Cadmium telluride

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

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: 19 March 2020. Final report: 25 September 2020

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to same study

Objective of study:

bioaccessibility (or bioavailability)

distribution

excretion

toxicokinetics

Qualifier:

equivalent or similar to guideline

Guideline:

other: • Guideline on Bioanalytical Method Validation, European Medicines Agency (EMA), EMEA/CHMP / EWP/192217/2009, 21 July 2011.

Qualifier:

equivalent or similar to guideline

Guideline:

other: • Guidance for industry: Bioanalytical Method Validation, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) and Center for Veterinary Medicine (CVM), May 2018.

Qualifier:

equivalent or similar to guideline

Guideline:

other: • ICH Harmonised Tripartite Guideline S3a. Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies.

Qualifier:

equivalent or similar to guideline

Guideline:

other: EC No 440/2008, B.26 Repeated Dose (90 days) Toxicity (oral), 2008. • OECD 408, Repeated Dose 90-day Oral Toxicity Study in Rodents, 2018. • OPPTS 870.3100, EPA 712-C-98-199, 90-Day Oral Toxicity in Rodents, 1998.

Principles of method if other than guideline:

- Principle of test: The objective of this study was to determine the toxicology, accumulation and toxicokinetics of cadmium telluride in the rat and for a direct comparative bioavailability assessment with the chosen reference substance, cadmium chloride. It was proposed that this study should follow, as closely as possible, the experimental design used in the study by Loeser and Lorke, 1977, a study that investigated the sub-chronic toxicity and accumulation of cadmium in the liver and kidney in the rat dosed with cadmium chloride in the diet at 30 ppm (ref: : Loeser and Lorke, 1977. Semichronic oral toxicity of cadmium. I. Studies on rats. Toxicology 7: 215-224 https://doi.org/10.1016/0300-483X(77)90067-1)

-Short description of test conditions:
Wistar Han rats were treated with Cadmium telluride for 13 weeks by dietary administration at dose levels of 750 or 1500 ppm (powder diet). One additional group of Wistar Han rats was treated with 30 ppm Cadmium chloride (reference item) by dietary administration. The rats of the control group received standard powder diet without the test item.
In Weeks 1, 4 and 8 three animals/sex/test item group were sacrificed for bioanalytical purposes. Prior to sacrifice, blood, urine and faeces were collected to determine the Cadmium and Tellurium content. In Week 13, the remaining animals were sacrificed for bioanalytical and toxicological assessment purposes. Control group animals were only sacrificed in Weeks 1 and 13.
Samples of diets were collected for analysis. Chemical analyses of dietary preparations were conducted on Weeks 1 and 6 to assess concentration and homogeneity.

- Parameters analysed / observed:
clinical signs, body weights, food consumption, clinical pathology parameters (haematology, coagulation and clinical chemistry), toxicokinetic parameters, gross necropsy findings and organ weights

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:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: 5-7 weeks old at initiation of dosing
- Weight at study initiation: males: between 155 and 201g; females: between 120 and 156g
- Housing:
Polycarbonate cages (Makrolon type IV, height 18 cm) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS -J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) equipped with water bottles. Up to 3 animals of the same sex and same dosing group together. In the cage racks the control group cages were placed on top of the cage rack
followed by Groups 2 and 3. The cages of Group 4 (Cadmium chloride group) were placed in a separate cage rack. T
- Diet:ad libitum, except during designated procedures
- Water: ad libitum
- Acclimation period: 12 days before the commencement of dosing

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Targeted: 18 to 24°C; Actual mean: 19 to 21°C
- Humidity (%): Targeted: 40 to 70% ; Actual mean: 49 to 87%
- Air changes (per hr): Ten or more air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark (except during designated procedures)

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency):
Diets were prepared freshly for use at room temperature for a maximum of three weeks. Diets were kept at room temperature until use, if not used on the day of preparation. Any remaining
food left after filling the food hoppers was stored at room temperature for a maximum of three weeks for supplementing food during the respective food consumption measurement
interval. Diets were prepared freshly for use at room temperature for a maximum of three weeks in advance of first use.
- Mixing appropriate amounts with (Type of food): The test item was mixed without the use of a vehicle, directly with the required amount of
powder feed. A premix was prepared to gradually mix the test item with the required amount
of powder feed, which included no sieving or mortaring of the test item. Standard powder
rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany) was used.
- Storage temperature of food: room temperature

Duration and frequency of treatment / exposure:

90 days, oral feed exposure

Dose / conc.:

750 ppm (nominal)

Dose / conc.:

1 500 ppm (nominal)

No. of animals per sex per dose / concentration:

3

Control animals:

yes, historical

Positive control reference chemical:

CdCl2 in the diet: 30 ppm

Details on study design:

- Dose selection rationale: The dose levels were selected based on results of a 14-day repeated dose toxicity study with oral exposure of Cadmium telluride and Cadmium chloride in rats, Test Facility Reference No. 20170590, where no signs of toxicity were observed in any of the groups and designed to follow the method described in Loeser and Lorke et al 1977 (https://doi.org/10.1016/0300-483X(77)90067-1). The high-dose level should not produce toxic effects, nor excessive lethality that would prevent meaningful evaluation. The mid- and low-dose level was expected to produce no toxic effects.

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled : urine, faeces, plasma, kidney, liver
- Time and frequency of sampling:
In Weeks 1, 4 and 8 three animals/sex/test item group were sacrificed for bioanalytical purposes. Prior to sacrifice, blood, urine and faeces were collected to determine the Cadmium and Tellurium content. In Week 13, the remaining animals were sacrificed for bioanalytical and toxicological assessment purposes. Control group animals were only sacrificed in Weeks 1 and 13.

Statistics:

All statistical tests were conducted at the 5% significance level. All pairwise comparisons were conducted using two sided tests and were reported at the 1%
or 5% levels.
Numerical data collected on scheduled occasions was analysed according to sex and occasion.
Descriptive statistics number, mean and standard deviation were reported whenever possible.
Values may also be expressed as a percentage of predose or control values when deemed appropriate. Inferential statistics were performed according to the matrix below when possible, but did exclude semi-quantitative data, and any group with less than 2 observations.
The following pairwise comparisons were made:
Group 2 vs. Group 1
Group 3 vs. Group 1
Group 4 vs. Group 1

Preliminary studies:

14-day repeated dose toxicity study with oral exposure of Cadmium telluride and Cadmium chloride in rats, Test Facility Reference No. 20170590, where no signs of toxicity were observed in any of the groups (at levels up to 1500 ppm)

Type:

distribution

Results:

at 750 and 1500 ppm CdTe: no detectable and/or reliable levels of either cadmium or tellurium in the target organs (liver and kidney), plasma. In contrast, at a much lower dose level of 30 ppm CdCl2: Cadmium levels increased in the kidney and liver

Type:

excretion

Results:

Urine: at 750 and 1500 ppm CdTe and at 30 ppm CdCl2: no detectable and/or reliable levels of either cadmium or tellurium

Type:

excretion

Results:

Faeces: a 1:1 mean molar ratio and linear increase in Mean Cadmium and Tellurium concentration in faeces was observed between 750 and 1500 ppm CdTe. The mean Cadmium concentration in males and females at 30ppm CdCl2 was lower compared to the CdTe groups

Details on absorption:

NA

Details on distribution in tissues:

CONTROL group:
- The plasma, 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:
• In kidney:
Cadmium: The mean Cadmium concentration in the kidney in males and females at 750 ppm Cadmium telluride was below the LLOQ (0.155 μg/g). At 1500 ppm Cadmium telluride, the results were just above the LLOQ, but still well below the 3xLLOQ.
Tellurium:The mean concentration of Tellurium in the kidney in males and females at 750 and 1500 ppm Cadmium telluride were all below the LLOQ(0.455 μg/g)
• In liver:
Cadmium: The mean concentration of Cadmium in the liver in males and females at 750 and 1500 ppm Cadmium telluride were all below the LLOQ (0.155 μg/g).
Tellurium: The mean concentration of Tellurium in the liver in males and females at 750 and 1500 ppm Cadmium telluride were all below the LLOQ (0.455 μg/g).
• In plasma:
Cadmium: The mean concentration of Cadmium in plasma in males and females at 750 and 1500 ppm Cadmium telluride were all below the LLOQ (50.0 ng/mL).
Tellurium: The mean Tellurium concentration in plasma in males and females at 750 and 1500 ppm Cadmium telluride were all below the LLOQ (50.0 ng/mL).


CADMIUM CHLORIDE group:
• In kidney:
Cadmium: At 30 ppm Cadmium chloride, an increase in mean Cadmium concentration in the kidney was observed over time in males and females. Higher concentrations of Cadmium where observed in females compared to males at 30 ppm Cadmium chloride.
Tellurium: The mean concentration of Tellurium in the kidney in males and females at 30 ppm Cadmium chloride were all below the LLOQ (0.455 μg/g).
• In liver:
Cadmium: At 30 ppm Cadmium chloride, mean Cadmium concentration in the liver in males and females increased over time. Higher concentrations of Cadmium in the liver were observed in females compared to males at 30 ppm Cadmium chloride
Tellurium: The mean concentration of Tellurium in the liver in males and females at 30 ppm Cadmium chloride were all below the LLOQ (0.455 μg/g).
• In plasma:
Cadmium:The mean concentration of Cadmium in plasma in males and females at 30 ppm Cadmium chloride, were all below the LLOQ (50.0 ng/mL).
Tellurium: The mean Tellurium concentration in plasma in males and females at 30 ppm Cadmium chloride were all below the LLOQ (50.0 ng/mL).

Details on excretion:

CONTROL group:
- The urine and faeces concentrations of cadmium and tellurium in the vehicle dosed (control) animals were all below the lower limit of quantification (LLOQ). In faeces, only a very low level of Tellurium was measured in one control male at Week 13 (No. 4, 1.04 μg/g).

CADMIUM TELLURIDE group:
• In urine:
Cadmium: The mean concentration of Cadmium in urine in males and females at 750 and 1500 ppm Cadmium telluride were all below the LLOQ (50 ng/mL).
Tellurium: Mean Tellurium concentrations in urine were generally above the LLOQ (50 ng/mL), but below the 3xLLOQ. In females at 750 ppm Cadmium telluride, mean concentration of Tellurium remained very stable in Weeks 1, 4 and 8 (ranged between 71 and 94 ng/mL), but was below the 3xLLOQ, and even dropped to below LLOQ in Week 13 (27.4 ng/mL). In males at 750 ppm Cadmium telluride, mean concentration of Tellurium remained very stable in Weeks 1, 4, 8 and 13 (ranged between 78 and 97 ng/mL). At 1500 ppm Cadmium telluride, mean Tellurium concentration in urine increased in Weeks 4 and 8 in males (118 and 167 ng/mL respectively) and females (90.8 and 148 ng/mL, respectively) compared to Week 1 (males 83.7 ng/mL; females 74.2 ng/mL) and decreased again in Week 13 (males 122 ng/mL; females 119 ng/mL). Only the mean Tellurium concentration in males at 1500 ppm Cadmium telluride in Week 8 were above the 3xLLOQ. However it should be noted that, the results in urine might be affected by faecal particles that could be included in the collected urine samples.
• In faeces
Cadmium: At 750 ppm Cadmium telluride, a trend towards a small decrease in mean Cadmium concentration in faeces was observed throughout the study in both males and females. A consistent trend over time in cadmium concentration was not observed at 1500 ppm Cadmium telluride. At 750 ppm, the mean Cadmium concentration in males decreased from 608 to 514 μg/g and in females from 777 to 399 μg/g between Weeks 1 and 13. At 1500 ppm, the mean
Cadmium concentrations in faeces in males was decreased in Weeks 4 and 8 (1410 and 1370 μg/g, respectively) compared to Week 1 (1580 μg/g), but did increase in Week 13 (1660 μg/g). The level at Week 13 is comparable with that at Week 1. Notably, a relatively large variation in Cadmium concentrations was observed in males at 1500 ppm Cadmium telluride in Week 13. In females at 1500 ppm Cadmium telluride, a lower mean Cadmium concentration in faeces was seen in weeks 4, 8 and 13 compared to Week 1.
Tellurium:
At 750 ppm Cadmium telluride, mean concentration of Tellurium in faeces increased in males in Weeks 4 and 8 (802 μg/g and 811 μg/g, respectively) and decreased in Week 13 to a level below Week 1 (599 and 687 μg/g, respectively). In females at 750 ppm Cadmium telluride, a decrease in mean Tellurium concentration was seen over time with 487 μg/g in Week 13 compared to 884 μg/g in Week 1.
At 1500 ppm Cadmium telluride, mean Tellurium concentration in faeces in males remained high over the 13 weeks of treatment (between 1620 and 1820 μg/g), while a lower mean Tellurium concentration was seen in females in Weeks 4, 8 and 13 compared to Week 1.

CADMIUM CHLORIDE group:
• In urine:
Cadmium: The mean concentration of Cadmium in urine in males and females at 30 ppm Cadmium chloride were all below the LLOQ (50 ng/mL).
Tellurium:The mean concentration of Tellurium in urine in males and females at were all below the LLOQ(50 ng/mL)
• In faeces
Cadmium: At 30 ppm Cadmium chloride, the mean Cadmium concentration in faeces remained stable throughout the study (Weeks 1, 4, 8 and 13) in males and females and ranged between 30.82 and 40.6 μg/g. The mean Cadmium concentration in males and females at 30 ppm Cadmium chloride was lower compared to the Cadmium telluride groups.
Tellurium: At 30 ppm Cadmium chloride, mean Tellurium concentration in faeces in males and females were below the LLOQ (0.894 μg/g).

Metabolites identified:

no

Details on metabolites:

none

Bioaccessibility (or Bioavailability) testing results:

Significant difference in bioavailability potential between a relatively soluble cadmium compound, Cadmium chloride (the reference substance) and a relatively insoluble cadmium compound, cadmium telluride (test substance).
Cadmium telluride exhibited no evidence of bioavailability by dietary administration for 90 days at high dose levels of 750 and 1500 ppm. No detectable and/or reliable levels of either cadmium or tellurium were detected in the target organs (liver and kidney), plasma and urine.
In contrast, in the Cadmium chloride group, at a much lower dose level of (30 ppm), the Cadmium levels increased in the kidney and liver in line with the Loeser and Lorke study (1977) (https://doi.org/10.1016/0300-483X(77)90067-1). The results are shown schematically and attached in section 'Overal remarks, attachments'

attached in section 'Overal remarks, attachments' Figures 2 to 12 presenting the Kidney (fig 2 -3), Liver (fig 4 -5), Plasma (fig 6 -7), Urine (fig 8 -9), Faeces (fig 10 -12) concentrations of Cadmium and Tellurium in the Control, Cadmium tellurium and Cadmium chloride groups.

Conclusions:

The bioavailability of Cadmium in kidney and liver after diet administration with 750 and 1500 ppm Cadmium telluride was significantly lower (approximately at or below LLOQ) in rats even at significantly higher dose levels compared to diet administration with 30 ppm Cadmium chloride. At 30 ppm Cadmium chloride, Cadmium in males and females in the kidney and liver increased over time in line with the Loeser and Lorke study (1977) (https://doi.org/10.1016/0300-483X(77)90067-1).
The Cadmium and Tellurium were extensively excreted via the faeces in the Cadmium telluride groups and in the Cadmium chloride group. A linear increase in Mean Cadmium and Tellurium concentration in faeces was observed between 750 and 1500 ppm Cadmium telluride.
In urine, mean Tellurium concentrations remained stable in males at 750 ppm Cadmium telluride in Weeks 1, 4, 8 and 13 and in females at 750 ppm Cadmium telluride in Weeks 1, 4 and 8 and dropped to below LLOQ in Week 13. In urine, mean Tellurium concentrations increased over time in males and females at 1500 ppm Cadmium telluride in Weeks 1, 4 and 8, but decreased in Week 13. Mean Tellurium concentrations in urine were approximately at or below 3xLLOQ, however it should be noted that, concentrations in urine might be affected by faecal particles that could be included in the collected urine samples.
Mean Cadmium concentration in plasma and urine in males and females of the Cadmium telluride and Cadmium chloride groups were below LLOQ. In addition, mean tellurium concentration in the plasma, kidney and liver in males and females of the Cadmium telluride and Cadmium chloride groups were below LLOQ.

Administration of Cadmium telluride by dietary administration for at least 90 days was well tolerated in rats at levels up to 1500 ppm (corresponding to a mean test article intake of 103 and 121 mg/kg body weight in males and females, respectively). Only slight non-adverse changes in haematology and clinical chemistry parameters were seen. The findings observed in animals treated with 30 ppm Cadmium chloride were limited to alopecia and changes in several clinical chemistry parameters.

The results of this study have demonstrated a significant difference in bioavailability potential between a relatively soluble cadmium compound, Cadmium chloride (the reference substance) and a relatively insoluble cadmium compound, cadmium telluride (test substance).
Cadmium telluride exhibited no evidence of bioavailability by dietary administration for 90 days at high dose levels of 750 and 1500 ppm. No detectable and/or reliable levels of either cadmium or tellurium were detected in the target organs (liver and kidney), plasma and urine.
In contrast, in the Cadmium chloride group, at a much lower dose level of (30 ppm), the Cadmium levels increased in the kidney and liver in line with the Loeser and Lorke study (1977) (https://doi.org/10.1016/0300-483X(77)90067-1).

Executive summary:

The objective of this study was to determine the toxicology, accumulation and toxicokinetics of cadmium telluride in the rat and for a direct comparative bioavailability assessment with the chosen reference substance, cadmium chloride. It was proposed that this study should follow, as closely as possible, the experimental design used in the study by Loeser and Lorke, 1977 (https://doi.org/10.1016/0300 -483X(77)90067-1), a study that investigated the sub-chronic toxicity and accumulation of cadmium in the liver and kidney in the rat dosed with cadmium chloride in the diet at 30 ppm.

In Weeks 1, 4 and 8 three animals/sex/test item group were sacrificed for bioanalytical purposes. Prior to sacrifice, blood, urine and faeces were collected to determine the Cadmium and Tellurium content. In Week 13, the remaining animals were sacrificed for bioanalytical and toxicological assessment purposes. Control group animals were only sacrificed in Weeks 1 and 13.

Samples of diets were collected for analysis. Chemical analyses of dietary preparations were conducted on Weeks 1 and 6 to assess concentration and homogeneity.

The following parameters and end points were evaluated in this study: clinical signs, body weights, food consumption, clinical pathology parameters (haematology, coagulation and clinical chemistry), toxicokinetic parameters, gross necropsy findings and organ weights.

Test diets prepared were considered homogeneous at the concentrations tested in Week 1 and analysis of the accuracy revealed acceptable levels in Weeks 1 and 6. The diets of Groups 2 and 3 prepared for use in Week 1 were not homogeneous. As the homogeneity results were slightly outside the acceptable range (≤ 20%) and based on the evaluation made prior to start of the study (documented in appendix 3 of report), these results had no impact on the outcome of the study.

Overall, dietary analyses confirmed that diets were prepared accurately and were acceptable homogenously for the purposes of this study.

In plasma, the mean Cadmium and Tellurium concentration in males and females at 750 and 1500 ppm Cadmium telluride and at 30 ppm Cadmium chloride were all below the LLOQ.

The mean Cadmium concentration in males and females in the kidney at 750 ppm Cadmium telluride and in the liver in males and females at 750 and 1500 ppm Cadmium telluride was below the LLOQ. At 1500 ppm Cadmium telluride, the kidney results were just above the LLOQ, but still well below the 3xLLOQ. At 30 ppm Cadmium chloride, an increase in mean Cadmium concentration in the kidney and liver was observed over time in males and females.Higher concentrations of Cadmium were observed in females compared to males at 30 ppm Cadmium chloride. The results in the Cadmium chloride group were in line with the Loeser and Lorke study (1977), but the Cadmium telluride groups did not follow the same trend. The mean concentration of Tellurium in the kidney and liver in males and females at 750 and 1500 ppm Cadmium telluride and 30 ppm Cadmium chloride were all below the LLOQ, which indicates a lack of bioavailability.

The mean concentration of Cadmium in urine in males and females at 750 and 1500 ppm Cadmium telluride and 30 ppm Cadmium chloride were all below the LLOQ (50 ng/mL), which is somewhat comparable with the results in the Loeser and Lorke study (1977), where minimal dose-dependent amounts of Cadmium were detected in urine in animals dosed with 30 ppm Cadmium chloride. For Tellurium, mean concentrations in urine were generally above the LLOQ, but below the 3xLLOQ. In females at 750 ppm Cadmium telluride, mean concentration of Tellurium remained stable in Weeks 1, 4 and 8, but was below the 3xLLOQ and even dropped to below LLOQ in Week 13. In males at 750 ppm Cadmium telluride, mean concentration of Tellurium remained very stable in Weeks 1, 4, 8 and 13. At 1500 ppm Cadmium telluride, mean Tellurium concentration in urine increased in Weeks 4 and 8 in males and females compared to Week 1 and decreased again in Week 13. Only the mean Tellurium concentration in males at 1500 ppm Cadmium telluride in Week 8 were above the 3xLLOQ. At 30 ppm Cadmium chloride, mean Tellurium concentration in males and females were below the LLOQ. However it should be noted that, the results in urine might be affected by faecal particles that could be included in the collected urine samples.

At 750 ppm Cadmium telluride, a trend towards a small decrease in mean Cadmium concentration in faeces was observed throughout the study in both males and females. A consistent trend over time in cadmium concentration was not observed at 1500 ppm Cadmium telluride. At 1500 ppm, the mean Cadmium concentrations in faeces in males was decreased in Weeks 4 and 8 compared to Week 1, but did increase in Week 13. The level at Week 13 is comparable with Week 1. In females at 1500 ppm Cadmium telluride, a lower mean Cadmium concentration in faeces was seen in weeks 4, 8 and 13 compared to Week 1.

At 750 ppm Cadmium telluride, the mean concentration of Tellurium in faeces increased in males in Weeks 4 and 8 and decreased in Week 13 to a level below Week 1, while in females a decrease in mean Tellurium concentration was seen over time. At 1500 ppm Cadmium telluride, mean Tellurium concentration in faeces in males remained high over the 13 weeks of treatment, while a lower mean Tellurium concentration was seen in females in Weeks 4, 8 and 13 compared to Week 1. A 1:1 mean molar ratio and linear increase in Mean Cadmium and Tellurium concentration in faeces was observed between 750 and 1500 ppm Cadmium telluride. At 30 ppm Cadmium chloride, the mean Cadmium concentration in faeces remained stable throughout the study in males and females. The mean Cadmium concentration in males and females at 30 ppm Cadmium chloride was lower compared to the Cadmium telluride groups. At 30 ppm Cadmium chloride, mean Tellurium concentration in faeces in males and females were below the LLOQ.

In Conclusion, the bioavailability of Cadmium in kidney and liver after diet administration with 750 and 1500 ppm Cadmium telluride was significantly lower (approximately at or below LLOQ) in rats even at significantly higher dose levels compared to diet administration with 30 ppm Cadmium chloride. At 30 ppm Cadmium chloride, Cadmium in males and females in the kidney and liver increased over time in line with the Loeser and Lorke study (1977).

The Cadmium and Tellurium were extensively excreted via the faeces in the Cadmium telluride groups and in the Cadmium chloride group.  A linear increase in Mean Cadmium and Tellurium concentration in faeces was observed between 750 and 1500 ppm Cadmium telluride.

In urine, mean Tellurium concentrations remained stable in males at 750 ppm Cadmium telluride in Weeks 1, 4, 8 and 13 and in females at 750 ppm Cadmium telluride in Weeks 1, 4 and 8 and dropped to below LLOQ in Week 13. In urine, mean Tellurium concentrations increased over time in males and females at 1500 ppm Cadmium telluride in Weeks 1, 4 and 8, but decreased in Week 13. Mean Tellurium concentrations in urine were approximately at or below 3xLLOQ, however it should be noted that, concentrations in urine might be affected by faecal particles that could be included in the collected urine samples.

Mean Cadmium concentration in plasma and urine in males and females of the Cadmium telluride and Cadmium chloride groups were below LLOQ. In addition, mean tellurium concentration in the plasma, kidney and liver in males and females of the Cadmium telluride and Cadmium chloride groups were below LLOQ.

Administration of Cadmium telluride by dietary administration for at least 90 days was well tolerated in rats at levels up to 1500 ppm (corresponding to a mean test article intake of 103 and 121 mg/kg body weight in males and females, respectively). Only slight non-adverse changes in haematology and clinical chemistry parameters were seen. The findings observed in animals treated with 30 ppm Cadmium chloride were limited to alopecia and changes in several clinical chemistry parameters.

The results of this study have demonstrated a significant difference in bioavailability potential between a relatively soluble cadmium compound, Cadmium chloride (the reference substance) and a relatively insoluble cadmium compound, cadmium telluride (test substance).

Cadmium telluride exhibited no evidence of bioavailability by dietary administration for 90 days at high dose levels of 750 and 1500 ppm. No detectable and/or reliable levels of either cadmium or tellurium were detected in the target organs (liver and kidney), plasma and urine.

In contrast, in the Cadmium chloride group, at a much lower dose level of (30 ppm), the Cadmium levels increased in the kidney and liver in line with the Loeser and Lorke study (1977).

Reference 2

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Objective of study:

bioaccessibility (or bioavailability)

distribution

excretion

toxicokinetics

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 or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: 6 weeks old
- Weight at study initiation: between 127 and 147 g
- Housing: animals were group housed (up to 3 animals of the same sex and same dosing group together) in polycarbonate cages (Makrolon type IV, height 18 cm or Makrolon type 2000P, height 21.5 cm) containing appropriate bedding (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) equipped with water bottles.
- Diet (e.g. ad libitum): ad libitum; Diet was provided ad libitum in stainless steel containers, covered by a stainless steel grid to prevent spillage, except during designated procedures. Diets remained in the food hopper for a maximum of one day, and on the day of weighing the remaining food in the food hopper was replaced with new diet. Food hoppers were shaken on a daily basis to divide any sawdust equally over the diet in order to facilitate food consumption. The feed was analyzed by the supplier for nutritional components and environmental contaminants. Results of the analysis were provided by the supplier and are on file at the Test Facility. It is considered that there were no known contaminants in the feed that would interfere with the objectives of the study.
- Water (e.g. ad libitum): Municipal tap water was freely available to each animal via water bottles. Periodic analysis of the water is performed, and results of these analyses are on file at the Test Facility. It is considered that there are no known contaminants in the water that would interfere with the objectives of the study.
- Acclimation period: The animals were allowed to acclimate to the Test Facility toxicology accommodation for 8 days before the commencement of dosing

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 20
- Humidity (%): 48 to 50
- Air changes (per hr): en or greater air changes per hour with 100% fresh air (no air recirculation) were maintained in the animal rooms.
- Photoperiod (hrs dark / hrs light):12 hour light/12 hour dark

IN-LIFE DATES: From: 14 Feb 2019 To: 1 March 2019

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 / concentration:

3

Control animals:

yes, historical

Positive control reference chemical:

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 (https://doi.org/10.1016/0300-483X(77)90067-1). 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:

CONTROL group:
- The 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:
No cadmium or tellurium was present in the kidney and liver of animals treated with cadmium telluride.

CADMIUM CHLORIDE group:
the average cadmium concentrations in kidney and liver were 773 and 695 ng/g respectively of animals treated with 30 ppm 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).

Description of key information

Animal data:  

In a 14-day pilot study (Dose Range Finding study) (Wagenaar, 2019), it was determined 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).

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.

 

A 90-day toxicokinetic study in the rat was performed by Charles River Laboratories Den Bosch BV (Lourens, 2020). The study was in accordance to OECD Test Guideline 408 and was conducted according to the principles of GLP. The objective of the study was to determine the toxicology, accumulation and toxicokinetics of cadmium telluride in the rat in comparison to cadmium chloride as a reference substance. The dose levels were selected based on the study of Loeser and Lorke (1977) (https://doi.org/10.1016/0300 -483X(77)90067-1), a study that investigated the sub-chronic toxicity and accumulation of cadmium in the liver and kidney in the rat dosed with cadmium chloride in the diet at 30 ppm) and the results of a 14-day repeated dose range-finding toxicity study with oral exposure of cadmium telluride and cadmium chloride (cadmium telluride: 750; 1500 ppm, cadmium chloride: 30ppm) (Wagenaar 2019).

 

Study Design 

In Weeks 1, 4 and 8 three animals/sex/test item group were sacrificed for bioanalytical purposes. Prior to sacrifice, blood, urine and faeces were collected to determine cadmium and tellurium content. In Week 13, the remaining animals were sacrificed for bioanalytical and toxicological assessment purposes. Control group animals were only sacrificed in Weeks 1 and 13. 

Samples of diets were collected for analysis. Chemical analyses of dietary preparations were conducted on Weeks 1 and 6 to assess concentration and homogeneity.

Toxicokinetic parameters were studied by measuring cadmium and tellurium concentration in the blood, urine, feces and target organs (kidney, liver).

 

Main Findings of the 90-day Toxicokinetic study 

The bioavailability of cadmium in kidney and liver after diet administration with 750 and 1500 ppm CdTe was significantly lower (approximately at or below LLOQ) in rats even at significantly higher dose levels compared to diet administration with 30 ppm CdCl2. At 30 ppm CdCl2, cadmium in males and females in the kidney and liver increased over time in line with the Loeser and Lorke study (1977). In rats fed with CdTe, the cadmium and tellurium were extensively excreted via the faeces. A linear increase in mean cadmium and tellurium concentrations in faeces was observed between 750 and 1500 ppm Cadmium telluride.  A 1:1 mean molar ratio and linear increase in mean cadmium and tellurium concentration in faeces was observed in 750 and 1500 ppm CdTe.

In urine, mean tellurium concentrations remained stable in males at 750 ppm CdTe in Weeks 1, 4, 8 and 13 and in females at 750 ppm CdTe in Weeks 1, 4 and 8 and dropped to below LLOQ in Week 13. In urine, mean tellurium concentrations increased over time in males and females at 1500 ppm CdTe in Weeks 1, 4 and 8, but decreased in Week 13. Mean tellurium concentrations in urine were approximately at or below 3xLLOQ, however it should be noted that, concentrations in urine might be affected by faecal particles that could be included in the collected urine samples.

Mean cadmium concentration in plasma and urine in males and females of the CdTe and CdCl2 groups were below LLOQ. In addition, mean tellurium concentration in the plasma, kidney and liver in males and females of the CdTe and CdCl2 groups were below LLOQ. 

Administration of CdTe by diet for at least 90 days was well tolerated in rats at levels up to 1500 ppm (corresponding to a mean test article intake of 103 and 121 mg/kg body weight in males and females, respectively). Only slight non-adverse changes in haematology and clinical chemistry parameters were seen. The findings observed in animals treated with 30 ppm CdCl2 were limited to alopecia and changes in several clinical chemistry parameters. 

The results of this study have demonstrated a significant difference in bioavailability potential between a relatively soluble cadmium compound, CdCl2 (the reference substance) and a relatively insoluble cadmium compound, CdTe (test substance). CdTe exhibited no evidence of bioavailability by dietary administration for 90 days at high dose levels of 750 and 1500 ppm. No detectable and/or reliable levels of either cadmium or tellurium were detected in the target organs (liver and kidney), plasma and urine. In contrast, in the CdCl2 group, at a much lower dose level of 30 ppm, the cadmium levels increased in the kidney and liver in line with the Loeser and Lorke study (1977).

The results of this 90-day Toxicokinetic study were published by Poland et al. 2021 ‘Bioaccessibility as a Determining Factor in the Bioavailability and Toxicokinetics of Cadmium Compounds’ (https://doi.org/10.10.1016/j.tox.2021.152969).

Additional information

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.