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In vitro solubility and bioaccessibility

Cr(III) substances vary considerably in their water solubility: for example, whereas substances like Cr(III) chloride and sulfate have water solubilities of approx. 585 g/L (25°C) and 700 g/L (35°C) respectively, Cr (III) oxide is often described as “insoluble” (Schneider et al., 2001). Thus, the solubility of chromium (III) oxide in physiological fluids is expected to be low.

 

In published bioaccessibility tests with a loading of 100 mg/L simulating dissolution in body fluids, dissolved Cr concentration of 2.06 microg/L and < 2 microg/L were determined in artificial lysosomal fluid and sweat after 7 days (Hedberg et al. 2010; Hedberg and Midander, 2010).

 

In another bioaccessibility test (Knopf, 2020) in three different surrogate lung fluids (GMB, ALF, HTC) with a loading of 2g/L, dichromium trioxide was similarly poorly soluble (< 0.005% of loading): after 168h a maximum of total dissolved chromium (3kDa filtered to be particle-free) was measured to be 19.6 µg/L, 61.3µg/L and 0.55µg/L in GMB, ALF and HTC respectively. In all three media, Cr(III) concentrations were measured to be close to or below the LOD. Based on the known complexation behaviour of trivalent chromium, it can be hypothesized that dissolved Cr(III) formed complexes with e.g. anions such as acetate or citrate, or also with proteins such as BSA or Lysozyme (as contained in the media) and was thus observed in the chromatograms as “CrComplex”. The highest Cr(VI) concentration of 21.6 µg/L was measured after 24 h in GMB and can without doubt be attributed to the analytically verified very minor CrVI impurity of dichromium trioxide (< 0.01 %). Thus, the rate and extent to which chromium (III) oxide produces soluble (bio)available ionic and other chromium-bearing species is extremely limited.

Overall, the poor solubility and bioaccessibility of chromium (III) oxide is expected to be reflected in similarly poor systemic bioavailability, thus explaining the lack of any overt toxicity of Cr(III).

 

in vivo bioavailability (animal data)

The retention and clearance of chromium in the lung, heart, liver, kidney, spleen, plasma and blood cells was investigated in rats after a single exposure to either Cr (VI) or Cr (III)) aerosols with different chromium levels (7.4-15.9 mg Cr/m3) and different particle size distributions. The investigation was carried out from 0.5 h up to 7 days after exposure. The initial concentrations of lung chromium were in proportion to the exposure levels for each inhalation series of Cr (VI) or Cr (III) compounds. Chromium clearance from the lungs in the Cr (VI) groups was dependent on the size distribution of the aerosol particles. In the groups exposed to smaller Cr (VI) aerosol particles, the lung chromium clearance showed two phases. The biological half-time of the first phase was 31.5 h and that of the following second phase was 737 h. Chromium clearance from lungs exposed to larger particles of Cr (VI) or to Cr (III) aerosols showed a single phase, the biological half-time of which ranged from 151 to 175 h. Chromium transport from the lungs into the blood, kidneys and liver was more rapid in the Cr (VI) groups than in the Cr (III) groups. In the former groups, the kidneys and liver also showed two-phase chromium clearance (Suzuki et al., 1984).

 

As part of a chronic oral bioassay (NTP, 2010), the tissue distribution of (III) picolinate monohydrate was investigated in female B6C3F1 mice and rats (n=30) fed diets of 0, 2,000, 10,000 and 50,000ppm) for durations of 4,11 and 180 days. On days 4, 11 and 180 animals were placed in metabolism cages to collect urine and faeces. At the end of the collection phase, blood samples were taken and liver, kidney, stomach (glandular and forestomach parts) were removed. The chromium content was determined in all tissues and excreta via ICP-MS. The highest tissue levels were generally in liver and kidneys.

The absorption, distribution, metabolism and excretion was investigated in detail in adult male Fischer 344/N rats and female B6C3F1 mice using a combination of non-labelled and 14C-labelled chromium (iII) picolinate, administered by gavage as single doses (range 15-20 mg/kg bw) either dissolved in propylene glycol (PG) as an aqueous slurry:

- rats dosed orally with [14C]-chromium picolinate in PG excreted an average of 53% of the 14C dose in urine, 39% in faeces, and 1.5% as CO2 in breath in 24 hours. No measurable dose was collected as volatiles in breath. An additional 8% of the 14C dose was excreted during the collections at 48 and 52 hours. An average of 1.25% ± 0.24% and 97.5% ± 7.4% of the chromium dose was excreted in urine and faeces, respectively, in 48 hours. An average of 49.0% ± 1.2% the 14C dose received was excreted in 24 hours as N-picolinoylglycine. An average of 1.9% ± 0.4% and 1.1% ± 0.7% of the 14C dose received was excreted in 24 hours as picolinic acid and chromium picolinate, respectively. Less than 1% of the 14C dose was found in any of the tissues.

- rats dosed orally with a water slurry excreted an average of 41% of the 14C dose in urine, 47% in faeces, and 1.4% as CO in breath in 24 hours. An additional 4% of the 14C dose was excreted during the collections at 48 hours. An average of 1.53% ± 0.51% and 97.6% ± 7.4% of the chromium dose was excreted in urine and faeces, respectively, in 48 hours. Less than 1% of the 14C dose administered was found in the non-gastrointestinal tract tissues at 48 hours; the gastrointestinal tract tissues and contents contained 0.15% of the administered radioactivity.

- mice administered via PG excreted an average of 42.0% ± 7.8% of the 14C dose in urine and 55.1% ± 5.6% in faeces in 48 hours. An average of 3.9% ± 1.1% and 91.3% ± 12.7% of the chromium dose was excreted in urine and faeces, respectively, in 48 hours. A total of less than 1% of the 14C dose was found in the tissues of animals at 48 hours post dosing. An average of 31.8% ± 7.6% of the 14C dose was excreted in 48 hours as N-picolinoylglycine, the urinary metabolite isolated and identified from rat urine. An average of 1.3% ± 0.8% and 2.8% ± 1.0% of the 14C dose was excreted in 48 hours as picolinic acid and chromium picolinate, respectively. Also present in mouse urine was an additional metabolite, MUr1, that accounted for an average of 0.25% ± 0.11% of the 14C dose.

- in mice receiving an aqueous slurry, the excretion amounted to an average of 26% of the 14C dose in urine and 59% in faeces in 48 hours. Less than 0.1% of the 14C dose was excreted as CO2 in breath in 48 hours, and an average of 0.2% of the 14C dose was recovered in the digested carcasses (data not shown). An average of 1.1% ± 0.7% and 105% ± 7.8% of the chromium dose was excreted in urine and faeces, respectively, in 48 hours. An average of 22.3% ± 4.2% of the 14C dose was excreted in 24 hours as N-picolinoylglycine, the urinary metabolite isolated and identified from rat urine. An average of 0.29% ± 0.04% and 0.51% ± 0.20% of the 14C dose was excreted in 24 hours as picolinic acid and chromium picolinate, respectively. Also present in mouse urine was an additional metabolite, MUr1, that accounted for an average of 0.16% ± 0.12% of the 14C dose.

 

As reviewed by EPA (1998), historical data form a number of animal studies confirm that trivalent chromium is poorly absorbed in the gastrointestinal tract. Visek et al. (1953) estimated that less than 0.5% of ingested CrCl3 was absorbed through the gastrointestinal tract of the rat. Mertz et al. (1965) estimated that rats absorbed less than 3% of a single dose of CrCl3 by gavage. MacKenzie et al. (1959) estimated that less than 3% of a single dose of CrCl3 by stomach tube was absorbed in rats. Ogawa (1976) found gastrointestinal absorption of CrCl3 to be less than 3% in rats. Henderson et al. (1979) determined that hamsters absorbed less than 1.5% of an administered oral dose of trivalent chromium. Furthermore, Mertz et al. (1965) reported that absorption in rats was independent of the administered dose and dietary chromium status (deficient or supplemented in chromium) of the animals. Cr(III) was found to be better absorbed in fasted than in fed rats (MacKenzie et al., 1959).

 

in vivo bioavailability (human data)

The investigation of the urinary excretion of chromium in workers exposed to chromium lignosulfonate confirmed That the chromium in the dust was in the trivalent (II) oxidation state, and 30 % of the airborne particles were less than 5 pm in diameter. Personal sampling of total dust concentrations in air varied from 0.1 to12 mg/m3, and the chromium content in air was between 5 and 230 ug/m3. Chromium (III) lignosulfonate dust was rapidly absorbed, and a peak of urinary excretion was seen immediately after exposure. No appreciable accumulation of chromium occurred over 3 d, as evaluated by comparison with pre-shift urinary chromium concentrations. The addition of EDTA to the urine of exposed persons greatly enhanced the capacity of chromium to traverse a dialysis membrane; the same effect was seen with chromium (III) chloride. It was concluded that chromium (111) lignosulfonate yields chromium (III), which acts pharmacokinetically like water-soluble hexavalent chromium compounds (Kiilunen et al., 1983).

As supportive data, the following historical human data are cited in an EPA review: “based on faecal excretion of 51Cr following oral administration of 51CrCl3 to human patients, Donaldson and Barreras (1966) estimated absorption to be approximately 0.4%. When 51CrCl3 was administered intraduodenally, absorption was not appreciably changed. In rats, approximately 2% of the intragastric dose of CrCl3 appeared to be absorbed based on faecal excretion of chromium. Jejunal administration only slightly increased the apparent absorption of CrCl3. Anderson et al. (1983) confirmed the low absorption of trivalent chromium in humans following the administration of 200 μg of Cr(III) trichloride, and they suggested that the absorption efficiency of trivalent chromium is dependent on dietary intake. Anderson et al. (1986) reported that at low levels of dietary intake (10 μg) about 2% of trivalent chromium was absorbed. When intake increases to > 40 μg, the absorption efficiency dropped to approximately 0.5%. Bunker et al. (1984) determined that elderly subjects absorbed less than 3% of trivalent chromium ingested in the diet (EPA, 1998).

 

Physiologically based pharmacokinetic (PBPK) models

A multi-compartment (PBPK) model has been developed to describe the behaviour of CrIII (and CrVI) in humans, including compartments for gastrointestinal lumen, oral mucosa, stomach, small intestinal tissue, blood, liver, kidney, bone and a combined compartment for remaining tissues. The model development is based on toxicokinetic data for total Cr in human tissues and excreta identified from the published literature. Overall, the PBPK model provides a good description of chromium toxicokinetics and is consistent with the available total chromium data from Cr(III) and Cr(VI) exposures in humans (Kirman et al., 2013).

In view of its function as an essential trace element, the bioavailability Chromium(III) from the most important commercially used human oral Cr supplements was investigated by using radiolabelled compounds and whole-body-counting in rats and also in humans. In rats, the apparent oral absorption of 51Cr(III) from Cr-picolinate, Cr-nicotinate, Cr-phenylalaninate, Cr-proprionate, or Cr-chloride was generally low (0.04–0.24 %) in rats with slightly higher values for Cr-chloride and -phenylalaninate. Considering the rapid urinary excretion, the true absorption of 51Cr was higher for CrPic3 (< 1 %). The bioavailability of CrPic3 and Cr(D-Phen)3 was additionally analysed in human volunteers by intraindividual comparison. The apparent absorption (=Cr bioavailability) of 51Cr from both compounds was substantially higher in humans (0.8–1 %) than in rats. Like in fats, most of the freshly absorbed CrPic3 was rapidly excreted via urine (Laschinsky et al., 2012).

A similar multi-compartment PBPK model Cr(III) and Cr(VI) was developed by the same group of investigators in rats and mice, involving the model compartments GI lumen, oral mucosa, forestomach/stomach, small intestinal mucosa (duodenum, jejunum, ileum), blood, liver, kidney, bone and a combined compartment for remaining tissues. Data from ex vivo Cr(VI) reduction studies were used to characterise reduction of Cr(VI) in fed rodent stomach fluid as a second-order, pH-dependent process. For model development, tissue time-course data for total chromium were collected from rats and mice exposed to Cr(VI) in drinking water for 90 days at six concentrations ranging from 0.1 to 180 mg Cr(VI)/L. These data were used to supplement the tissue time-course data collected in other studies with oral administration of Cr(III) and Cr(VI), including that from recent NTP chronic bioassays. Clear species differences were identified for chromium delivery to the target tissue (small intestines), with higher concentrations achieved in mice than in rats. Species differences are described for distribution of chromium to the liver and kidney, with liver:kidney ratios higher in mice than in rats. This rodent PBPK model used in conjunction with the human PBPK model for Cr(VI) facilitates understanding of species differences in toxicokinetic factors (Kirman et al., 2012).

The bioaccessibility of chromium from Cr-III-oxide was assessed in comparison to that from Cr-contaminated soil samples. The bioaccessibility of Cr2O3 was substantially lower (<0.1%) than that of the CrIII in soils with a maximum of 9%. No CrVI was detected in any of the soil samples. The bioaccessibility tests were carried out at a loading of 10g/L of extraction fluid. Surrogate gastric medium (pH 1.8 buffered with citric, acetic, and malic acids) were used.  Half the subsamples of soils were incubated for 1 h under shaking at 275 rpm and 37°C, after which the remainder continued to the intestinal phase. All extracts were filtered through 0.45μm filters immediately after the extraction was complete, and were analysed by ICP MS (Koch et al., 2012).

Another PBPK was already developed much earlier, but likely suffers from a lack of input/validation data, compared to those described above. Since the reduction of Cr(VI) to Cr(III) and the differences in kinetics are important determinants of the disposition and toxicity of chromium. This PBPK takes into account different absorption and reduction rates in: the lung and gastrointestinal tract; different efficiencies of transfer of Cr(III) and Cr(VI) into tissues including erythrocytes, where Cr(VI) is reduced to Cr(III) and retained for an extended period of time; uptake and storage in bone; and reabsorption of chromium from the gastrointestinal tract. The model is shown to be capable of generating the observed distributions of chromium between plasma and erythrocytes in rats given Cr(VI) intragastrically, intraduodenally, or intratracheally (O'Flaherty & Radike, 1991; O’Flaherty, 1993).

 

Overall summary

The very poor solubility of Cr(III)oxide in comparison to soluble trivalent chromium is mirrored in its in vitro bioaccessibility and in vivo bioavailability. The existing toxicokinetic studies show that trivalent chromium (in contrast to hexavalent chromium) is poorly absorbed. Less than 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 of 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 chromium III is mainly excreted in the urine and to a lesser extent in the faeces.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information