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Description of key information

For assessing the repeated dose toxicity of CdZnS, reference has been made to toxicity data obtained by 28 days repeated dose inhalation toxicity testing on CdTe, a sparingly soluble Cd-compound. Bio-elution data demonstrate that the solubility of Cd in CdZnS is much lower than the solubility of Cd from CdTe.
Exposures to the Cadmium telluride (CdTe) in the form of a dry aerosol to Wistar rats for up to 28 consecutive days at concentration levels of 0.003, 0.01, 0.03 and 0.09 mg/L was 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.
Using this LOAEC of 0.3mg/m3 measured for the reference substance CdTe, and considering the much lower bioaccessibility of Cd from CdZnS (1156x10E3 times lower than in CdTe in lysosomal fluid), it is estimated that the LOAEC is much higher than 3 mg/m3 i.e. >>600mg/m3.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
3 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

Animal data:

No animal studies were located regarding chronic effects after dermal and oral exposure to CdZnS or CdTe, used in this report as reference substance. 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). Repeated dose oral studies were also not available. However, they are not considered necessary since the oral route is as well not the most appropriate route given the exposure to humans via oral uptake is very low and the gastrointestinal absorption of soluble and less-soluble cadmium in rats is usually less than 5% (see Toxicokinetics-absorption). Furthermore the acute toxicity test shows no toxicity after oral exposure (see acute oral toxicity).

The available animal data on repeated dose toxicity by inhalation of CdTe showed adverse effects on the respiratory tract at the lowest tested concentration from which a LOAEC of 3 mg/m3 can be set (Grósz, CiToxLAB Hungary, 2013).

For assessing the repeated dose toxicity of CdZnS, reference has been made to these toxicity data obtained by 28 days repeated dose inhalation toxicity testing on CdTe, a sparingly soluble Cd-compound. Bio-elution data demonstrate that the solubility of Cd in CdZnS is much lower than the solubility of Cd from CdTe.

For repeated dose inhalation exposure toxicity, both extracellular (e.g. interstitial) and intracellular (e.g. lysosomal) dissolution may play a role as the particles can remain in the respiratory tract for prolonged periods of time allowing more time for intracellular dissolution to take place. Intracellular fluid may be more important for water insoluble particles than for water soluble ones. Release of Cd++ion in relevant lung fluids can provide information on the mechanism of action and ultimately on the potential to cause toxicity. Therefore, bioaccessibility data in synthetic lung fluids (as a surrogate for bioavailability) notably lysosomal fluid in the case of the insoluble CdZnS has been utilized in the read-across assessment for repeated dose inhalation toxicity, recognizing that additional factors my play a role on respiratory toxicity (i.e. surface reactions), particularly for chronic local effects.

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).

Human data:

No human studies were located regarding chronic effects after specific exposure to CdZnS or CdTe, used in this report as reference susbstance. Reference is made to human data after exposure to the more soluble cadmium compounds. Considering the very low bioaccessibility of Cd in CdZnS, these human exposure data are considered very conservative for CdZnS.

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) (Cortonaet 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.


Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Read across has been made to the toxicity data of CdTe. Based on bio-elution data demonstrating in lysosomal fluid a much lower solubility of Cd from CdZnS than from CdTe, a LOAEC >>600mg/m3 can be estimated.

Justification for classification or non-classification

Table- Bio-elution data on CdTe and CdZnS measured in lysosomal fluid,along with the measured LOAEC value in rat

Test substance

Lysosomal

Bioaccessibility 168 hours as % Cd released of total Cd content

Measured LOAC (mg/L)

Repeated dose tox inhalation classification

CdTe

92.5

0.003

STOT RE1

CdZnS

0.00008

 

No

Factor difference CdTe/CdZnS

1156x103

 

 

Using the reference substance CdTe, an estimated LOAEC value of >> 600 mg/m3 could be derived and requires no classification for CdZnS for STOT RE according to EC criteria. This derived LOAEC gives an indication on significant toxic effects (adverse effects on the respiratory tract) in a 28 -day rat inhalation study, which are well above the criterion of "inhalation rat ≤ 0.6 mg/L for 28 days" used for classification with STOT RE2 H373 for the inhalation route