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Administrative data

Description of key information

For assessing the acute toxicity of CdZnS, reference has been made to toxicity data obtained by standard acute toxicity testing on CdTe, a sparingly soluble Cd-compound. Bio-elution data in different artificial body fluids demonstrate that the solubility of Cd in CdZnS is lower than the solubility of Cd from CdTe.
Assessment of the acute oral toxicity of cadmium telluride in Nagy, Labresearch Ltd et al., 2008:
A limit study with Wistar CRL: (WI) BR rats was carried out according to OECD guideline no 423 to assess the oral LD50. No deaths and no abnormalities in clinical signs, body weights, and necropsy findings were observed for any of the animals. An LD50 value >2000mg/kg bw was reported.
Considering the LD50 value of >2000mg/kg bw for CdTe and the >50x lower bioaccessibility of Cd in CdZnS, as compared to CdTe, an LD50 of >>2000mg/kg bw can be estimated for CdZnS.
Assessment of the acute inhalation toxicity of cadmium telluride in Nagy, Labresearch Ltd et al., 2008:
A study was carried out according to OECD guideline no 403 to assess the acute inhalation toxicity of CdTe when administered to rats for a single continuous 4 -hour period, followed by an observation period of 14 days.
The acute inhalation median lethal concentrations (4hr LC50) (and 95% confidence limits) of CdTe, in Wistar Crl: (WI) BR strain rats, were calculated to be: All animals: 2.71 mg/L; Male only: 2.53 mg/L; Female only: 2.87 mg/L
Using the reference substance CdTe, a LC50 value >>2.7mg/L can be derived from the interstitial bio-elution data showing 400 times lower (at 168 hours) bioaccessibility of Cd in CdZnS, as compared to solubility in CdTe.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
not applicable
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented and scientifically good . Tests done according to standard protocol. Good quality and considered useful for setting the reference value for acute oral toxicity
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (Europe)Laboratories Inc. (TOXI-COOP KFT, 1103 Budapest, Hungary)
- Weight at study initiation (g): 210-212
- Housing: in groups of 3 in solid-floor cages (Type III) with stainless steel mesh lids and softwood flake bedding.
- Diet: ssniff SM R/M-Z+H “Autoclavable Complete Feed for Rats and Mice – Breeding and Maintenance” (ssniff Spezialdiäten GmbH, D-59494 Soest,
Germany)
- Water: tap water from municipal supplies, as for human consumption, ad libitum.
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30-70 %
- Air changes (per hr): 8-12
- Photoperiod (hrs dark / hrs light): 12 hours of continuous artificial light in each twenty-four hour period.
Route of administration:
oral: gavage
Vehicle:
other: 1% carboxymethylcellulose
Details on oral exposure:
On the day prior to treatment, food was withheld from the animals overnight; water was available to them during this period. On the day of treatment, animals were weighed before dosing. The exact volume to be given was calculated base on each animal‟s body weight and a constant dose volume of 10 ml/kg. The test item formulation was stirred continuously throughout the dosing procedure to ensure each animal was treated with a homogenous solution. A single administration by oral gavage was given to a group of three female rats. Food was made available to the animals 3 hours after the treatment. The treatment was followed by a fourteen-day observation period.
Doses:
2000mg/kg
No. of animals per sex per dose:
6
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Morbidity/Mortality: Animals were checked daily during the observation period for morbidity and/or mortality.
Clinical Signs: All animals were observed for clinical signs once during the first 30 minutes after treatment, approximately one, two, three, four and six hours after dosing and subsequently once daily for fourteen days. Individual observations were performed on 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.
Bodyweight: Individual bodyweights were recorded prior to treatment on the day of dosing (Day 0) and on Days 7 and 14.
Necropsy: At the end of the fourteen-day observation period the animals were sacrificed by exsanguination under anaesthesia and gross necropsies performed. After examination of the external appearance, the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs was observed. All gross pathological changes were recorded for each animal on the post mortem record sheets.

Statistics:
Data evaluations included the relationship, if any, between the animals‟ treatment with the Test Item and the incidence and severity of all abnormalitiesincluding mortality, behavioural or clinical observations, bodyweight changes, macroscopic abnormalities or any other toxicological effects
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No mortality observed
Clinical signs:
No clinical signs observed
Body weight:
Normal body weight development was noted during the study, with the exception of a single female animal which showed a slight body weight loss during week 2 only
Gross pathology:
Necroscopy:
Occasional occurrences of pale, raised areas were observed in the lungs of two animals at necropsy. Several instances of pin-prick sized haemorrhage in the lungs were also noted but such alterations are frequently recorded at this facility and are considered to be caused by the termination method used. Mild hydrometra was noted in one female, this is a sporadic occurrence in laboratory maintained rat and is without toxicological significance.
Other findings:
none

none

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Tests done according to standard protocol. Good quality and considered useful for setting the reference value for acute oral toxicity (LD50>2000mg/kg)
Executive summary:

The purpose of this study was to assess the acute oral toxicity of CdTe.

No deaths occurred in two groups of three rats treated at a dose level of 2000 mg/kg. The acute oral lethal dose (LD50) of CdTe, in Wistar Crl:(WI) BR strain rats, was therefore considered to be greater than 2000 mg/kg.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
not applicable
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented and scientifically good . Tests done according to standard protocol. Good quality and considered useful for setting the reference value for acute inhalation toxicity
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Qualifier:
according to guideline
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (Europe)Laboratories Inc. (TOXI-COOP KFT, 1103 Budapest, Hungary)
- Weight at study initiation (g): 224-299
- Housing: in groups of 5, by sex, in solid-floor cages (Type III) with stainless steel mesh lids and softwood flake bedding.
- Diet: ssniff SM R/M-Z+H “Autoclavable Complete Feed for Rats and Mice – Breeding and Maintenance” (ssniff Spezialdiäten GmbH, D-59494 Soest,
Germany)
- Water: tap water, as for human consumption, ad libitum.
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30-70 %
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 hours of continuous artificial light in each twenty-four hour period.
Route of administration:
inhalation
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Solid Aerosol Generator (SAG 410) (TOPAS GmbH, D-01279 Dresden, Germany) (for group 1) and a rotating brush powder disperser (Palas GmbH, Karlsruhe, Germany) and compressed air (for group 2 and 3)
- Method of holding animals in test chamber: the animals were held in polycarbonate restraint tubes located around the chamber which allowed only the animal‟s nases to enter the exposure port.
- Source and rate of air: Compressed air was supplied by means of an oil-free compressor and passed through a suitable filter system prior to introduction to the dust generator. The aerosol generated was supplied, using suitable tubing, to a glass particle-size separation (sedimentation) device before entering the exposure system (for group 1). The compressed air was supplied by an oil-less compressor and passed through respiratory quality filters and condensate traps prior to use. The aerosol generated was supplied, using suitable tubing, to a glass particle-size separation (sedimentation) device before entering the exposure system (for group 2 and 3)
- Method of particle size determination:
determined three times during the exposure period using a 7-stage impactor of Mercer style (TSE Systems GmbH, Bad Homburg, Germany). Such devices employ an inertial separation technique to isolate particles in the discrete aerodynamic size ranges. Samples were taken from an unoccupied exposure port (representing the animal‟s breathing zone). The collection substrates and the backup filter were weighed before and after sampling and the weight of test item, collected at each stage, calculated by 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 0.33, 0.5, 0.77, 1.21, 1.93, 3.13 and 5.09 m was calculated. From these data, using software supplied with the impactor (TSE Systems GmbH, Bad Homburg, Germany), the Mass Median Aerodynamic Diameter (MMAD), and Geometric Standard Deviation were calculated. In addition, the proportion (%) of aerosol less than 4m (considered to be the respirable portion) was determined.
- Temperature, humidity, pressure in air chamber: monitored continuously and recorded every minute during each exposure period by the TSE-DACO monitoring system integrated into the exposure system:


TEST ATMOSPHERE
- Brief description of analytical method used: The test atmosphere was sampled at regular intervals during each exposure period. Samples were taken from an unoccupied exposure port (representing the animal‟s breathing zone) by pulling a suitable, known volume of test atmosphere through weighed GF10 glass fibre filters (Schleicher & Schuell GmbH, Dassel, Germany or similar).
- Samples taken from breathing zone: yes


Animal exposure system:
The animals were exposed, nose-only, to an atmosphere of the test item using a TSE Rodent Exposure System (TSE Systems GmbH, Bad Homburg, Germany). This system comprises of two, concentric anodised aluminium chambers and a computer control system incorporating pressure detectors and mass flow controllers.
Fresh aerosol from the generation system was constantly supplied to the inner plenum (distribution chamber) of the exposure system from where, under positive pressure, it was distributed to the individual exposure ports. The animals were held in polycarbonate restraint tubes located around the chamber which allowed only the animal‟s nares to enter the exposure port. After passing through the animal‟s breathing zone, spent aerosol entered the outer cylinder from where it was exhausted through a suitable filter system. Atmosphere generation was therefore dynamic.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
group 1: 5,73 mg/L
group 2: 1,07 mg/L
group 3: 3,03 mg/L
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
mortality/viability: once daily during the acclimatisation phase, once before exposure on the day of exposure (test day1), once per hour during exposure, once after exposure on test day 1, and twice daily during the remainder of the observation period
body weights: recorded on test datys 1 (before exposure), 4, 8 and 15 (day of necroscopy) using a Mettler PM 4000 balance
clinical signs: once per hour during exposure (only grosly abnormal signs, as the animals were in restraint tubes), once after exposure on test day 1, and once daily thereafter
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
log/probit method: to calculate the median lethal concentration values and 95% confidence intervals
Sex:
male/female
Dose descriptor:
LC50
Effect level:
2.71 mg/L air
Exp. duration:
4 h
Sex:
male
Dose descriptor:
LC50
Effect level:
2.53 mg/L air
Exp. duration:
4 h
Sex:
female
Dose descriptor:
LC50
Effect level:
2.87 mg/L air
Exp. duration:
4 h
Mortality:
The total deaths were respectively 10/10, 0/10 and 7/10 for group 1, 2 and 3
Clinical signs:
other: Wet fur and fur staining on various occasions were commonly recorded both during and for several hours after exposure. These observations were considered to be related to the restraint and exposure procedures and, in isolation, are considered not to be bi
Body weight:
The majority of surviving animals (9/13) during the observation period showed strong bodyweight losses, especially in the first week of the observation period.
Gross pathology:
Necroscopy:
Amongst animals that died during the course of the study, the following abnormalities were detected:
Lungs: dark red, edemic;
Trachea: foamy content;
Liver: congestion;
Kidneys: pale;
Intestines: empty;
Tracheobronchial lymph nodes: enlarged
Spleen: enlarged.
In the dead animals the alteration found in the lungs and in the liver (congestion) can be in connection with an acute circulatory insufficiency.
Amongst animals necropsied at terminal kill, the following macroscopic abnormalities were recorded:
Lungs – dark red, edemic, greyish-green colored areas;
Trachea: foamy content;
Kidneys: one-side pyelectasis;
Tracheobronchial lymph nodes: enlarged (bean sized), greyish-green colored;
Spleen: enlarged;
Uterus: slight hydrometra (in female animlas);
Nourishment: undernourishment;
Liver: congestion
In the surviving animals the hydrometra and the pyelectasis in an alteration with sporatic occurrence in experimental rats without toxicological meaning.
The alteration (dead and surviving animals too) found in the trachea, in the lungs (edemic, discoloration), in the tracheobronchial lymph nodes can be in connection with the effect of the test item. Macroscopic alteration in connection with the effect of the test item (CdTe) was found in the lungs and in the tracheobronchial lymph nodes.
Other findings:
none
none
Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Tests done according to standard protocol. Good quality and considered useful for setting the reference value for acute inhalation toxicity (LC50, 4h=2.7mg/L)
Executive summary:

The purpose of this study was to assess the acute inhalation toxicity of CdTe when administered to rats for a single continuous 4 -hour period, followed by an observation period of 14 days.

The acute inhalation median lethal concentrations (4hr LC50) (and 95% confidence limits) of CdTe, in Wistar Crl:(WI) BR strain rats, were calculated to be: All animals: 2.71 mg/L; Male only: 2.53 mg/L; Female only: 2.87 mg/L

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
2 700 mg/m³

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Data waiving:
other justification
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

- An LD50 for acute oral toxicity >2000mg CdTe/kg bw (Nagy, Labresearch Ltd et al., 2008) is used for the risk characterisation as well as classification

- An LC50 for acute inhalation toxicity of 2.7mg CdTe/L (Nagy, Labresearch Ltd et al., 2008) is used for the risk characterisation as well as classification

In Rusch et al (1986), in which Sprague-Dawley rats were exposed to different cadmium compounds (cadmium red, cadmium yellow, cadmium carbonate and cadmium fume) following single acute inhalation exposures to aerosols containing approximately 100mg/m3 of cadmium, a 2 hours exposure to 97 mg/m3 CdSSe or 99 mg/m3 CdZnS did not cause death in none of the rats by day 30. Therefore the LC50 could not be determined. On the contrary exposure to cadmium fumes (at 112 mg/m3) produced a high incidence of mortality (25/32 within 7 days). A 2 hour exposure to Cd carbonate (132mg/m3) resulted in a lower incidence of death (3/32 by day 30). From these data it can be concluded thatthe different Cd compounds tested in rats were not equivalent with respect to toxicity: CdO fumes and Cd carbonate, representative of more soluble compounds, appeared to be more toxic than the two insoluble cadmium pigments.

- There are no available data on which to evaluate acute dermal toxicity. However, acute dermal toxicity can be considered to be low in view of the poor absorption by this route.

For assessing the acute toxicity of CdZnS, reference has been made to toxicity data obtained by standard acute toxicity testing on CdTe, a sparingly soluble Cd-compound. Bio-elution data in different artificial body fluids demonstrate that the solubility of Cd in CdZnS is much lower than the solubility of Cd from CdTe (cfr Summary bioaccessibility results- under section 7.1 Toxicokinetics).

Bioaccessibility data in gastric fluid, mimicking the oral route of exposure, can provide important information regarding the potential bioavailability and subsequent toxicity for oral systemic endpoints including acute toxicity (and also other endpoints such as repeated dose oral toxicity, reproductive toxicity). The in vitro bioaccessibility data in gastric fluid (reflecting oral exposure) confirms the in vivo toxicokinetics data. The bioaccessibility data shows that the amount of Cd++available for absorption is much lower for Cd red and Cd yellow pigments in comparison to CdTe, a sparingly soluble Cd-compound. In vivo, in a subacute feeding study (7days), in which the uptake of cadmium resulting from ingestion of cadmium chloride was compared to the uptake seen with several cadmium pigments (red and yellow), it was shown that cadmium uptake was greatest in the cadmium chloride dosed group. Average calculated cadmium absorption ratio's indicate respectively 246 and 319 times more cadmium absorbed following exposure to CdCl2than after exposure to Cd red and Cd yellow pigments (Hazleton Laboratories America, Inc, 1977).

In the case of toxicity or mortality (e.g. LC50) after acute inhalation exposure, the target site may be the whole respiratory tract. Extracellular (e.g. interstitial) dissolution may be more important for acute toxicity effects than the intracellular fluid (e.g. lysosomal) since in vivo acute toxicity studies usually involve exposure for a few hours followed by observation for a few days, and as such the potential for intracellular dissolution is more limited.

The in vitro bioaccessibility data in interstitial fluid (reflecting inhalation exposure) confirms the in vivo toxicokinetics data. The bioaccessibility data shows that the amount of Cd++available for absorption is much lower for Cd red and Cd yellow pigments in comparison to CdTe, a sparingly soluble Cd-compound. In vivo following single acute inhalation exposures (2-hours) of Sprague-Dawley rats, the blood levels of cadmium (µg Cd/ml) in the cadmium fume-exposed rats showed a marked elevation immediately following the exposure, while those in the carbonate-exposed group showed a slight elevation. Cadmium fume and carbonate-exposed groups approached background levels by the 24-hr sample period. The blood levels of cadmium in the Cd red- and Cd yellow-exposed rats were similar to those seen in the control group at all intervals (Rusch et al 1986).


Justification for selection of acute toxicity – oral endpoint
Only one study available and has Klimisch score 1

Justification for selection of acute toxicity – inhalation endpoint
Only one study available and has Klimisch score 1

Justification for selection of acute toxicity – dermal endpoint
The rules for adaptation in Column 2 of the REACH Annex VIII state that, “in addition to the oral route (8.5.1), for substances other than gases, the information mentioned under 8.5.2 to 8.5.3 [inhalation and dermal acute toxicity] shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure. If there is only one route of exposure, information for only that route need be provided”. The rules for adaptation also state that, “Testing by the dermal route is appropriate if…(1) inhalation of the substance is unlikely…”. As oral and inhalation routes of exposure are more relevant and data for these have been provided, testing for acute dermal toxicity is therefore waived based on this information.

Justification for classification or non-classification

Table- Bio-elution data on CdTe and CdZnS measured in gastric and interstial fluids, along with the measured LD50, LC50 values in rat

Test substance

Gastric

Bioaccessibility
2 hours as % Cd released of total Cd content

Measured acute rat LD 50 (mg/kg bw)

Acute oral classification

Interstitial

Bioaccessibility 24- 168 hours as % Cd released of total Cd content

Measured acute rat LC 50 (mg/L)

Acute inhalation classification

CdTe

 

35.35 ± 8.69

 

>2000

No


0.10 - 0.08

2.7

Cat 4

CdZnS


0.70 ± 0.09

 

No

0.0002 - 0.0002

 

No

Factor difference CdTe/CdZnS

 

51

 

 

400

 

 

Using the reference substance CdTe which is of very low acute oral and dermal toxicity not requiring a classification according to the EC criteria, a classification for CdZnS for acute oral and dermal toxicity is not required, neither.

Considering the LC50 value of the reference substance CdTe of 2.7mg/L, and the 400x lower bioaccessibility of Cd in CdZnS, as compared to CdTe, an LC50 of >>2.7mg/L can be estimated for CdZnS. The estimated LC50 of CdZnS is much higher than 5mg/L above which no classification for acute inhalation toxicity is required according to EC criteria.