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Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Study plan: signed on 13 Nov 2018. Dosing: initiated on 15 Feb 2019. In-life phase of the study: completed on 01 Mar 2019. Experimental start date: 14 Feb 2019, Experimental completion date: 23 May 2019. Final report: 28 October 2019
Objective of study:
distribution
excretion
toxicokinetics
bioaccessibility
Principles of method if other than guideline:
- Principle of test: The objectives of this 14-day pilot study (Dose Range Finding study) was to determine whether cadmium telluride up to 100 mg/kg bw/day (1500 ppm) was well tolerated, when given via diet for 14 days to Wistar Han rats and to provide data for the selection of the dose levels for a subsequent sub-chronic (90-day) oral toxicokinetic study. In addition, the cadmium and tellurium concentrations in the liver, kidney, faeces and urine were compared to the reference group (cadmium chloride).
GLP compliance:
no
Remarks:
Palatability studies have a non-GLP status but are carried out in the quality assured environment of Charles River Den Bosch GLP test facility. No guidelines are applicable as this study is used for dose level selection purposes only.
Specific details on test material used for the study:
Batch (Lot) Number: CdTe #217824-B
Expiry date: 13 September 2020 (expiry date)
Physical Description: Black powder
Purity/Composition: 99.999 %
Storage Conditions: At room temperature
Test item handling: No specific handling conditions required
Stability at higher temperatures: Stable
Species:
rat
Strain:
Wistar
Details on species / strain selection:
Han
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation:
- Weight at study initiation:
- Housing:
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):

IN-LIFE DATES: From: To:
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Duration and frequency of treatment / exposure:
14 days, oral feed exposure
Dose / conc.:
750 ppm (nominal)
Dose / conc.:
1 500 ppm (nominal)
No. of animals per sex per dose:
3
Control animals:
yes, historical
Positive control:
CdCl2 in the diet: 30 ppm (nominal)
Details on study design:
- Dose selection rationale: The dose levels were selected based on information provided by the Sponsor, and designed to follow the method described in Loeser and Lorke, 1977: Semichronic oral toxicity of cadmium. I. Studies on rats. Toxicology 7: 215-224. The high-dose level should not produce toxic effects, nor excessive lethality that would prevent meaningful evaluation. The mid-dose level is expected to produce no toxic effects.

Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled : urine, faeces, kidney, liver
- Time and frequency of sampling: 1 sampling after 14d of diet exposure

Statistics:
Descriptive statistics number, mean and standard deviation
Type:
distribution
Results:
No cadmium or tellurium was present in the kidney and liver of animals treated with cadmium telluride. Whereas, the average cadmium concentrations in kidney and liver were 773 and 695 ng/g respectively of animals treated with cadmium chloride.
Type:
excretion
Results:
At 750 and 1500 ppm CdTe: In faeces: average Cd conc: 629500 and 1118333 ng/g, ; average Te conc: 697500 and 1240000 ng/g. In urine: average Cd conc: < LLOQ; average Te concentrations: respectively below the lower limit of quantification and 52 ng/mL.
Details on distribution in tissues:
No cadmium or tellurium was present in the kidney and liver of animals treated with cadmium telluride. Whereas, the average cadmium concentrations in kidney and liver were
773 and 695 ng/g respectively of animals treated with cadmium chloride.
Details on excretion:
CONTROL group:
- The urine, faeces, kidney and liver concentrations of cadmium and tellurium in the vehicle dosed (control) animals were all below the lower limit of quantification (LLOQ).

CADMIUM TELLURIDE group:
- At 750 and 1500 ppm cadmium telluride, respectively:
• In faeces: the average cadmium concentrations were 629500 and 1118333 ng/g, and the average tellurium concentrations were 697500 and 1240000 ng/g.
• In urine, the average cadmium concentrations were below the lower limit of quantification, and the average tellurium concentrations were respectively below the lower limit of quantification and 52 ng/mL.
• The kidney and liver concentrations of cadmium and tellurium were all below the lower limit of quantification.

CADMIUM CHLORIDE group:
- In the 30 ppm cadmium chloride group (Reference Group), the average cadmium concentration in faeces, kidney and liver were 30633, 773 and 695 ng/g respectively. The average tellurium concentration in faeces was 947 ng/g. The kidney, liver and urine concentrations of tellurium and urine concentrations of cadmium were all below the lower limit of quantification.
Metabolites identified:
not measured
Details on metabolites:
none

Evaluation of Cadmium and Tellurium Levels in Control Samples (Vehicle):

The urine, faeces, kidney and liver concentrations of cadmium and tellurium in the vehicle dosed (control) animals were all below the lower limit of quantification.

Evaluation of Cadmium and Tellurium Levels in Samples from the Treatment Groups (750 and 1500 ppm Cadmium telluride)

When cadmium telluride was given via the diet for 14 days at 750 and 1500 ppm, the average cadmium concentrations in faeces were 629500 and 1118333 ng/g respectively. The average concentrations of tellurium in faeces were 697500 and 1240000 ng/g and below the lower limit of quantification and 52 ng/mL in urine at 750 and 1500 ppm respectively. The kidney and liver concentrations of cadmium and tellurium and urine concentrations of cadmium were all below the lower limit of quantification.

Evaluation of Cadmium and Tellurium Levels in Samples from the Reference Groups (30 ppm Cadmium chloride)

When cadmium chloride was given via the diet for 14 days at 30 ppm, the average cadmium concentrations in faeces, kidney and liver were 30633, 773 and 659 ng/g respectively. The average tellurium concentration in faeces was 947 ng/g, however, the source of the tellurium

in 2 of the animals in the reference group is unknown. The kidney, liver and urine concentrations of tellurium and urine concentrations of cadmium were all below the lower limit of quantification.

-

Remark: In the 30 ppm cadmium chloride group (Reference Group), some measurable concentrations of tellurium were detected in faeces of two animals (No. 11 and 12), leading to above mentioned average tellurium concentration of 947 ng/g, even though these animals were not

exposed to tellurium via their diet. It is unclear how tellurium could be present in the faecesof unexposed animals. The tellurium values ranged from 1200 to 1640 ng/g wet weight. Animals were group housed, therefore it is unlikely that these two animals (No. 11 and 12) were exposed to cadmium telluride while animal No. 10 was not. Moreover, samples from animal Nos. 10, 11 and 12 were measured subsequently, therefore, the possibility of contamination from ICP equipment with previous measured samples was not the source of tellurium contamination/measurements. Moreover, the samples of the reference group were measured after the samples of Group 1 followed by a blank sample, eliminating the possibility of contamination of the equipment. Therefore, the source of tellurium measured in the faeces of animal No’s 11 and 12 dosed with cadmium chloride is unknown.

Conclusions:
Based on the results of the 14-day Dose Range Finder study, administration of cadmium telluride in diet was well tolerated in rats at levels up to 1500 ppm (corresponding to an actual test article intake of 161 mg/kg bw/day). Moreover, no cadmium or tellurium was present in the kidney and liver of animals treated with cadmium telluride.
Executive summary:

The objectives of this 14-day pilot study (Dose Range Finding study) was to determine whether cadmium telluride up to 100 mg/kg bw/day (1500 ppm) was well tolerated, when given via diet for 14 days to Wistar Han rats and to provide data for the selection of the dose levels for a subsequent sub-chronic (90-day) oral toxicokinetic study. In addition, the cadmium and tellurium concentrations in the liver, kidney, faeces and urine were compared to the reference group (cadmium chloride).

The following parameters and endpoints were evaluated in this study: clinical signs, body weights, food consumption, test article intake, cadmium and tellurium concentrations in liver, kidney, urine and faeces, macroscopic findings and kidney and liver weights. No test item-related findings were noted for clinical signs, body weight, food consumption, macroscopic findings and organ weights.

-The urine, faeces, kidney and liver concentrations of cadmium and tellurium in the vehicle dosed (control) animals were all below the lower limit of quantification (LLOQ).

-At 750 and 1500 ppm cadmium telluride, respectively:

• In faeces: the average cadmium concentrations were 629500 and 1118333 ng/g, and the average tellurium concentrations were 697500 and 1240000 ng/g.

• In urine, the average cadmium concentrations were below the lower limit of quantification, and the average tellurium concentrations were respectively below the

lower limit of quantification and 52 ng/mL.

• The kidney and liver concentrations of cadmium and tellurium were all below the lower limit of quantification.

-In the 30 ppm cadmium chloride group (Reference Group), the average cadmium concentration in faeces, kidney and liver were 30633, 773 and 695 ng/g respectively. The average tellurium concentration in faeces was 947 ng/g. The kidney, liver and urine concentrations of tellurium and urine concentrations of cadmium were all below the lower limit of quantification.

In the 30 ppm cadmium chloride group (Reference Group), some measurable concentrations of tellurium were detected in faeces of two animals (No. 11 and 12), leading to above mentioned average tellurium concentration of 947 ng/g, even though these animals were not exposed to tellurium via their diet. It is unclear how tellurium could be present in the faeces of unexposed animals. The tellurium values ranged from 1200 to 1640 ng/g wet weight. Animals were group housed, therefore it is unlikely that these two animals (No. 11 and 12) were exposed to cadmium telluride while animal No. 10 was not. Moreover, samples from animal Nos. 10, 11 and 12 were measured subsequently, therefore, the possibility of contamination from ICP equipment with previous measured samples was not the source of tellurium contamination/measurements. Moreover, the samples of the reference group were measured after the samples of Group 1 followed by a blank sample, eliminating the

possibility of contamination of the equipment. Therefore, the source of tellurium measured in the faeces of animal No’s 11 and 12 dosed with cadmium chloride is unknown.

Based on the results of the 14-day Dose Range Finder study, administration of cadmium telluride in diet was well tolerated in rats at levels up to 1500 ppm (corresponding to an actual

test article intake of 161 mg/kg bw/day).

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Remarks:
Study is ongoing and Draft report expected:: 20 March 2020
Adequacy of study:
key study
Study period:
Study plan: signed on 11 Sept 2019. Dosing: initiated on 23 sept 2019. Experimental start date: 11 Sept 2019, Experimental completion date: 13 March 2020. Draft report expected: 20 March 2020
Justification for type of information:
EXPERIMENTAL STUDY ONGOING:
See document attached under attached justification below:
- Final study plan 'A 90-Day Toxicokinetics Study of Cadmium telluride by Dietary Administration in Wistar Han Rats'
Objective of study:
distribution
excretion
toxicokinetics
bioaccessibility
Principles of method if other than guideline:
The objective of this 90d study is to determine the toxicokinetic characteristics and the accumulation of Cadmium telluride, when given via diet for 90 days to Wistar Han rats, and compared to when Cadmium chloride is being dosed.

GLP compliance:
yes
Specific details on test material used for the study:
Batch (Lot) Number: CdTe #217824-B
Expiry date: 13 September 2020 (expiry date)
Physical Description: Black powder
Purity/Composition: 99.999 %
Storage Conditions: At room temperature
Test item handling: No specific handling conditions required
Stability at higher temperatures: Stable
Species:
rat
Strain:
Wistar
Details on species / strain selection:
Han
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation:
- Weight at study initiation:
- Housing:
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):

IN-LIFE DATES: From: To:
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Duration and frequency of treatment / exposure:
90 days, oral feed exposure
Dose / conc.:
750 ppm (nominal)
Remarks:
equals 50 mg/kg bw/day
Dose / conc.:
1 500 ppm (nominal)
Remarks:
equals 100 mg/kg bw/day
No. of animals per sex per dose:
3
Control animals:
yes, historical
Positive control:
CdCl2 in the diet: 30 ppm equals 2mg/kg bw/day
Details on study design:
- Dose selection rationale: The dose levels were selected based on information from the 14 DRF palatability study.
Details on metabolites:
none

Currently in-life results collected until Week 10. No test item-related clinical signs were observed in any of the test item groups. The absolute body weights and body weight gain was comparable with controls.  Food consumption is still comparable with controls for all test item groups.

Completion of In-life is foreseen 23 Dec 2019 (last date of necropsy).

Bioanalytical results is foreseen to be available 24 January 2020 , with Bioanalytical Draft Report and Toxicokinetic Draft Report foreseen for 7 February and 14 February respectively

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).