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Reference
Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Remarks:
Test according to state-of-the-art operating procedures for testing of metal bioelution.
Qualifier:
according to
Guideline:
other: ASTM D5517-07: Standard Test Method for determining the extractability of metals from art materials - ASTM, 2007 (American Society for Testing and Materials).
Principles of method if other than guideline:
The release/dissolution of cadmium from cadmium telluride in simulated gastric fluid was measured. The resulting value is termed bio-accessibility, and is defined as the fraction of a substance that is soluble under physiological conditions and therefore potentially available for absorption into systemic circulation. The simulated gastric fluid represents an exposure-relevant exposure route (oral exposure). The compound was introduced as powder in a test item / solution ratio of 200 mg/L during 2 hours.

GLP compliance:
yes
Details on test animals and environmental conditions:
not applicable
Details on exposure:
not applicable
Preliminary studies:
not applicable
Type:
other: bioaccessibility
Results:
gastric fluid (2hours) as %Cd released of total Cd content: average : 1.5
Details on absorption:
not applicable
Details on distribution in tissues:
not applicable
Details on excretion:
not applicable
Bioaccessibility testing results:
gastric bioaccessibility (2hours) as %Cd released of total Cd content: 1.5

cadmium telluride, loading 0.2 g/L              2h gastric at pH 1.5

Analyte                                                      Xavg ±Sbetween CVbetween

Cadmium (Cd)

dissolution

1.37±0.04 mg/L

3%

absolute Cd release

6.84± 0.22 mg/g

3%

% of total available Cd eluted 

1.5 %

 

xavg= average of 3 test vessels (2 samples per test vessel; blank corrected, if the blank values arehigherthan the reporting limit, otherwise blank assumed as 0).

sbetween= between vessel standard deviation (N=3).

CVbetween= between vessel Coefficient of Variation (%).

Conclusions:
The dissolution in gastric fluid is used to estimate bioavailability after oral exposure
Bio-elution test according to state-of-the-art procedures, useful for determining dissolution capacity of Cd in gastric fluid.
Executive summary:

During this study on Cadmium telluride,at a loading of 0.2 g/L in simulated gastric fluid (pH 1.5), it was shown that for cadmium an average value of 1.37 mg/L Cd (CVbetween-vessel = 3 %; N = 3) was found after 2 hours of extraction, corresponding with a cadmium release of 1.5 %.

The results can be assumed reliable since the test conditions stayed constant during the experimentand the coefficient of variation between replicates was rather small (3 %) and met the 20 % quality criterion at the 2 hours endpoint.

Description of key information

Key value for chemical safety assessment

Additional information

Uptake of cadmium can occur in humans via the inhalation of polluted air, the ingestion of contaminated food or drinking water and, to a minor extent, through exposure of the skin to dusts or liquids contaminated by the element (ECB, 2008; SCOEL, 2010).

In occupational settings, mainly inhalation exposure occurs although the dermal route may also play a role when metal, powder or dust is handled or during maintenance of machinery. Additional uptake is possible through food and tobacco (for example in workers who eat or smoke at the workplace).

For the general population, uptake of cadmium occurs principally via the ingestion of food or, to a lesser extent, of contaminated drinking water. In industrial sites polluted by cadmium, inhalation of air and/or ingestion of soil or dusts may contribute to significant exposure. Tobacco is an important additional source of cadmium uptake in smokers. Finally, the consumer could be exposed (skin, inhalation or oral) through the use of consumption products.

For cadmium and its various compounds, systemic toxicity is attributed to the cadmium ion and differences in toxicity are principally linked to bioavailability. Although several factors influence bioavailablity, the main physico-chemical property of importance is solubility in water or biological fluids. Substances with higher solubility are expected to penetrate more easily into the organism and therefore generally show higher toxicity. 
CdTe
is a sparingly soluble Cd-compound. This is known from water solubility data (cfr IUCLID section 4.8) and demonstrated by in vitro methods ‘bio-elution assays’ in which the amount of ion ‘available for absorption’ is measured. The dissolution (e.g. elution or extraction) of Cd++ion from surrogate (synthetic) tissue fluid is measured. The resultant value is termed bioaccessibility and is defined as the amount of a substance (e.g Cd++) available for absorption (Stopford et al 2003). The bio-elution data (for details cfr IUCLID) are summarized below .

Table- Bio-elution data on CdTe measured in different physiological fluids

Test substance

 

Gastric Bioaccesibility

2 hours as % Cd released of total Cd content

Interstitial
Bioaccesibility

24- 168 hours as % Cd released of total Cd Content

Lysosomal
Bioaccesibility

24- 168 hours as % Cd released of total Cd Content

Sweat
Bioaccesibility

24- 168 hours as % Cd released of total Cd Content

CdTe

 

35.35 ± 8.69 (ref ECTX 2013)*

1.5 (ref ECTX 2018)

 


0.10 - 0.08


79.9-92.5


1-1.97

* ECTX 2013, 2 hours Bio-elution Study on Cadmium telluride at a 0.2 g/L loading in a simulated gastric fluid was repeated in ECTX 2018 with CdTe sample as smallest put on the market (75-250 µm)
Reason for performing ECTX 2018 was because of variable results between repeated experiments in ECTX 2013 and to perform the test in a series of tests in comparison with other Cadmium CMR compounds.

Absorption

Gastrointestinal absorption of cadmium is usually less than 5% but varies with the form of cadmium present, the composition of the diet, age and the individual iron status. High gastrointestinal absorption rates (up to 20%) have been observed for example in women with lowered iron stores (serum ferritin <20μg/L) (Sasser and Jarboe, 1977; Weigel et al.,1984; ECB, 2007).

Cadmium is absorbed by the respiratory route at rates varying between 2 and 50% depending on the cadmium compound involved (water soluble or insoluble), the size of the particles (dusts or fumes), the deposition pattern in the respiratory tract and the ventilation rate. Values of 10 to 30% for dusts and 25-50% for fumes are cited in the EU Summary Risk Assessment Report (RAR) (ECB, 2007) and various publications (Boisset et al.,1978; Glaser et al.,1986; Oberdörster et al.,1979; Oberdörster and Cox, 1989; Oberdörster, 1992; Dill et al.,1994; Hadley et al.,1980).

The results from studies in mouse, rat, rabbit and in vitro human skin models suggest that, although cadmium may penetrate through skin, absorption of soluble and less soluble compounds is generally lower than 1% (Kimura and Otaki, 1972; Lansdown and Sampson, 1996; Wester et al.,1992; ECB, 2008).

Distribution

Following absorption, the deposition of cadmium (Cd2+) is assumed to be independent of the chemical form to which exposure occured (ECB, 2007). Cadmium is a cumulative toxicant. It is transported from its absorption site (lungs or gut) to the liver, where it induces the synthesis of metallothionein which sequestrates cadmium. The cadmium-metallothionein complex is then slowly released from the liver and transported in the blood to the kidneys, filtrated through the glomerulus and reabsorbed in the proximal tubule where it may dissociate intracellularly (Chan and Cherian, 1993). There, free cadmium again induces the synthesis of metallothionein, which protects against cellular toxicity until saturation.

In non-occupationally exposed individuals, cadmium concentrations in kidney is generally between 10 and 50 mg/kg wet weight, with smokers showing 2 to 5-fold higher values than non-smokers (Nilsson et al.,1995). After long-term low level exposure, approximately half the cadmium body burden is stored in the liver and kidneys, one third being in the kidney where the major part is located in the cortex (Kjellström et al.,1979). The kidney: liver concentration ratio decreases with the intensity of exposure and is, for instance, lower in occupationally exposed workers (7 to 8-fold ratio) (Ellis et al.,1981; Roels et al.,1981) than in the general population (10 to 30-fold ratio) (Elinder et al.,1985). The distribution of cadmium in the kidney is important as this organ is one of the critical targets after long-term exposure.

In blood, most cadmium is localised in erythrocytes (90%) and values measured in adult subjects with no occupational exposure are generally lower than 1μg/L in non-smokers. Blood cadmium (Cd-B) values are 2 to 5-fold higher in smokers than in non-smokers (Staessen et al.,1990; Järup et al.,1998; Ollson, 2002). In the absence of occupational exposure, the mean urinary cadmium concentration (Cd-U) is generally below 1 to 2μg/g creatinine in adults. While Cd-B is influenced by both recent exposure and cadmium body burden, Cd-U is mainly related to the body burden (Lauwerys and Hoet, 2001). Smokers excrete more cadmium than non-smokers and their Cd-U is on average 1.5-fold higher than for non-smokers.

The placenta provides a relative barrier, protecting the foetus against cadmium exposure. Cadmium can cross the placenta but at a low rate (Trottier et al.,2002; Lauwerys et al.,1978; Lagerkvist et al.,1992).

Metabolism

Cadmium is not known to undergo any direct metabolic conversion such as oxidation, reduction or alkylation. The cadmium (Cd2+) ion does bind to anionic groups (especially sulfhydryl groups) in proteins and other molecules (Nordberg et al.,1985). Plasma cadmium circulates primarily bound to metallothionein and albumin (Foulkes and Blanck, 1990; Roberts and Clark, 1988).

Excretion

Absorbed cadmium is excreted very slowly, with urinary and fecal pathways being approximately equal in quantity (< 0.02% of the total body burden per day) (Kjellström et al.,1985). It accumulates over many years, mainly in the renal cortex and to a smaller extent in the liver and lung. The biologic half-life of cadmium has been estimated to be between 10 to 30 years in kidney and 4.7 to 9.7 years in liver (Ellis et al.,1985). The half-life in both organs is markedly reduced with the onset of renal toxicity when tubule loss of cadmium is accelerated. The total cadmium body burden reaches about 30 mg by the age of 30.

Biomonitoring

Biomonitoring methods for either Cd-B or Cd-U are often used rather than airborne measurements because they integrate all possible sources of occupational and environmental exposures (e. g. digestive exposure at the workplace, tobacco smoking and diet). In addition, since cadmium is a cumulative toxicant, a measure of the body burden (i. e. Cd-U) is the most appropriate exposure parameter for conducting risk assessments. In workers with substantial cadmium exposure (i. e. Cd-U > 3μg/g creatinine), 30 years exposure to 50μg/m³ of cadmium would lead to a Cd-U of 3μg/g creatinine (SCOEL, 2010).