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Description of key information

Animal data:

Repeated dose toxicity, inhalation:

In a 28-Day Dose Range Finding Inhalation Toxicity Study (Nose-only) in the Rat, exposures to Cadmium telluride (CdTe) in the form of a dry aerosol at concentration levels of 0.003, 0.01, 0.03 and 0.09 mg/L were associated with adverse effects. The associated adverse effects at the lowest tested concentration were slight, transient tachypnea during the last week of the exposure, increase in lungs weights (by about 1.5-2 times), which correlated with minimal alveolar/interstitial/bronchiolar inflammation and minimal hyperplasia of the Type II pneumocytes. Since at the lowest possible concentration (0.003mg/L achieved by 2 hours exposure session to 0.01 mg/L) adverse effects on the respiratory tract were observed, a LOAEC of 3 mg/m3 could be set but no NOAEL could be determined in this study (Grosz, M 2013).

A full 28-day inhalation toxicity study (nose-only) in the rat was finalised by CiTox LAB Hungary Limited (Grósz, M 2015). The study followed the guideline OECD 412 and was conducted according to the principles of GLP. Doses were selected based on the previous results of the 28 -Day Dose Range Finding inhalation Toxicity Study (Grosz, M 2013)

Study Design

The OECD 412 guideline requires that the substance to be tested has a Mass Median Aerodynamic Diameter(MMAD) < 3 µm to ensure that the substance is respirable under the conditions of the test. The substance that was tested had to be milled to achieve a suitable MMAD. Due to the large particle size of CdTe, the sample was therefore extensively abraded by milling and grinding with a Retsch Mixer Mill MM 400 before testing, to achieve a MMAD of 1.08 – 1.8 µm. This process significantly altered the substance to a size and form not representative of CdTe at manufacturing sites, as placed on the EU market and used downstream (information from exposure questionnaires sent to cadmium telluride downstream users).

The dose levels chosen were 1 mg/m3, 0.3 mg/m3and 0.1 mg/m3as a result of dose range finding studies of 7-day and 28-day duration. Typically, in a nose only repeat dose study, the rats are exposed to the test concentration for 6 hours per day, however in this study an atmosphere generation at concentration <1 mg/m3could not be achieved. At concentrations < 1.0 mg/m3the laboratory could not achieve stability, reproducibility and accuracy of the gravimetric analysis, due to the standard commercial equipment available at the laboratory, which was designed to run at test concentrations in the > 1 mg/m3range.

Therefore, the laboratory proposed to conduct the “full” study by reducing the exposure time at the 1 mg/m3dose level to achieve the 0.1 and 0.3 mg/m3dose levels. This was done by the application of Haber’s Rule/Law (concentration x time of exposure = dose). The final dosing strategy resulted in the situation where each group was exposed to a target concentration of 1 mg/m3and the exposure doses at 0.3 mg/m3and 0.1 mg/m3were achieved by reduction of the exposure time to 2 hours and 40 minutes respectively. Control animals were exposed for 6 hours/day to clean air.

However, this dosing strategy does introduce a high level of uncertainty into this study and it is impossible to know if testing at the actual lower dose levels over 6 hours would give rise to a different toxicity profile. It would have been much more desirable to obtain the correct testing equipment in order to achieve the low dose levels.

Finally, a further group of animals at the high dose were retained for 14-days post exposure to determine any reversibility of effects observed during the study. As cadmium and cadmium compounds are known to have a long clearance time from the lung, the choice of a 14-day reversibility period was on reflection, too short. A more useful reversibility period would have been 3 months.

In conclusion, the study design does raise uncertainties which could have had a significant effect on the outcome of the study and the interpretation of the results. These are:

i.                    Excessive milling and grinding required to achieve a respirable sample of CdTe.

ii.                  The use of Haber’s Rule/Law to achieve the required dose levels at low concentrations. 

Main Findings of the 28-day Repeat Dose Toxicity inhalation Study

An exposure to Cadmium telluride (CdTe) in the form of a dry aerosol to Hannover Wistar rats for 28 consecutive days at concentration of 1 mg/m3 for 6 hours and 0.3 mg/m3 (achieved by exposure to the 1.0 mg/m3for two hours) was associated with the following findings, taken from the study report:

i.                    Enlarged, grey mottled lungs and enlarged, grey coloured lung associated lymph, increase in lungs weight (absolute and relative values) in both sexes by approximately 94-106% (at 1 mg/m3) and 50-65% (0.3 mg/m3).

ii.                  The above effect was correlated with minimal to mild diffuse alveolar/interstitial inflammation, accumulation of foamy alveolar macrophages and black cytoplasmic pigment in interstitial macrophages of the lungs. 

iii.                Lymphoid hyperplasia and aggregates of macrophages, presence of black pigment in macrophages and degeneration/necrosis of the macrophages were found in the lung associated lymph nodes.

iv.                Inflammatory changes of lungs were detectable by bronchoalveolar lavage.

v.                  Increase in neutrophil granulocyte count in peripheral blood detected at haematology.

vi.                These changes were still present following 14-day treatment free period. 

vii.               Exposure at 0.1 mg/m3(achieved by exposure to the 1.0 mg/m3 for 40 minutes) resulted in increase of lungs weight by approximately 35-45% (males) and 20-24% (females), without any macroscopic observation, except enlarged lung associated lymph nodes. Microscopically minimal diffuse alveolar/interstitial inflammation was observed in lungs in 4 of 5 males and 4 of 5 females, in addition to mild changes in lung-associated lymph nodes (mild lymphoid hyperplasia and aggregates of macrophages, presence of black pigment).

viii.             The LOAEL of this study was therefore determined to be 0.1 mg/m3, the lowest dose tested, and no NOAEL could be established.

 

There were no reported incidences of nasal irritation or irritation/cell damage in the lung. No investigation into the presence or incidence of fibrosis was carried out during the study or in the reversibility satellite group. Unlike the blood analysis, a full white cell count in the BAL fluid was not conducted.

Some of the findings in this study are indicative of cadmium toxicity e.g. cell proliferation, hyperplasia, particle accumulation (long clearance rate). However, the duration of exposure in this study is too short to be conclusive and only partial histopathology was conducted as is typical for studies of this duration.

This study was given a Klimisch score of 2 due to the dosing regime and the toxicological uncertainty of reducing the exposure period to achieve the low dose levels. The severe attrition of the substance to achieve a respirable dose also raises the question of the representativeness of the tested substance in comparison to the form placed and subsequently used on the EU market.

Repeated dose toxicity, oral:

No animal studies were located regarding long term effects after oral exposure to cadmium telluride.

Results from studies with cadmium and cadmium compounds in animals and observations in humans indicate that the sensitive targets of cadmium toxicity are kidney and bone following oral exposure and kidney and lungs following inhalation exposure (ATSDR, 2008).

Cadmium being a cumulative toxicant, the systemic manifestations associated with chronic exposure are related to the body burden of the element (liver and kidney content), assessed with biomarkers such as urinary concentration (Cd-U).

 

Therefore, as cadmium accumulates in tissues over time in a repeat dose study, a critical cumulative dose has to be achieved before toxicity is observed. The integrated testing strategy for cadmium telluride proposes to conduct a toxicokinetic study over 90 days to show that cadmium telluride does not cause an accumulation of cadmium in the kidney and liver (two sensitive target organs) and is therefore not bioavailable by the oral route. 

Repeated dose toxicity, dermal:

No animal studies were located regarding long term effects after dermal exposure to cadmium telluride. However, repeated dose toxicity via the dermal route is not expected to be significant as uptake of less-soluble cadmium compounds applied onto the skin of animals appears to be low (<1%) (see Toxicokinetics-absorption).

Human data:

No human studies were located regarding chronic effects after specific exposure to CdTe. Reference is made to human data after exposure to the more soluble cadmium compounds. Considering the lower bioaccessibility of Cd in CdTe, these human exposure data are considered very conservative for CdTe.

In workers exposed to cadmium, a body burden corresponding to 200 ppm in kidney cortex, ie ca. 10μg Cd/g creatinine is considered to represent a critical level based on the occurrence of low molecular weight proteinuria. SCOEL (2010) recommends an Occupational Exposure Level (OEL) equivalent to 4 µg Cd/m3 (respirable fraction) as protective against long-term local effects (respiratory effects, including lung cancer). This is based on human data that shows changes in residual volume of the lung for a cumulative exposure to CdO fumes of 500 µg Cd/m3 x years, corresponding to 40 years exposure to 12.5 µg Cd/m3 (LOAEL) (Cortona et al.,1992). Applying an uncertainty factor of 3 (LOAEL to NOAEL) leads to a value of 4 µg/m3 (SCOEL 2010).

On the basis of studies conducted in Europe (Buchet et al.,1990; Hotz et al.,1999; Järup et al.,2000), the United States (Noonan et al.,2002) and Asia (Jin et al.,2002), it appears that renal effects can be detected in the general population for Cd-U below 5μg Cd/g creatinine and even from 2μg Cd/g creatinine or below. These studies show associations between Cd-U and markers of tubular effect. There is, however, a scientific debate about the health significance of these early changes. This lower value in the general population compared to that identified in workers is thought to reflect, among other parameters, an interaction of cadmium exposure with pre-existing, concurrent or subsequent renal diseases (mainly renal complications of diabetes) that are less prevalent in healthy young individuals in occupational settings (SCOEL, 2010).

Recent evidence questions the causality of these associations between U-Cd and biomarkers of kidney effects (urinary proteins) in populations with low levels of exposure. Literature is showing that the association between Cd and protein excretion probably represents normal variability in renal physiology resulting in a temporarily increased or decreased Cd excretion, independent of kidney cadmium concentration (Kidney Cd) (Chaumont et al., 2012, Akerstrom et al., 2013). The excretion of Cd and proteins is assumed to change in the same direction due to temporary changes in the renal activity, since Cd bound to metallothionein and LMW proteins share the same tubular binding site (Christensen et al., 2009), thus resulting in an association between U-Cd and urinary proteins excretion. Overall, Akerstrom concludes that “these associations are unlikely to be caused by Cd toxicity but rather reflect temporary changes in urinary flow or other sources of normal physiological variability that affect the excretion of U-Cd and urinary proteins in the same direction, resulting in an overestimation of the risk of renal toxicity from low-level Cd exposure” (Akerstrom et al. 2013). These recent findings suggest that at low environmental exposures, U-Cd would be more a reflection of the functional integrity of the nephron than of the Cd exposure or of the Cd body burden (Chaumont 2012).

These reverse causality mechanisms might have important implications in the risk assessment of Cd for the general population, which currently largely relies on the use of U-Cd as exposure indicator (Chaumont et al 2012). In conclusion, the scientific debate on the causal effect of low Cd exposures (measured as Cd-U) on kidney function is ongoing. Taking this debate into account, it is strongly recommended to consider the anticipated effects on kidney at low Cd exposure with caution. However, it is emphasized that at higher exposures, the causal relationship is not questioned (Chaumont et al. 2011). The use of biological indicators in e. g. worker environment is thus justified.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
The integrated testing strategy (see attached doc 'Testing Strategy for Cadmium Telluride (22-08-2017) is ongoing. the 14-day pilot study (dose range finding study- DRF) has shown the feeding of Cadmium telluride up to 1500 ppm (100 mg/kg/bw) for 14 days is tolerated by Wistar Han rats and provided data for the selection of the dose levels for the subsequent sub-chronic (90-day) TK oral toxicity study with Cadmium telluride. In addition, it was evaluated what the cadmium concentrations in the liver and kidney were compared to when Cadmium chloride is being dosed. It was shown no cadmium or tellurium was present in the kidney and liver of animals treated with cadmium telluride (see also section 7.1.1 14d DRF).

The 90d TK oral toxicity study is ongoing (see section 7.1.1 90d ongoing): 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
Draft report foressen to be available: 20 March 2020

See documents attached under attached justification below:
- Repeat dose oral testing strategy for Cadmium telluride
- Statement of Work signed by Charles River and sponsor
Endpoint conclusion
Endpoint conclusion:
no study available (further information necessary)

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
0.1 mg/m³
Study duration:
subacute
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

Based on the following findings, as documented under IUCLID 7.5.2 Waiving RDT inhalation:

  1. The particle size distribution of cadmium telluride and electrostatic binding of the dust and large particles indicate that there would be no deposition in the lung during workplace activities.
  2. The requirement for grinding/milling of the material in inhalation studies results in a sample which is not representative of cadmium telluride as placed on the EU market or as handled by downstream users (information in exposure questionnaires sent in 2016 to cadmium telluride downstream users).
  3. SWeRF analysis and MPPD modelling indicate that an inhalation exposure will not occur at the workplace.

confirming the non-inhalable nature of cadmium telluride, it is proposed that the substance does not require classification as a STOT-RE via the inhalation route.