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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
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, and also incorporates the older UK HSE review (1986). 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

Reference
Reference Type:
review article or handbook
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

Materials and methods

Objective of study:
other: The reviewed studies cover all aspects of toxicokinetics
Test guideline
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

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
Strain:
other: various
Sex:
male/female
Details on test animals and environmental conditions:
Various studies were reviewed that used rats, mice, guinea pigs and rabbits.

Administration / exposure

Route of administration:
other: various
Vehicle:
water
Duration and frequency of treatment / exposure:
The studies summarised in the EU RAR are of various designs.
Doses / concentrations
Remarks:
Doses / Concentrations:
The studies summarised in the EU RAR are of various designs.
No. of animals per sex per dose:
The studies summarised in the EU RAR are 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:
Following inhalation or intratracheal instillation of highly water-soluble Cr (VI) compounds, approximately 20-30% of the chromium dose 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 stomach. When food was given ad libitum, only 1-3% of orally administered Cr (VI) was absorbed in rats and mice; the amount increased if food had been withdrawn for 16-48 hours. In contrast, one study reported at least 18% absorption in unstarved guinea pigs receiving potassium chromate orally.
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.

In humans, data from volunteer studies shows that chromium is poorly absorbed through the GI tract (2-9%) and intact skin. Diabetic patients may absorb up to 4 times more chromium through the GI tract than healthy individuals.
Details on distribution in tissues:
Once absorbed, Cr (VI) appears to be widely distributed. A substantial proportion of Cr (VI) is absorbed by erythrocytes, and once inside the erythrocytes is rapidly reduced to Cr (III) by glutathione, becoming irreversibly boung to haemoglobin. Cr (VI) is also reduced to Cr (III) in plasma. Ascorbic acid, cysteine and cytochrome P450 enzymes can also reduce Cr (VI). Extra-cellular reduction to Cr (III) prevents cellular uptake.
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 clearance of senescent chromium-laden erythrocytes. Parenteral administration studies in pregnant rats (intravenous, intraperitoneal, subcutaneous) and mice (intravenous) using water-soluble 51Cr (VI) compoun ds have shown that radioactivity in the bloodstream can cross the placenta and be distributed within the embryo.
Details on excretion:
Inhaled Cr (VI) is excreted in similar amounts in the urine and faeces (in the range of 20-70% of administered dose). 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.
Repeated daily exposure (inhalation, oral and s.c.) to highly-water soluble Cr (VI) compounds resulted in chromium accumulation in many organs and tissues. High levels were found in the lungs, spleen, dudodenum, kidneys, liver and testes following inhalation exposure.

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. Following 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).

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 chromium 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) is 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.