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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
30 September 2011 - 25 April 2013
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report Date:
2013

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Principles of method if other than guideline:
This Dose Range Finding study was performed to obtain information on the toxicity of the test item cadmium telluride (CdTe) and to determine the Maximum Tolerated Concentration (MTC) when administered to Wistar rats via the inhalation route in the form of a dry aerosol for 28 days.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
aerosol dispenser: not specified
Remarks:
migrated information: aerosol
Details on test material:
Name: Cadmium telluride
Short name (used for raw data): CdTe
Batch number: 138683 and 163568
CAS number: 1306-25-8
Appearance: Black solid
Purity: > 99.99%
Expiry date: 2 years from the first opening (24 May 2013, 05 November 2013, resp.) if kept under inert atmosphere (e.g. nitrogen)
Storage conditions: at Room Temperature (15 - 30ºC) under inert gas (e.g. nitrogen)
Use of the substance: Photovoltaic modules and semiconductor industry
Safety Precautions: Routine safety precautions (gloves, goggles, lab coat) for unknown materials were applied to assure personnel health and safety. For respiratory protection, face mask with P3R particulate filter were used. Precautions required in handling are outlined in the Material Safety Data Sheet.

Test animals

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: 8-9 weeks approximately
- Weight at study initiation: not exceeded ± 20% of the mean weight for each sex at onset of treatment- Males: 212-272 g; females: 144-188 g
- Housing: Group caging (5 animals, by sex, per cage); 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: 19-20 d


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.1-25.0
- Humidity (%): 31-65
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle)
Mass median aerodynamic diameter (MMAD):
ca. 1.19 - ca. 2.61 µm
Geometric standard deviation (GSD):
2.39
Remarks on MMAD:
MMAD / GSD: MMAD = 1.19-2.61 µm (geometric standard deviation = 1.76-2.39
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:
Dust particles were produced using Palas RBG 1000 powder disperser (Palas®GmbH, 76229 Karlsruhe, Germany) located at the top of the exposure chamber. Dispersion was carried out by a high velocity air flow over the tightly woven precision brush. In order to improve aerodynamic size distribution, large particles were trapped by impaction in the subsequent simple pre-separator (double glass). For the low concentration (0.01 mgL) the pre-separation device was doubled.
- Method of holding animals in test chamber: nose-only exposure unit, in a TSE Rodent Exposure System with each individual concentration or control group in a dedicated tower. Four identical, modular multilevel flow - past nose-only exposure units (towers) were used.
- Method of particle size determination:
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 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).
The collection substrates and the backup filter were weighed (analytical balance) before and after sampling and the weight of test item, collected at each stage, calculated by this difference.
The total amount collected for each stage was used to determine the cumulative amount below each cut-off point size. In this way, the proportion (%) of aerosol less than < 0.550, 0.550, 0.960, 1.550, 2.105, 3.555, 6.655 and 10.550 µm was calculated.
From these data, using the software supplied with the impactor (TSE Systems GmbH, Bad Homburg, Germany), the Mass Median Aerodynamic Diameter (MMAD), and Geometric Standard Deviation (GSD) were calculated. In addition, the proportion (%) of aerosol less than 3 µm was determined.
Results of the particle size analysis from the samples taken at the animal’s breathing zone indicated that the test atmospheres were respirable to the rats and should ensure particle deposition both in the upper and the lower respiratory tract.
- 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 least 0.5 L/min. This flow rate was considered adequate to minimise re-breathing of the test atmosphere and maintained 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 with exception of 3 mg/m3, exposed 2hours/day at 10 mg/m3
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/m³ air (analytical)
Dose / conc.:
3 mg/m³ air (analytical)
Dose / conc.:
10 mg/m³ air (analytical)
Dose / conc.:
30 mg/m³ air (analytical)
Dose / conc.:
90 mg/m³ air (analytical)
No. of animals per sex per dose:
 5 M and 5 F per dose 
Control animals:
yes
Details on study design:
- Dose selection rationale: The concentration levels were set by the Sponsor in consultation with the Study Director, based on available data from previous experimental work, including the results of a Dose range finding 7-day inhalation toxicity study (CiToxLAB study code 11/115-103PE), where the Maximum Tolerated Concentration (MTC) was found to be close to 0.05 mg/L with six hours exposure.
- Post-exposure recovery period in satellite groups: no
Positive control:
None

Examinations

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: As a minimum, individual, clinical observations were performed prior to exposure and twice during exposure whilst the animals were 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.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weight of each animal was recorded with a precision of 1 g at randomization, then on Day 0 (before the exposure), and twice a week thereafter and at the termination on Days 25/24 (High Dose animals) or Day 28 (prior to necropsy, fasted).
For the High Dose females, the terminal (Day 24) body weight values were used for statistical evaluation, as the values were similar to these obtained one day earlier, on Day 23.
Body weights were recorded at death, for animals found dead during the course of the study.


FOOD CONSUMPTION:
- 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

CLINICAL CHEMISTRY: Yes .

URINALYSIS: Yes
Urinalysis was performed during the last week of the study. Urine samples were collected for 16 hours during an overnight period of food deprivation. Animals were placed in metabolic cages during collection. The evaluation of the urine samples was performed by observation or test strips as applicable.

NEUROBEHAVIOURAL EXAMINATION: Yes / No / No data
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:

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 is detected, a one-way analysis of variance was carried out. If the obtained result is positive, Duncan’s Multiple Range test was used to assess the significance of inter-group differences. Where significant heterogeneity is found, the normal distribution of data was examined by Kolmogorov-Smirnov test. If the data is not normal distributed, the non-parametric method of Kruskal-Wallis One-Way analysis of variance was used. If there is a positive result, the inter-group comparisons was performed using Mann-Whitney U-test. The frequency of clinical observations and necropsy and histopathology findings were calculated as applicable.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
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
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY:
mortality:Exposure to the test atmosphere at 0.09 mg/L (High Concentration Group) six hours/day, caused the loss of two animals and the premature termination of the exposure due to ethical reasons in Week 4. (Study Days 24 and 23, males and females, respectively).
clinical signs:
The main clinical sign was increased respiratory rate (tachypnea) and was observed throughout the study with dose related incidence and severity. The incidence and severity increased with the duration of the study.
At 0.09 mg/L (Group 5) slight tachypnea appeared first on Day 0 following the exposure in single animals, in week 2 was noted as moderate, and thereafter became severe and permanent. Additionally, from Day 21 (males) and Day 15 (females), slight to moderate decreased activity was observed. Due to continuous body weight loss, the animals became thin from Day 17/14 (males/females) and some of them cachectic by the termination of the study.
In found dead animals, in addition, partially closed eyelids and, in the male, signs of hematuria (e.g. red/brown staining of the fur at urogenital area) were observed.
In animals exposed to a concentration of 0.03 mg/L for six hours (Group 4), slight/moderate tachypnea was observed from Day 12-15 in few animals, with increasing severity and incidence on following days. Persistent moderate tachypnea was observed in males from Day 26 and in females (slight to moderate) from Day 17 up to the termination of the study.
At 0.01 mg/L (Group 3, six-hour exposure), slightly increased respiratory rate was first observed on Day 19/20 in single female and male during/following the exposure, moderate tachypnea was observed on Day 24 in males and from Day 22 in females, and the sign became persistent in females only, from Day 25 up to the termination of the study.
In the animals exposed at 0.003 mg/L (Group 2), slightly increased respiratory rate was observed following the exposure from Day 20. Following the last exposure on Day 27, moderate tachypnea was observed in 2 of 5 females.
Ruffled coat was noted in all animals including controls, however, with higher incidence in Groups 4 and 5.
Wet fur and fur staining were commonly recorded during and following the exposure. These observations were considered to be related to the restraint and exposure procedures and were considered not to be toxicologically significant.


BODY WEIGHT AND WEIGHT GAIN:
Test item related effects on body weight was observed in both males and females exposed at (0.03 and 0.09 mg/L).
Permanent body weight loss was observed at 0.09 mg/L (High Concentration Group) and was up to 23% in males and 29% in females at the termination of the treatment on Day 24 or 23, compared to the initial values.
At 0.03 mg/L (Mid Concentration) moderate body weight gain suppression was observed in males throughout the exposure period, while in females following a severe body weight gain suppression on weeks 2 and 3, slight body weight loss was recorded in week 4.
The lower mean body weight was in accordance with the decreased food consumption in Groups 4 and 5.
At 0.01 mg/L (Mid-low Concentration), minimal body weight gain suppression was noted in males; however, the mean body weight value was comparable with the control. No effect was observed in females in this group.
The mean body weight and body weight gain of males and females in Group 2 (Low Concentration, 0.003 mg/L) were comparable to the control values during the 4-week exposure period.


FOOD CONSUMPTION:
There was a significant decrease in food consumption in both males and females in Groups 4 and 5, (exposed at 0.03 and, 0.09 mg/L for six hours). The lower food consumption was in accordance with the effect on body weight.

Slightly lower mean food consumption was recorded for Group 3 females during the last week of the exposure.

In both males and females in Group 2 (Low Concentration, 0.003 mg/L), no adverse effect was observed on food consumption.


HAEMATOLOGY:
Changes in hematology were found mostly in groups exposed at 0.03 and 0.09 mg/L (Mid and High Concentration) and consisted of slightly increased red blood cell (RBC) count, hemoglobin (HGB) concentration and hematocrit (HCT) value in both males and females, decreased reticulocyte count in males and females at 0.09 mg/L, increased neutrophil granulocyte count with concomitant decrease in lymphocyte count in both males and females (relative values were evaluated), increased monocyte count in males and decreased platelets count in females at 0.09 mg/L.

CLINICAL CHEMISTRY:
Test item related clinical chemistry findings occurred mostly at 0.09 mg/L and consisted of increased activity of Aspartate Aminotransferase (AST), Alkaline Phosphatase (ALKP) and Gamma Glutamyltransferase (GGT) in both males and females. AST and ALKP activity was also slightly increased at 0.03 mg/L. Albumin concentration was decreased in both males and females at 0.09 mg/L, with concomitant increase in Calcium (Ca++) concentration, decreased albumin to globulin (A/G) ratio and lower creatinine concentration. Sodium (Na+) concentration was increased in both males and females at 0.03 and 0.09 mg/L. Blood urea concentration was slightly increased in females at 0.01, 0.03 and 0.09 mg/L.

URINALYSIS:
The urinalysis parameters were comparable to the controls in both males and females in Groups 2, 3 and 4 (exposed at 0.003, 0.01 and 0.03 mg/L, respectively). The mild differences were recorded in the urine volume in females in Groups 3 and 4 (p<0.05), i.e. compared with the control, smaller samples were collected for some of the females, however without any changes in the specific gravity values. The finding was not directly attributable to the test item exposure. Protein content was detected in all samples from both males and females in Group 4 (exposed at 0.03 mg/L), however this finding was noted with lower incidence also in the control animals. It should be noted, that for the animals in Group 5 (exposed at 0.09 mg/L) due to insufficient sample collection only few urine samples were examined.


ORGAN WEIGHTS:
Adrenal weights were lower in both sexes (by approximately 20-30%) at 0.09 mg/L and ovary weights were decreased at 0.03 and 0.09 mg/L.
Liver and kidney weights were decreased by approximately 30%, and 15-25% respectively at 0.09 mg/L, and were considered to be secondary effect related to the significant body weight loss of the animals.
Weights of lungs were dose dependently increased in all test atmosphere exposed animals, and were approximately 1.5-2 times higher in the Low Concentration Group and up to 3 times higher at 0.09 mg/L.

GROSS PATHOLOGY:
Inflammatory changes in lungs of all treated animals were detectable in bronchoalveolar lavage (BAL) in the form of increased activity of lactate dehydrogenase and protein concentration.

HISTOPATHOLOGY: NON-NEOPLASTIC:
Gross observation and increase in weight of lungs correlated microscopically with alveolar/interstitial/bronchiolar inflammation and hyperplasia of Type II pneumocytes and black pigment in the cytoplasm of macrophages. In addition, at 0.03 and 0.09 mg/L, interstitial fibroplasia was observed. The lung changes were accompanied by dose related, minimal to moderate hyperplasia and degeneration/necrosis of the macrophage in the lung-associated lymph nodes at 0.01, 0.03 and 0.09 mg/L. At a concentration of 0.003 mg/L (achieved by exposure to 0.01 mg/L for two hours) minimal alveolar/interstitial/bronchiolar inflammation, minimal hyperplasia of the Type II pneumocytes and minimal lymphoid hyperplasia of the lung-associated lymph nodes was experienced.
Decreased thymus weight in exposed animals correlated microscopically with lymphoid atrophy, and with reduced peripheral lymphocyte counts detected during hematological examination.
In the testes of exposed animals minimal, multifocal, tubular atrophy and in the epididymes minimal hypospermia were observed.


Effect levels

Dose descriptor:
LOAEL
Effect level:
3 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: adverse effects on respiratory tract

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

None

Applicant's summary and conclusion

Conclusions:
CdTe administered to Han Wistar rats as dry aerosol by the inhalation route, daily for 28 days at the lowest possible concentration of 0.01 mg/L for 2 hours was considered to have an adverse effect on the respiratory tract. Therefore the no observed adverse effect-level (NOAEL) was not found in this study.
Executive summary:

An exposure 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 following effects:

-Exposure to the test atmosphere at 0.09 mg/L for six hours/day, caused the loss of two animals and early termination of the exposure due to ethical reasons on Week 4.(Study Days 24 and 23, males and females, respectively). Exposure resulted in severe tachypnea (increased respiratory rate) and decreased activity, expressed body weight loss and reduced food consumption. Changes in hematology and clinical chemistry parameters reflected poor condition of the animals, however changes in some of the parameters might be indicative for liver and kidney impairment. An increase in lung weights (2-3 times versus control) was associated with mild to moderatealveolar/interstitial inflammation,mild to moderate interstitial fibroplasia and degeneration/necrosis of the macrophages in the lung associated lymph nodes. Weight of the thymus was markedly decreased.

-Exposure at 0.03 mg/L for six hours was associated with slight/moderate tachypnea, moderate body weight gain suppression and/or in females slight temporary body weight loss and minimal changes in a few clinical chemistry parameters. An increase in lung weights (2-3 times versus control), correlated with minimal to mild alveolar/interstitial/bronchiolar inflammation, minimal to mild interstitial fibroplasiasand degeneration/necrosis of the macrophages in the lung-associated lymph nodes.

-Exposure at 0.01 mg/L for six hours resulted in slight tachypnea, minimal body weight gain suppression in males and an increase in lungs weight (2-2.7 times versus control), which correlated with minimal alveolar/interstitial/bronchiolar inflammationand minimal degeneration/necrosis of the macrophages in the lung-associated lymph nodes.

-Exposure at 0.003 mg/L (achieved by exposure of 0.01 mg/L for two hours) was associated with 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 .

 

In conclusion, under the conditions of this study, CdTe administered to Han Wistar rats as dry aerosol by the inhalation route, daily for 28 days at the lowest possible concentration of 0.01 mg/L for 2 hours was considered to have an adverse effect on the respiratory tract. Therefore the no observed adverse effect-level (NOAEL) was not found in this study.