic studies

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.

Metabolite characterisation studies

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.

Any other information on results incl. tables

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

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): 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.