Reaction mass of chromium (+ 3) hydroxide sulfate and sodium sulfate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

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.

Objective of study:

toxicokinetics

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

Radiolabelling:

yes

Remarks:

in some studies

Route of administration:

other: Various routes of administration were used in the studies reviewed.

Duration and frequency of treatment / exposure:

Various experimental protocols

Remarks:

Doses / Concentrations:
Various doses were used in the studies reviewed.

Control animals:

no

Details on absorption:

See details below

Details on distribution in tissues:

See details below

Details on excretion:

See details below.

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.

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.

Reference 2

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.

Objective of study:

toxicokinetics

Qualifier:

no guideline followed

Principles of method if other than guideline:

Various test protocols, dose levels and routes of administration were used in the studies reviewed.

GLP compliance:

not specified

Radiolabelling:

yes

Remarks:

in some studies

Route of administration:

other: Various routes of administration were used in the studies reviewed.

Vehicle:

not specified

Duration and frequency of treatment / exposure:

Various study protocols were followed

Remarks:

Doses / Concentrations:
Various dose levels were used in the studies reviewed.

Details on absorption:

See details below

Details on distribution in tissues:

See details below

Details on excretion:

See details below.

Metabolites identified:

no

Details on metabolites:

Data indicate that Cr (III) is not converted to other forms of Cr in the body.

Absorption

The disposition of chromium following inhalation of Cr(III) in a highly water-soluble form has been studied in rats, mice and hamsters using chromium(III) chloride. In rats exposed whole body to 10.7 mg Cr (III)/m3 for 2 hours, post-exposure clearance of chromium from the lungs was slow, with a half-life of 164 hours. A considerable increase in blood chromium from the lungs was seen immediately post-exposure, although levels declined from 30 minutes onwards. In another study in rats, inhalation of 14.1 mg Cr(III)/m3 produced very high levels of chromium in the lung, but also increased the liver chromium content 20 to 30-fold, over one to seven days. In mice exposed head-only to 1 mg Cr(III)/m3 for 30 mins, calculated inhaled doses of radiolabled Cr(III) in the respiratory tract immediately post-exposure were 40% nasopharynx, 1.5% trachea, 10% lungs. Lung clearance was slow with a decrease of only 20% in 17 days. In hamsters exposed head-only to 1 or 25 mg Cr (III)/m3 for 30 minutes, some radioactivity was detected in the liver and kidneys at 2 hours. Lung clearance was slow with 60% of the radioactivity disappearing from the lung in 21 days. Absorption studies of orally administered Cr (III) in a highly water-soluble form have been conducted using rats and mice. In rats and mice given radiolabeled chromium chloride, only 0.1-2% of the chromium was absorbed and subsequently excreted in urine over 7 days. In the blood, 99% of the chromium was associated with plasma, of which 90% was bound to transferrin. In rats given chromium chloride in drinking water for 1 year, increased chromium levels were found in the spleen, kidneys, bone and liver (in descending order)-the only tissues examined. Studies involving skin application of highly water-soluble chromium(III) compounds have been conducted using guinea pigs and in vitro methods. Approximately 2% of radiolabeled chromium chloride was absorbed in 5 hours following dermal application in guinea pigs. At 5-24 hours after topical application, considerable levels of radioactivity were found in blood, lymph nodes and kidneys with detectable levels in the liver, spleen, lung, heart and bone. Application of chromium(III) chloride solution to skin fragments from hairless mice resulted in very slow rates of penetration: 0.07% and 0.18% in 3h and 60h, respectively.

Distribution

The fate of the highly water-soluble chromium(III) compound, chromium chloride, was monitored in rats, rabbits and guinea pigs. Radioactivity was high in the lung but very low in the blood and other organs of rats 24 h after intratracheal administration of 0.5 ug Cr (III)/kg. In guinea pigs given 200 ug Cr(III) intratracheally, lung clearance of chromium was slow, 12% of the dose remained in the lungs at 60 days and no marked increase was observed in chromium content of other organs. In anaesthetised rabbits given 40 ug Cr(III)/kg intratracheally, blood radioactivity was highest at 20 minutes, and then declined slowly over the following 4 hours. When the experiment was terminated at 4 hours, 85% of the administered Cr remained in the lung, 0.8% in the blood, 0.3% in the kidneys and 0.2% in the liver. In pregnant rats and mice, parenterally-administered highly water-soluble chromium(III) chloride was concentrated in the placenta, and some transfer to pups was apparent from days 8 to 11 of gestation.

Excretion

Excretion of intravenously injected highly water-soluble Cr(III), as chromium chloride, was predominantly in the urine, 15-75% of the dose appearing in the urine in three to seven days. However, some Cr(III) was also eliminated in the faeces, by way of biliary excretion of low molecular weight Cr(III) complexes. Several studies reported faecal excretion of 5-20% of administered chromium in rats and 2-3% in sheep.

Conclusions:

Chromium(III) compounds are poorly absorbed and show low systemic bioavailability regardless of route of administration.

Executive summary:

Cr(III) does not easily cross biological membranes. In animals, administration of chromium(III) compounds via the respiratory tract resulted in fairly rapid absorption of a small proportion of chromium into the bloodstream, the extent of absorption depending on water solubility. However, some of the chromium was cleared from the lungs only slowly, substantial proportions of the dose remaining in the lungs for long periods of time. Cr(III) was poorly absorbed (0.1 -2% of dose) from the gastrointestial tract or through the skin. In the blood, Cr(III) remained almost entirely within the plasma, mainly bound to transferrin.

Following administration of chromium(III) compounds by various exposure routes, chromium was widely distributed: several tissues retained significant amounts of intravenously administered Cr(III) for several weeks.

Excretion of Cr(III) was predominantly via the urine, although there was also some biliary excretion into the faeces. In pregnant rats and mice, some transfer of chromium to the fetus occurred following oral and parenteral administration of chromium(III) compounds.

Reference 3

Endpoint:

basic toxicokinetics

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.

Objective of study:

toxicokinetics

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

Radiolabelling:

other: in some studies

Species:

other: various

Strain:

other: various

Sex:

male/female

Route of administration:

other: various routes of administration were used in the studies reviewed.

Vehicle:

not specified

Duration and frequency of treatment / exposure:

Various treatment protocols were used

Remarks:

Doses / Concentrations:
Various dose levels were used in the studies reviewed.

Control animals:

no

Details on absorption:

See details below

Details on distribution in tissues:

See details below

Details on excretion:

See details below

Metabolites identified:

no

Details on metabolites:

Cr (III) is not metabolised. The data indicate that there is no convesrion to other forms of Cr in the body.

Absorption

Oral studies conducted in male and female rats using radiolabeled water-soluble chromium (III) showed that the bioavailability of chromium chloride over a wide dose range was low (about 1%). Intestinal absorption of water-soluble chromium (III) chloride given orally to volunteers was low ranging from non-detectable to about 4%. It should be noted that occupational exposure to airborne dusts/aerosols of chromium (III) compounds is variably transformed to oral intake due to muciliary clearance of the substance from the respiratory system. No increases in chromium levels were detected in blood and urine samples taken over a 24 hour period after a male research volunteer held his hand in a tanning solution containing 7 g/L chromium as basic chromium sulphate for one hour. Rats were exposed to aerosols of the water soluble chromium (III) compound, chromium chloride hexahydrate, for 2 hours at 10.7 mg/m3 or for 6 hhours at 8 mg/m3. Chromium concentrations in the lungs and other tissues were highest at 0.5 h postexposure. This indicates that a fraction of the deposited chromium had been absorbed rapidly, and the remaining lung chromium was cleared more slowly.

Distribution

Retention of radiolabeled chromium chloride was less than 1% of the dose two days after oral administration to male and female rats and 0.3% on day 20.

Tanners on retirement (exposure was mainly to basic chromium sulphate) for at least 15 months exhibited normal chromium levels in serum, urine and hair, demonstrating that markedly increased long-term body burdens of chromium had not developed.

In rats exposed to aerosols of chromium chloride hexahydrate, lung chromium concentrations at 0.5 hours postexposure were nearly proportional to the product of exposure concentration and time. Radiolabelled chromium chloride in different tissues was measured 24-h after intratracheal instillation in rats. About 5% of the dose was recovered in lung lavage, 23% was still contained in the lungs and trachea. The highest tissue levels were found in the kidney, femur, large intestine and blood.

Excretion

After the first 6 days, the elimination of radiolabeled chromium chloride in the rat followed a half-time of about 92 days. Over 20 post-administration days, 99% of the oral dose was excreted in faeces and 0.8% in the urine. Regarding exposures to soluble basic chromium sulphate among tanners, chromium in serum decreased by more than 50% over 9 -months postexposure and, in another study with a follow-up of 40 days, chromium decreased in urine with an apparant half-time of about one month. Concentrations of chromium chloride hexahydrate in rats exposed to water soluble chromium (III) aerosols declined monoexponentially with an elimination half-time of 6.8 days.

Conclusions:

This review supports the conclusion that trivalent chromium compounds have low systemic availability by all routes of exposure.

Executive summary:

Absorption is plausible for a water soluble compound even if the ability of chromium (III) to penetrate biological membranes is limited because chromium (III) is known to form complexes with biological ligands which enhance penetration. Chromium (III) is absorbed from the normal diet in very low amounts, about 5 -10% of inhaled water-soluble chromium (III) aerosols were taken up by circulating blood within hours to one day, and water-soluble (III) compounds are able to cross the skin penetration barrier and enter the epidermis.

A significant fraction of chromium appears to be absorbed into the blood and then distributed widely to parenchymal organs. Inhalation and intratracheal studies show that chromium (III) chloride is retained in the lung in proportion to the dose and is cleared realtively slowly from this organ.

Chromium (III) is mainly excreted in the faeces and urine. The delayed elimination seen in studies with water-soluble chromium (III) is consistent with intracellular binding.

Description of key information

Absorption

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.

Distribution

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.

Excretion

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.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

Although the behaviour of chromium in biological tissue varies according to degree of water solubility, in general, trivalent chromium compounds (in contrast to hexavalent chromium) are poorly absorbed and taken up by cells when not organically complexed.

Up to 1% of chromium III is absorbed from the normal diet, inhaled chromium III uptake is a very slow process, and chromium III compounds were not shown to be absorbed across the skin into systemic circulation. The prominent tissues for chromium distribution are the liver, kidneys and spleen as well as bone and the remaining carcass (muscle, skin and hair). There is no clear evidence to show the valency of trivalent chromium changes during metabolism and absorbed chromium III is mainly excreted in the urine and to a lesser extent in the faeces.