Registration Dossier

Administrative data

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) has started Mid November 2018 to examine whether the feeding of Cadmium telluride up to 100 mg/kg/bw (1500 ppm) for 14 days is tolerated by Wistar Han rats and to provide data for the selection of the dose levels for a subsequent sub-chronic (90-day) TK oral toxicity study with Cadmium telluride. In addition, it will be evaluated what the cadmium concentrations in the liver and kidney will be compared to when Cadmium chloride is being dosed (see also section 7.1.1 14d dose range finding)

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

Link to relevant study records

Referenceopen allclose all

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
19 November 2013 - 27 January 2015
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633 Sulzfeld.
- Age at study initiation: less than 9 weeks old at the initiation of treatment
- Weight at study initiation: At initiation of treatment: (Main and Recovery) Males: 199-226 g; Females: 149-180 g- The weight variation in groups did not exceed ± 20% of the mean weight for either sex
- Housing: Group caging (up to 3 animals, by sex, per cage, (i.e.3+2 main and recovery and 2 satellite) Cage type: Polycarbonate solid floor cages (type III) with stainless steel mesh lids.
- Diet : ssniff® SM R/M-Z+H “Autoclavable Complete Feed for Rats and Mice – Breeding and Maintenance” (Ssniff Spezialdiäten GmbH, D-59494 Soest Germany) ad libitum
- Water : tap water as for human consumption ad libitum
- Acclimation period: At least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.0-25.0°C
- Humidity (%): 34-54 %
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle)
Mass median aerodynamic diameter (MMAD):
ca. 1.08 - ca. 1.8 µm
Geometric standard deviation (GSD):
2.78
Remarks on MMAD:
MMAD / GSD: MMAD = 1.08-1.80 μm (geometric standard deviation = 1.75-2.78)

Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:
An extended technical trial was carried out before animals were exposed. During this period, airflow settings, test item input and the atmosphere generation system was adopted to achieve the required atmospheric concentration of 1 μg/mL and of good constancy. Palas RBG 1000 powder disperser (Palas®GmbH, 76229 Karlsruhe, Germany) was selected as the most appropriate generator for the study purpose. Dispersion of the test item was carried out by a high velocity air flow over the
tightly woven precision brush. In order to improve test atmosphere quality, before entering the exposure system the test aerosol was optimised by passing though subsequent pre-separation and dilution devices.
- Method of holding animals in test chamber: nose-only exposure unit, in a TSE Rodent Exposure System for exposure of test item atmosphere or control group in dedicated towers. Two modular multilevel flow-past nose only exposure units (towers) were used.
- Method of particle size determination:
An aerosol atmosphere was generated to contain particles with a mass median aerodynamic diameter (MMAD) between 1 to 3 μm with a geometric standard deviation (δg) in the range of 1.5 to 3.
Particle size analysis of generated atmospheres was performed using a 7-stage cascade impactor of Mercer style (TSE Systems GmbH, Bad Homburg, Germany). Such devices employ an inertial separation technique to isolate
particles into discrete aerodynamic size ranges. Samples were collected at least once a week at each concentration tested. Samples were collected from a vacant animal exposure port (animals breathing zone) and the resulting data
used to calculate the mass median aerodynamic diameter (MMAD), Geometric Standard Deviation (GSD) and percentage < 4 μm (considered to be inhalable in the rat).
Test item deposition on each stage was measured by gravimetric analysis and confirmed by ICP analysis for Cd by ICP/MS method (determination of cadmium content) as appropriate at the Test Site.
- Air flow rate: Airflows and relative pressures within the system were constantly monitored and controlled by the computer system thus ensuring a uniform distribution and constant flow of fresh aerosol to each exposure port (breathing zone). The flow of air through each port was at approximately 1 L/min. This flow rate is considered adequate to minimise re-breathing of the test atmosphere and to maintain oxygen concentrations at greater than 19% and a carbon dioxide
concentration not exceeding 1%.
- Temperature, humidity, pressure in air chamber: test atmosphere temperature, relative humidity, oxygen and carbon dioxide concentration were considered to be satisfactory for this type of study.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentrations  were monitored automatically (measured concentrations within 85% of nominal conc)
Duration of treatment / exposure:
28 days
Frequency of treatment:
28 consecutive days, in continuous daily 6 hour sessions; but 0.3 and 0.1 mg/m3 achieved by exposure to the test atmosphere concentration of 1 mg/m3 for 2 hours/day and 40 min/day, respectively.
Dose / conc.:
0 mg/m³ air (analytical)
Dose / conc.:
0.1 mg/m³ air (analytical)
Dose / conc.:
0.3 mg/m³ air (analytical)
Dose / conc.:
1 mg/m³ air (analytical)
No. of animals per sex per dose:
- 5 males and 5 females in 4 Main groups (control and 3 test item-treated groups) sacrificed one day following the last exposure on Day 28
- 5 males and 5 females in 2 Recovery groups (control and High dose groups) sacrificed following 14-day treatment free observation period
Control animals:
yes
Details on study design:
- Dose selection rationale: The concentration levels of 0.1, 0.3 and 1 μg/L were set by the Sponsor in consultation with the Study Director, based on available data from previous experimental work, including the results of previous, 28-day inhalation study (CitoxLAB study code 11/115-103P) (Grosz et al 2013, Cadmium telluride ( CdTe ): 28-Day Dose Range Finding Inhalation Toxicity Study (Nose-only) in the Rat" (CiToxLAB Hungary Ltd. study code: 11/115-103P, 2013)).
In this study, rats were exposed to the test atmospheres achieved by dispersion of ground CdTe in air, for 6 hours/day. The lowest dose level of 0.003 mg/L (achieved from 0.01 mg/L by reduction of the exposure duration to 2 hours) was associated with adverse effects in the respiratory tract in the form of increase in lungs weight (by approximately 1.5-2 times) correlated with minimal alveolar/interstitial /bronchiolar inflammation, minimal hyperplasia of the Type II. pneumocytes
and minimal lymphoid hyperplasia of the lung-associated lymph nodes. The NOAEL was not determined in this preceding study.
- Post-exposure recovery period in satellite groups: yes
Positive control:
None
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule:Checks were made twice daily, early and late during the normal working day, for mortality and/or morbidity amongst the test animals.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Individual clinical observations were performed prior to exposure and twice during exposure whilst the animals are still restrained. Following exposure clinical observation was performed twice (as soon as practicable after removal from restraint, and approximately one hour after completion of the exposure). Detailed clinical observations were made on all animals outside the home cage in a standard arena once a week.
The animals were observed for changes in the skin and fur, eyes and mucous membranes and also respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern. Particular attention was
directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma. All changes were recorded.

BODY WEIGHT: Yes
- Time schedule for examinations: The body weight of each animal was recorded with a precision of 1 g at randomization, then on Day 0 (before the exposure), twice a week thereafter and on Days 28 and 42 (prior to necropsy, fasted).

FOOD CONSUMPTION: YES
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Food consumption was recorded with precision of 1 g weekly.

HAEMATOLOGY: Yes
- Time schedule for collection of blood:
At the end of the treatment or recovery periods, prior to scheduled necropsy on Day 28 or 42, blood samples for clinical pathology evaluation (haematology,
coagulation, and clinical biochemistry) were collected by heart puncture under pentobarbital anaesthesia.
After an overnight period of food deprivation of animals, 3 blood samples were collected, for haematology (approximately 1.2 mL blood in tubes with K3-EDTA as anticoagulant, 1.6 mg/mL blood), for blood clotting times
(approximately 1.4 mL blood for APTT and PT measurements, in tubes with sodium citrate as anticoagulant) and one to obtain serum (approximately 1 mL blood as practical in tubes with no anticoagulant) for clinical chemistry.
- Animals fasted: Yes


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the end of the treatment or recovery periods, prior to scheduled necropsy on Day 28 or 42, blood samples for clinical pathology evaluation (haematology,
coagulation, and clinical biochemistry) were collected by heart puncture under pentobarbital anaesthesia.
After an overnight period of food deprivation of animals, 3 blood samples were collected, for haematology (approximately 1.2 mL blood in tubes with K3-EDTA as anticoagulant, 1.6 mg/mL blood), for blood clotting times
(approximately 1.4 mL blood for APTT and PT measurements, in tubes with sodium citrate as anticoagulant) and one to obtain serum (approximately 1 mL blood as practical in tubes with no anticoagulant) for clinical chemistry.
- Animals fasted: Yes
- Parameters checked in table [YES] were examined: Glucose ; T-BIL ; Urea ; Chol. ; Creat. ; Trig. ; Phos. ; Na+ ; K+ ; Ca++ ; Cl- ; Tot. Prot. ; Alb. ; A/G ; AST/GOT ; ALT/GPT ; ALKP Alkaline. Phosphatase – activity; GGT Gamma Glutamyltransferase -activity : Bile acids


URINALYSIS: Yes
Urinalysis was performed prior to scheduled necropsy on Days 28 and 42. Urine samples were collected for 16 hours during an overnight period of food deprivation. Animals were placed individually in metabolic cages during
collection. The evaluation of the urine samples was performed by observation (e.g. appearance, colour) or test strips as applicable.

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
organ weight measurements
bronchoalveolar lavage
tissue preservation and microscopic evaluation
Statistics:
The heterogeneity of variance between groups was checked by Bartlett’s homogeneity of variance test. Where no significant heterogeneity was detected, a one-way analysis of variance was carried out. If the obtained result was positive, Duncan’s Multiple Range test was used to assess the significance of inter-group differences. Where significant heterogeneity was found, the normal distribution of data was examined by Kolmogorov-Smirnov test. If the data was not normal distributed, the non-parametric method of Kruskal-Wallis One-Way analysis of variance was used. If there was a positive result, the intergroup comparisons were performed using Mann-Whitney U-test. For recovery groups T test was used.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No clinical signs of toxicological importance were noted in any of the experimental group.
Ruffled fur was occasionally observed in single animals in all test item exposed animals and in control males. This observation was considered to be procedure related. Additionally, red-brown staining of the fur on the nose/snout, around eyes and on the head was observed in the test item exposed animals and control.
This clinical sign, related to porphyrin discharge was considered to be a common observation in animals treated by the inhalation route.
A staining of the fur by test item was noted following the exposure mostly in animals exposed for 6 hour/day in both sexes.
Wet fur was commonly recorded in both test item exposed animals and control. This observation was considered to be related to the restraint and exposure
procedures and not to be toxicologically significant.
During a 14-day recovery period the animals were symptom-free.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
· Increase in neutrophil granulocyte count in all exposed males and in females in Mid and High dose (exposure levels of 0.3 and 1 mg/L, respectively) groups on Day 28 and in high dose groups following recovery period (Day 42). The differences attained statistical significance, except males on 42 day.
· Decrease in lymphocyte percentage in all exposed males and in females in Mid and High dose (exposure slevels of 0.3 and 1 mg/L, respectively) groups on Day 28 and in high dose groups following recovery period (Day 42), without any significant changes in absolute number, however slightly higher values were measured for females on Day 28. The change in percentage was a consequence of increase in neutrophil granulocyte.
· A minimal increase in total white blood cells (WBC) count in both males and females in Mid and High dose (exposure levels of 0.3 and 1 mg/L, respectively) groups on Day 28 and in High dose recovery groups. The differences to control attained statistical significance for females on Day 28, only.
· Decreased platelet count in High dose (exposure level of 1 mg/L) females, on Day 42 (p<0.05). On Day 28 the values were at control level, and the relatively higher control mean value on was attributable to one female (151) with individual value of 1042 K/mL. It should be noted, that the differences were of low magnitude, and all values, including control were relatively low.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Clinical chemistry evaluation did not reveal any obvious toxicity for test item following 28-day exposure at any of dose levels.
Compared to controls, high dose females (exposure of 1 mg/L) had slightly higher mean calcium, phosphorus and sodium concentration on Day 28 and the
differences attained statistical significance. Slightly higher mean phosphorus concentration was measured also for Mid dose, while
sodium concentration for low dose females (exposure levels of 0.3 and 0.1 mg/L, respectively).
As the mean and individual values remained within the normal ranges, the changes were not considered toxicologically significant.
Following the end of the recovery period, these parameters did not differ from the control mean.
No statistically significant changes were recorded for these parameters in the males.
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
No effects were noted, which could be related to the test item.
Statistical differences were recorded in the urine volume in females on Day 42 (p<0.05), however, without any changes in the specific gravity values. This
finding was attributable to the relatively smaller samples collected for some of the control females.
Results of sediment analysis revealed no significant differences between control and treated animals.
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Dose dependent increase in lungs weight (absolute and relative values) was noted in both sexes in all treated groups on Days 28 and 42. Increase was in the range of approximately 35-45% (males) and 20-24% (females) in the Low dose group, 50-65% in Mid dose group and 94-106% in the High dose, compared to control mean. Following the recovery period, the mean lungs weights were in the range of 120-126% and 106-110% in males
and females, respectively.
The changes in organ weights correlated with macroscopic observations, i.e. enlarged, gray mottled lungs with enlarged and gray coloured lung-associated lymph nodes (high dose Days 28 and 42), enlarged lungs and the lungassociated lymph nodes (mid dose) and enlarged lung-associated lymph nodes (low dose).

Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Enlarged, gray mottled lungs with enlarged and gray coloured lung-associated lymph nodes (high dose Days 28 and 42), enlarged lungs and the lung associated lymph nodes (mid dose) and enlarged lung-associated lymph nodes
(low dose).
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Evaluation of bronchoalveolar lavage (BAL) fluid on Day 28, revealed inflammatory changes in the form of dose dependent increase in total cell
counts (all exposed groups) and significant increase in lactate dehydrogenase (LDH) activity, protein concentration in Mid and High dose (exposure level of
0.3 and 1 µg/L, respectively) groups. Similar alterations were noted on Day 42.
Microscopically diffuse alveolar/interstitial inflammation was observed in lungs at all exposure levels. The changes were minimal in Low dose groups
and were noted in 4 of 5 males and 4 of 5 females, while minimal to mild inflammation was observed in all animals in the Mid and High groups, with
slightly increased severity in high dose animals.
Additionally, minimal accumulation of alveolar foamy macrophages and minimal to mild cytoplasmic deposits of black pigment in interstitial macrophages were observed with dose dependent manner in Mid and High dose (exposure level of 0.3 and 1 µg/L, respectively) groups in both sexes.
In the lung-associated lymph nodes mild to moderate lymphoid hyperplasia, aggregates of macrophages and presence of black pigment in macrophages
were noted at all exposure levels. Minimal to mild degeneration/necrosis of the macrophages was noted in the lung-associated lymph nodes at Mid and High
dose (exposure level of 0.3 and 1 µg/L, respectively) groups.
Following recovery period changes in the lungs and lung-associated lymph nodes were still present, although severity of diffuse alveolar/interstitial
inflammation of lungs slightly increased, which was expected consequence of the slow clearance of particles from lungs.

Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY:
mortality: no mortality at any of the exposure level.
clinical signs:
No clinical signs of toxicological importance were noted in any of the experimental group.

BODY WEIGHT AND WEIGHT GAIN:
No effect on body weight was observed in any of the test item exposed groups.

FOOD CONSUMPTION:
No effect on food consumption was observed in any of the test item exposed groups.

HAEMATOLOGY:
Dose dependent increase in neutrophil granulocyte count was observed in all exposed males and in Mid and High dose females (exposure level of 0.3 and 1 mg/L, respectively) on Day 28 and in High dose (1 mg/L) groups following recovery period (Day 42).

Decrease in lymphocyte percentage in all exposed males and in females in Mid and High dose (exposure slevels of 0.3 and 1 mg/L, respectively)
groups on Day 28 and in high dose groups following recovery period (Day 42), without any significant changes in absolute number, however
slightly higher values were measured for females on Day 28. The change in percentage was a consequence of increase in neutrophil
granulocyte.

A minimal increase in total white blood cells (WBC) count in both males and females in Mid and High dose (exposure levels of 0.3 and
1 mg/L, respectively) groups on Day 28 and in High dose recovery groups. The differences to control attained statistical significance for
females on Day 28, only.

Decreased platelet count in High dose (exposure level of 1 mg/L) females, on Day 42 (p<0.05). On Day 28 the values were at control
level, and the relatively higher control mean value on was attributable to one female (151) with individual value of 1042 K/mL. It should be
noted, that the differences were of low magnitude, and all values, including control were relatively low.

There were no test item related adverse effects in blood clotting, clinical chemistry or urinalysis parameters at any dose level.

CLINICAL CHEMISTRY:
Clinical chemistry evaluation did not reveal any obvious toxicity for test item following 28-day exposure at any of dose levels.

URINALYSIS:
No effects were noted, which could be related to the test item.

ORGAN WEIGHTS:
Dose dependent increase in lungs weight (absolute and relative values) was noted in both sexes in all treated groups on Days 28 and
42. Increase was in the range of approximately 35-45% (males) and 20-24% (females) in the Low dose group, 50-65% in Mid dose group and 94-106% in
the High dose, compared to control mean. Following the recovery period, the mean lungs weights were in the range of 120-126% and 106-110% in males
and females, respectively.
The changes in organ weights correlated with macroscopic observations, i.e. enlarged, gray mottled lungs with enlarged and gray coloured lung-associated
lymph nodes (high dose Days 28 and 42), enlarged lungs and the lungassociated lymph nodes (mid dose) and enlarged lung-associated lymph nodes
(low dose).

GROSS PATHOLOGY:
Enlarged, gray mottled lungs with enlarged and gray coloured lung-associated lymph nodes (high dose Days 28 and 42), enlarged lungs and the lung associated lymph nodes (mid dose) and enlarged lung-associated lymph nodes (low dose).

HISTOPATHOLOGY: NON-NEOPLASTIC:
Changes in the lungs were characterized by minimal to mild diffuse alveolar/interstitial inflammation and occurred in all test item exposed groups.
The changes were minimal in Low dose (exposure level of 0.1 µg/L) groups and were noted in 4 of 5 males and 4 of 5 females. In Mid and High dose
groups (exposure level of 0.3 and 1 µg/L, respectively), the alveolar/interstitial inflammation was classified as minimal to mild diffuse change and was
observed in all animals in these groups, with slightly increased severity in high dose animals.

In addition, minimal accumulation of alveolar foamy macrophages and minimal to mild cytoplasmic deposits of black pigment in interstitial
macrophages was observed in Mid and High dose (exposure level of 0.3 and 1 µg/L, respectively) groups in both sexes. The severity of these changes
suggested dose dependency. Pulmonary inflammatory changes were consistent with the BAL fluid findings.
Dose dependence was also noted in changes in the lung-associated lymph nodes. Clearance of test item particles from the lung to the lung-associated
lymph nodes resulted only in lymphoid hyperplasia and minimal/mild degeneration/necrosis of the macrophages at the highest doses.
In all test item exposed groups mild to moderate lymphoid hyperplasia in the cortex/paracortex, aggregates of macrophages in the paracortex/medulla and
the presence of black pigment in macrophage cytoplasm, were detected, while minimal to mild degeneration/necrosis of the macrophages was observed in
Mid and High dose (exposure level of 0.3 and 1 µg/L, respectively) groups in both sexes.
After the recovery period, changes in the lungs and lung-associated lymph nodes were still present.
Mild to moderate diffuse alveolar/interstitial inflammation of the lungs occurred in all High dose animals (1 µg/L). It should be noted that moderate
intensity was not microscopically detected in animals sacrificed on Day 28.
Minimal accumulation of alveolar foamy macrophages (9/10) and minimal to moderate black pigment in the cytoplasm of interstitial macrophages (10/10)
were present in the Recovery High dose animals. These changes were considered as expected consequence of the slow clearance of insoluble
particles from lungs.
Moderate lymphoid hyperplasia in the cortex/paracortex and aggregates of macrophages in the paracortex/medulla in the lung-associated lymph nodes
were detected in all High dose animals, in addition to the presence of black pigment in the cytoplasm of macrophages (10/10) and minimal to mild
degeneration/necrosis of the macrophages (10/10).



Dose descriptor:
LOAEL
Effect level:
0.1 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
other: adverse effects on respiratory tract
Remarks on result:
other: 0.1 mg/m3 air achieved by exposure to 1mg/m3 for 40 minutes)
Critical effects observed:
not specified

None

Conclusions:
CdTe administered to Han Wistar rats as dry aerosol by the inhalation route, daily for 28 days at the lowest possible concentration of 1 µg/L for 40 minutes was considered to have a minimal adverse effect on the respiratory tract. The no observed adverse effect-level (NOAEL) is below this exposure level.
Executive summary:

An exposure to the Cadmium telluride (CdTe) in the form of a dry aerosol to Hannover Wistar rats for 28 consecutive days at concentration of 1 mg/L for 6 hour and 0.3 μg/L (achieved by exposure to the 1.0 μg/L for two hours) was associated with enlarged, gray mottled lungs and enlarged, gray coloured lung associated lymph, increase in lungs weight (absolute and relative values) in both sexes by approximately 94-106% (at 1 mg/L) and 50-65% (0.3 mg/L), correlated with minimal to mild diffuse alveolar/interstitial inflammation, accumulation of foamy alveolar macrophages and black cytoplasmic pigment in interstitial macrophages of the lungs. Additionally, 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. Inflammatory changes of lungs were detectable by bronchoalveolar lavage and increase in neutrophil granulocyte count in peripheral blood detected at haematology. Changes were still present following 14-day treatment free period.

Exposure at 0.1 μg/L (achieved by exposure to the 1.0 μg/L 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).

In conclusion, under the conditions of this study, CdTe administered to Hannover Wistar rats as dry aerosol by the inhalation route, daily for 28 days at the lowest possible concentration of 1.0 μg/L for 40 minutes was considered to have a minimal adverse effect on the respiratory tract. The no observed adverse effect-level (NOAEL) is below this exposure level.

Endpoint:
sub-chronic toxicity: inhalation
Data waiving:
study technically not feasible
Justification for data waiving:
other:
Justification for type of information:
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 (info in questionnaires sent to CdTe DU)
DETAILED JUSTIFICATION DOCUMENT ATTACHED UNDER Isection below 'attached justification' ‘CdTe inhalation waiver‘
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.