Registration Dossier

Administrative data

acute toxicity: inhalation
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
2012-04-30 to 2012-05-31
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Zircon, cadmium yellow is a zircon-type oxide/pigment with the main structural element ZrSiO4 (Zr in an dodecahedral O environment) which forms a strong and inert matrix. Zr and Si are the main components with percentages of ~46% w/w and 15% w/w respectively. The amount of Cd as component is about 2% w/w.

The read-across substance Silicic acid, zirconium salt, cadmium pigment encapsulated is a zircon-type pigment as well with an identical crystallographic structure and a very similar composition. Zr content is ~46% w/w and the Si content is ca. 14% w/w. Cd is present in about 4.7% w/w. Minor amounts of Se and S (1.53 and 1.04% w/w, respectively) are present as well.

Besides the obvious structural analogy the solubility of both pigments in aqueous and physilogical media are as follows (determination of Zr and Cd):

Solubility of Cd from the pigment Zircon, cadmium yellow in physiological media was in a range of 0.180 µg/L (PBS) and 0.398 µg/L (ALF) after 2 hours. After 24 hours a dissolution range from 0.140 µg/L (GMB) - 0.722 µg/L (GST) was measured.

Solubility of Zr from the pigment Zircon, cadmium yellow in physiological media was in a range of below LOD and 0.812 µg/L (ALF) after 2 hours. After 24 hours a dissolution range from below LOD (ASW) - 1.44 µg/L (ALF) was measured.

The read-across substance Silicic acid, zirconium salt, cadmium pigment encapsulated afforded after 2 hours a solubility for the element Cd in range of 0.07 µg/L (GMB) 2.58 µg/L (GST) and after 24 hours a solubility of 0.07 µg/L (GMB) to 6.13 µg/L (GST).

Solubility of Zr from the pigment Silicic acid, zirconium salt, cadmium pigment encapsulated in physiological media was in a range of below LOD and 0.52 µg/L (ALF) after 2 hours. After 24 hours a dissolution range from below LOD - 1.25 µg/L (ALF) was measured.

T/D testing of the pigment Zircon, cadmium yellow afforded the following solubility at 1mg loading after 28 days:
Cadmium: below LOD (<0.0048) and 0.2077 ± 0.0993μg/L at pH 8 and pH 6, respectively
T/D testing of the read-across substance Silicic acid, zirconium salt, cadmium pigment encapsulated afforded the following solubility at 1mg loading after 28 days:
Cadmium: 0.34 ± 0.09 μg/L and 0.86 ± 0.39 μg/L at pH 8 and pH 6, respectively
In sum, the two zircon type pigments are structurally identical with very similar composition and both show a very low solubility in different artificial and aqueous media. In fact, the read-across substance Silicic acid, zirconium salt, cadmium pigment encapsulated shows slightly higher dissolution and bioaccessibility without showing any signs of systemic or local toxicity in various studies (acute inhalation, skin/eye irritation, sensitisation). No toxicity on algae, fish and invertebrates could be observed in respective studies.
Hence, read-across to Silicic acid, zirconium salt, cadmium pigment encapsulated is fully justified.

Data source

Reference Type:
study report
Report Date:

Materials and methods

Test guideline
according to
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
Version / remarks:
GLP compliance:
yes (incl. certificate)
signed 2009-11-12
Test type:
acute toxic class method
Limit test:

Test material

Test material form:
solid: particulate/powder
Details on test material:
- Name of test material (as cited in study report): Silicic acid, zirconium salt, cadmium pigment encapsulated
- Chemical description: silicic acid, zirconium salt, cadmium pigment encapsulated
- Physical state: solid, bright red powder, odourless
- Melting point: >1000°C
- Water solubility: not soluble
- Relative density: 4.70
Specific details on test material used for the study:
- Storage condition of test material: at room temperature, kept dry in closed container

Test animals

other: Crl: CD(SD)
Details on test animals and environmental conditions:
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: males: approx. 8 weeks; females: approx. 9 weeks
- Weight at study initiation: males: 238 - 290 g; females: 210 - 241 g
- Fasting period before study: feeding was discontinued approx. 16 hours before exposure; only tap water was then available ad libitum.
- Housing: during the 14-day observation period, the animals are kept by sex in groups of 2 - 3 animals in MAKROLON cages (type III plus); bedding material: granulated textured wood (Granulat A2, J. Brandenburg, 49424 Goldenstedt, Germany)
- Diet: commercial diet, ssniff® R/M-H V1534 (ssniff Spezialdiäten GmbH, 59494 Soest, Germany)
- Water (ad libitum): drinking water
- Acclimation period: at least 5 adaptation days

The animals were randomised before use. They were acclimatised to the test apparatus for approx. 1 hour on 2 days prior to testing. The restraining tubes did not impose undue physical, thermal or immobilization stress on the animals.

- Temperature: 22°C ± 3°C (maximum range)
- Relative humidity: 55% ± 15% (maximum range)
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
clean air
Mass median aerodynamic diameter (MMAD):
2.81 µm
Geometric standard deviation (GSD):
Remark on MMAD/GSD:
The MMAD/GSD mentioned above are for the main study (limit test). The MMAD/GSD of the satellite group were as follows:
MMAD: 2.486 µm
GSD: 2.80
Details on inhalation exposure:
- Exposure apparatus: the study was carried out using a dynamic inhalation apparatus (RHEMA-LABORTECHNIK, 65719 Hofheim/Taunus, Germany) (air changes/h (≥ 12 times)) with a nose-only exposure of the animals according to KIMMERLE & TEPPER. The apparatus consists of a cylindrical exposure chamber (volume 40 L) which holds the animals in pyrex tubes at the edge of the chamber in a radial position.

- System of generating particulates/aerosols: the dust of the test material was generated with a rotating brush dust generator (RBG 1000, PALAS GmbH Partikel und Lasermesstechnik, 76229 Karlsruhe, Germany).
The generator was fed with compressed air (5.0 bar) from a compressor (ALUP Kompressorenfabrik, 73257 Köngen, Germany)(air was taken from the surrounding atmosphere of the laboratory room and filtered using an in-line disposable gas-filter).
At the bottom of the exposure chamber, the air was sucked off at a lower flow rate than it was created by the dust generator in order to produce a homogenous distribution and a positive pressure in the exposure chamber (inflow 900 L/h, outflow 800 L/h).
A manometer and an air-flow meter (ROTA Yokogawa GmbH & Co. KG, 79664 Wehr/Baden, Germany) were used to control the constant supply of compressed air and the exhaust, respectively. Flow rates were checked hourly and corrected if necessary.
The exhaust air was drawn through gas wash-bottles.

- Method of particle size determination: an analysis of the particle size distribution was carried out twice during the exposure period using a cascade impactor according to MAY (MAY, K. R. Aerosol impaction jets, J.Aerosol Sci. 6, 403 (1975), RESEARCH ENGINEERS Ltd., London N1 5RD, UK).
The dust from the exposure chamber was drawn through the cascade impactor for 5 minutes at a constant flow rate of 5 L/min. The slides were removed from the impactor and weighed on an analytical balance (SARTORIUS, type 1601 004, precision 0.1 mg). Deltas of slides’ weight were determined.
The mass median aerodynamic diameter (MMAD) was estimated by means of non-linear regression analysis. The 32 µm particle size range and the filter (particle size range < 0.5 µm) were not included in the determination of the MMAD in order not to give undue weight to these values.
The Geometric Standard Deviation (GSD) of the MMAD was calculated from the quotient of the 84.1%- and the 50%-mass fractions, both obtained from the above mentioned non-linear regression analysis.
In addition, a sample of approx. 10 g test material was taken from the exposure chamber to determine the median physical particle size with a CILAS 715 by My-Tec, 91325 Adelsdorf, Germany. This determination was non-GLP.

- Temperature, humidity, pressure in air chamber, oxygen content and carbon dioxide content: the oxygen content in the inhalation chamber was 21%. It was determined at the beginning and at the end of the exposure with a DRÄGER Oxygen-analysis test set (DRÄGER Tube Oxygen 67 28 081). Carbon dioxide concentration did not exceed 1%.
Temperature (22.4°C ± 0.1°C (main study) or 20.5°C ± 0.2°C (satellite group)) and humidity (60.4% ± 0.2% (main study) or 64.1% ± 0.3% (satellite group)) were measured once every hour with a climate control monitor (testo 175-HZ data logger).

The whole exposure system was mounted in an inhalation facility to protect the laboratory staff from possible hazards.

Exposition started by locating the animals into the exposure chamber after equilibration of the chamber concentration for at least 15 minutes (t95 approximately 8 minutes).

Before initiating the study with the animals, a pre-test was carried out with the exposure system in order to verify that under the experimental settings chosen, the limit concentration of 5 mg/L air could be achieved by gravimetric analysis.

The tests with the main study animals and the recovery animals were conducted in the same inhalation chamber but on different days. Between the exposure times the chamber was cleaned carefully.

- Brief description of analytical method used: the actual dust concentration in the inhalation chamber was measured gravimetrically with an air sample filter (Minisart SM 17598 0.45 µm) and pump (Vacuubrand, MZ 2C (Membrane Pump, Vacuubrand GmbH + Co. KG, 97877 Wertheim/Main, Germany)) controlled by a rotameter. Dust samples were taken once every hour during the exposure. For that purpose, a probe was placed close to the animals' noses and air was drawn through the air sample filter at a constant flow of air of 5 L/min for 1 minute. The filters were weighed before and after sampling (accuracy 0.1 mg).
Individual chamber concentration samples did not deviate from the mean chamber concentration.
- Samples taken from breathing zone: yes
Analytical verification of test atmosphere concentrations:
see above ("Details on inhalation exposure")
Duration of exposure:
4 h
Main study (limit test):
- actual concentration: 5.07 ± 0.01 mg/L air
- nominal concentration: 8.33 mg/L air
Satellite group:
- actual concentration: 5.08 ± 0.01 mg/L air
- nominal concentration: 8.33 mg/L air
No. of animals per sex per dose:
Main study (limit test):
3 males / 3 females
Satellite group:
3 males / 3 females
Control animals:
Details on study design:
- Duration of observation period following administration: 24 hours (satellite group) and 14 days (main study)
- Frequency of observations and weighing: during and following exposure, observations were made and recorded systematically; individual records were maintained for each animal. Careful clinical examinations were made at least twice daily until all symptoms subsided, thereafter each working day. Observations on mortality were made at least once daily (in the morning starting on test day 2) to minimize loss of animals to the study, e.g. necropsy or refrigeration of those animals found dead and isolation or sacrifice of weak or moribund animals.
Cageside observations included, but were not limited to: changes in the skin and fur, eyes, mucous membranes, respiratory, circulatory, autonomic and central nervous system, as well as somatomotor activity and behaviour pattern.
Particular attention was directed to observation of tremor, convulsions, salivation, diarrhoea, lethargy, sleep and coma. The animals were also observed for possible indications of respiratory irritation such as dyspnoea, rhinitis etc.
Individual weights of animals were determined once during the acclimatisation period, before and after the exposure on test day 1, on test days 3, 8 and 15. Changes in weight were calculated and recorded when survival exceeded one day. At the end of the test, all animals were weighed and sacrificed.
- Necropsy of survivors performed: yes
Necropsy of all main study and satellite animals (3 + 3 males and 3+3 females) was carried out and all gross pathological changes were recorded:
- Satellite animals: necropsy at 24 hours after cessation of exposure, as this is likely to be the time at which any signs of respiratory irritation would have manifested;
- Main study animals: necropsy at the end of the 14-day observation period.
The following organs of all animals were fixed in 10% (nose, i.e. head without brain, eyes and lower jaw) or 7% (larynx, trachea, lungs) buffered formalin for possible histopathological examination. No further organs were preserved.
Since no animal died prematurely, the calculation of an LC50 was not required.

Results and discussion

Effect levels
Key result
Dose descriptor:
Effect level:
> 5.07 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
No animal died prematurely.
Clinical signs:
other: Under the present test conditions, a 4-hour inhalation exposure to silicic acid, zirconium salt, cadmium pigment encapsulated at a concentration of 5.07 mg/L air revealed slight dyspnoea (reduced frequency of respiration with increased volume) until 3 hou
Body weight:
No influence in body weight gain was observed.
Gross pathology:
Marbled lungs were observed in all satellite animals (24-hour sacrifice).

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
LC50 (rats; 4 hours) > 5.07 mg/L air (actual concentration)
According to the Regulation (EC) No 1272/2008 and subsequent adaptations, the substance is not acutely toxic via the inhalation route.