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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
Variable
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: A review of proprietary studies reported in summary form.

Data source

Reference
Reference Type:
review article or handbook
Title:
Toxicological Profile for Chromium
Author:
Agency for Toxic Substances and Disease Registry
Year:
2000

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Various protocols, dose levels and routes of administration were used in the studies reviewed.
GLP compliance:
not specified
Remarks:
published studies assumed not to be GLP-compliant

Test material

Constituent 1
Chemical structure
Reference substance name:
Chromium hydroxide sulphate
EC Number:
235-595-8
EC Name:
Chromium hydroxide sulphate
Cas Number:
12336-95-7
Molecular formula:
CrHO5S
IUPAC Name:
chromium hydroxide sulphate
Constituent 2
Reference substance name:
not applicable
IUPAC Name:
not applicable
Details on test material:
Various water-soluble chromium (III) compounds were used as the test material.
Radiolabelling:
yes
Remarks:
in some studies

Administration / exposure

Route of administration:
other: Various routes of administration were used in the studies reviewed.
Duration and frequency of treatment / exposure:
Various experimental protocols
Doses / concentrations
Remarks:
Doses / Concentrations:
Various doses were used in the studies reviewed.
Control animals:
no

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
See details below
Details on distribution in tissues:
See details below
Details on excretion:
See details below.

Any other information on results incl. tables

Absorption

Absorption of chromium(III) compounds is via passive diffusion and phagocytosis. Inhalation exposure studies of chromium (III) compounds show absorption by the bloodstream and mucociliary clearance of only 5-30% in rats. Intratracheal administration to rats suggest that absorbed chromium(III) acetate hydroxide, a water-soluble compound, may be excreted more rapidly than absorbed chromium(VI) compounds because of poorer ability to enter cells. Approximately 0.5-2.0% of dietary chromium(III) is absorbed via the GI tract of humans as inferred from urinary excretion measurements. The absorption efficiency is dependent on dietary uptake. Studies with chromium in animals indicate that chromium and its compounds are poorly absorbed from the gastrointestinal tract after oral exposure. Dermal penetration of chromium(III) compounds is dependent upon the water solubility of the compound, the solvent and the preexisting condition of the skin. Chromium(III) can penetrate human skin to some extent, especially if the skin is damaged. Dermal absorption by humans of chromium(III) sulphate in aqueous solution was negligible, with slightly larger amounts of chromium(III) nitrate in aqueous solution absorbed.

Distribution

The distribution of insoluble chromium(III) was investigated in guinea pigs after intratracheal instillation of chromium trichloride. Sixty-nine percent of the dose remained in the lungs at 20 minutes post-instillation while only 4% was found in the blood and other tissues, with the remaining 27% cleared from the lungs and swallowed. The only tissue that contained a significant amount of chromium 2 days after instillation of chromium trichloride was the spleen. After 30 and 60 days, only 30 and 12% of the chromium(III) was retained in the lungs, respectively.

Autopsy studies in the US indicate that chromium concentrations in the body are highest in kidney, liver, lung, aorta, heart, pancreas and spleen at birth and tend to decrease with age. Tissue distribution of chromium has been studied in rats and mice. A 10-week feeding study with water-soluble chromium(III) chloride in rats resulted in increased chromium levels in liver, kidney, spleen, hair, heart, and red blood cells. A study of transplacental transfer of chromium(III) in different forms indicated that placental transport varies with chemical form and that fetal chromium is derived from specific chromium complexes in the diet (e.g., GTF). Addition of water-soluble chromium (III) acetate to the drinking water of rats fed a chromium deficient diet did not increase the levels of chromium in neonates while neonates whose dams were fed a commercial diet contained twice as much chromium.

Measurement of 51chromium in the organs and body fluids of guinea pigs revealed distribution, due to dermal absorption of chromium(III) and chromium(VI) compounds, to the blood, spleen, bone marrow, lymph glands, urine and kidneys. Absorption was greater for chromium(VI) than for chromium(III).

The distribution of poorly water-soluble chromium(III) in humans was analyzed after intravenous injection of radiolabeled chromium trichloride. Greater than 50% of the blood plasma chromium(III) distributed to various body organs within hours of administration with highest levels in the liver and spleen. In rats administered water-soluble chromium(III) nitrate intraperitoneally for 30 or 60 days, the highest levels of chromium were found in the liver, followed by kidneys, testes and brain.

Excretion

Tannery workers, exposed mainly to basic chromium sulphate via inhalation, had higher urinary chromium (III) concentrations in postshift urine samples taken on Friday afternoon and in preshift urine samples taken on Monday, compared to controls. These workers also had hair concentrations of chromium that correlated with urinary levels. Given the low absorption of chromium compounds by the oral route, the major pathway of excretion after oral exposure is through the faeces. The amont of chromium(III) in faecal samples was 99.6% of the dose six days after an acute oral dose of radioactive chromium chloride (water-soluble compound) was administered to humans. A five-fold increase in oral intake of chromium(III) in men and women resulted in about a five-fold increase in excretion, indicating absorption was proportional to the dose. In rats and hamsters fed chromium compounds, faecal excretion varied from 97-99% of the administered dose and urinary excretion varied from 0.6-1.4% of the dose administered as chromium (III) compounds. Radiolabeled chromium was detected in the urine of guinea pigs after chromium(III) trichloride solutions were placed over skin depots to monitor dermal absorption. Rats given a subcutaneous injection of water-soluble chromium nitrate excreted 8% and 24.2% of the chromium(III) in the urine and feces, respectively. Male Swiss mice exposed to water-soluble chromium chloride by single ip injection or subcutaneous injection had plasma clearance half-times of 41.2 and 30.6 hours, respectively. In each case, blood levels reached control levels by 6-10 days.

Applicant's summary and conclusion

Conclusions:
Water-soluble chromium(III) compounds show low systemic bioavailability after exposure by all routes of administration (oral, dermal and inhalation).
Executive summary:

Absorption after oral exposure in humans is approximately 0.5 -2.0% for chromium (III) compounds in the diet. Dermal absorption depends on the physical and chemical properties of the compound, the vehicle, and the integrity of the skin. Water-soluble chromium (III) compounds can penetrate human skin to some extent. Absorption of inhaled chromium compounds takes place in the lung via transfer across cell membranes and in the GI tract from particles cleared from the lungs.

Once in the blood, chromium compounds are distributed to all organs of the body with the greatest distribution in the lungs, liver, kidneys, blood, spleen, testes and brain.

Absorbed chromium is excreted primarily in the faeces, which is consistent with poor gastrointestinal absorption.Chromium has also been found in the urine, hair, fingernails and breast milk of nursing mothers after exposure.

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