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Description of key information

The data from Rusch et al. 1986, in which Sprague-Dawley rats were exposed to different cadmium compounds (cadmium red, cadmium yellow, cadmium carbonate and cadmium fume) following single acute inhalation exposures (2-hours) to aerosols containing approximately 100mg/m3 of cadmium, shows that inhalation exposures to more soluble cadmium compounds (cadmium carbonate and cadmium fume) result in more rapid uptake and greater body burdens than exposure to the highly insoluble cadmium pigments. When inhaled, the insoluble cadmium pigments appear to be transported via mucocilliary clearance to the gastrointestinal tract for excretion via feces with minimal systemic absorption. In comparison, the more soluble cadmium compounds showed greater absorption and increased retention. 
The report data from Hazleton Laboratories America, Inc (1977), in which the uptake of cadmium resulting from ingestion by Sprague-Dawley rats of cadmium chloride was compared to the uptake seen with cadmium red and cadmium yellow pigments, shows that the percentage of cadmium absorbed from the pigments is only 0.41% (for Cd red) and 0.31% (for Cd yellow) of the absorption from the CdCl2. This indicates that cadmium solubility is an important factor in determining the absorption of Cadmium. Cd red and Cd yellow shows respectively 246 and 319 times lower Cd absorption then CdCl2.
The in vitro bioaccessibility data in the different biological fluids (reflecting oral, inhalation and dermal exposure) confirms the in vivo toxicokinetics data and shows that the amount of Cd++ available for absorption is much lower for Cd red and Cd yellow pigments in comparison to CdTe, a sparingly soluble Cd-compound.
From these data a much lower bioaccessibility (potential bioavailability) of Cd++ from CdZnS is shown in comparison to the other slightly soluble cadmium compounds.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

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. 
CdZnS
is a highly insoluble 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 and have been incorporated into read-across assessments for CdZnS. To this end, they were compared with bio-elution data obtained on CdTe, another sparingly soluble Cd-compound.

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

Test substance

 

Gastric Bioaccessibility

2 hours as % Cd released of total Cd content

Interstitial
Bioaccessibility

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

Lysosomal
Bioaccessibility

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

Sweat
Bioaccessibility

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

CdTe (reference substance)

 

35.35 ± 8.69

 


0.10 - 0.08


79.9-92.5


1-1.97

CdZnS

0.70 ± 0.09

0.0002- 0.0002

<0.00008 -<0.00008

0.007 -0.008

Factor difference CdTe/CdZnS

 

51

  

400

 

1156x103

  

246

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).

A subacute feeding study (7days), in which the uptake of cadmium resulting from ingestion of cadmium chloride was compared to the uptake seen with several cadmium pigments (red and yellow), showed that cadmium uptake was greatest in the cadmium chloride dosed group (Hazleton Laboratories America, Inc, 1977).
Average calculated cadmium absorption ratio's indicate respectively 246 and 319 times more cadmium absorbed following exposure to CdCl2 than after exposure to Cd red (CdSSe) and Cd yellow (CdZnS) pigments.
Comparing the results with the bio-elution data in gastric fluid (oral route) suggests that the bio-elution gives actually a conservative estimate of the difference in gastro-intestinal absorption. Indeed, considering the 35% bioaccessibility of CdTe in the gastric fluid as compared to an assumed 100% bioaccessibility of CdCl2 suggests that the difference between CdCl2 and CdZnS should be 150 (CdCl2 -CdTe: factor of 3; CdTe - CdZnS: factor of 50).

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).
Rusch et al. (1986) compared in Sprague-Dawley rats the effects of different cadmium compounds (cadmium red, cadmium yellow, cadmium carbonate and cadmium fume) following single acute inhalation exposures (2-hours) to aerosols containing approximately 100mg/m3 of cadmium.
 The blood levels of cadmium (µg Cd/ml) in the cadmium fume-exposed rats showed a marked elevation immediately following the exposure, while those in the carbonate-exposed group showed a slight elevation. Cadmium fume and carbonate-exposed groups approached background levels by the 24-hr sample period. The blood levels of cadmium in the Cd red- and Cd yellow-exposed rats were similar to those seen in the control group at all intervals (see table below, from Rusch et al 1986). Cd from the pigments was, in other words, not absorbed.

Table- Average cadmium levels in blood (from Rusch et al 1986)

time

Control

Cd Yellow

Cd Red

Cd carbonate

Cd Fume

M

F

M

F

M

F

M

F

M

F

 

blood

0

24 hours

72 hours

168 hours

30 days

0.009

0.004

0.008

0.006

<0.004

0.008

0.004

0.008

0.009

0.004

0.005

<0.004

<0.004

0.007

<0.004

0.009

0.006

0.004

0.018

0.005

0.010

0.004

0.011

0.014

<0.004

0.007

0.008

0.010

0.004

<0.004

0.013

0.009

0.012

0.012

0.012

0.017

0.008

0.014

0.015

0.012

0.024

0.005

-

-

-

0.030

0.006

-

-

-

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.

The study from Rusch et al (1986) shows only minimal deposition after exposure to Cd yellow and Cd red pigments in comparison to Cd carbonate exposure. The levels of cadmium in the liver and the kidneys (µg Cd/g) were much higher following exposure to the carbonate than following exposure to red and yellow pigments (see table below, from Rusch et al 1986).

 

Table- Average cadmium levels in tissue samples (from Rusch et al 1986)

time

Control

Cd Yellow

Cd Red

Cd carbonate

M

F

M

F

M

F

M

F

liver

0

24 hours

72 hours

168 hours

30 days

0.004

0.004

0.015

0.013

<0.03

0.002

<0.011

<0.014

<0.050

<0.04

0.040

0.029

0.010

0.010

<0.040

0.060

0.039

0.016

0.013

0.03

0.066

0.041

0.021

0.005

<0.03

0.049

0.039

0.015

0.010

0.04

0.77

0.79

1.43

2.09

1.49

1.87

1.95

2.62

3.85

2.40

 

kidneys

0

24 hours

72 hours

168 hours

30 days

0.03

0.03

0.06

0.13

<0.01

0.03

0.03

0.03

0.03

<0.02

0.08

0.05

0.04

0.06

0.20

0.06

0.07

0.06

0.10

0.20

0.09

0.04

0.05

0.04

0.10

0.05

0.03

0.05

0.04

0.05

0.27

0.57

2.6

8.3

18.4

0.46

0.92

3.6

9.0

16.1

 

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.

The study from Rusch et al (1986) shows that following exposure to Cd yellow-, Cd red- pigments and Cd carbonate, approximately the same levels of excretion into the urine (average levels between 1.5 and 7.3 µg in a 24hr period). The data indicate that the majority of Cd yellow and Cd red dose was eliminated in the feces, whereas much lower amounts were eliminated in the feces of the Cd carbonate-exposed rats.

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).