Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Acute oral toxicity: LD50 > 10000 mg/kg bw (OECD 401 (1987); non-GLP compliant)

Acute inhalation toxicity: LC50 (rats; 4 hours) > 5.06 mg/L air (actual concentration) (OECD 436 (2009); GLP compliant)(read across to cobalt zinc aluminate blue spinel)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1987-09-08 to 1987-09-22
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
the purity of the test material was missing in the study report Minor deviations from the guideline: - in this study only males were given the test item. According to the guideline, after completion of the study in one sex one group of the other sex is dosed to establish that animals of this sex are not markedly more sensitive to the test substance. Where adequate information is available to demonstrate that the animals of the sex tested are markedly more sensitive, testing in animals of the other sex may be dispensed with. If males are more sensitive to the test item than females was not stated in the report, but since the LD50 for males lies above 10000 mg/kg it is assumed that the LD50 for the females is also above 2000 mg/kg and no testing of females is needed. - the acclimatisation period in this study was four days - the administered test volume was not stated - information on temperature and relative humidity (holding conditions) were missing. - time of appearance and disappearance of clinical signs was not stated. In addition, number of animals displaying signs of toxicity was not shown. - bodyweight should be determined at the day of administration and then weekly thereafter and at death. The body weight was determined at the day of administration and at the end of the study (Day 14). - the age of the rats was missing in the study report. Since the weight of the rats was between 200 and 300 g, it was assumed that the rats were young adults.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
1987-02-24
Deviations:
yes
Remarks:
, please refer to "Rationale for reliability incl. deficiencies" above
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 222 to 255 grams
- Fasting period before study: overnight prior to dosing food was denied.
- Housing: the rats were housed in groups of five in stainless steel wire mesh suspension cages.
- Diet (ad libitum, except during the fasting period prior to dosing): animals were maintained on PURINA LABORATORY CHOW
- Water (ad libitum): tap water
- Acclimation period: at least four days prior to dosing

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
DOSAGE PREPARATION: the test material was administered as a 50 % w/v formulation in distilled water.
Doses:
10000 mg/kg
No. of animals per sex per dose:
10 males
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed for gross signs of systemic toxicity and mortality several times during the day of dosing and once daily thereafter for 14 days.
- Necropsy of survivors performed: yes; at the end of the observation period, the rats were weighed, killed by carbon dioxide inhalation and given a gross necropsy.
Statistics:
not applicable
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
> 10 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred during the obervation period.
Clinical signs:
other: Clinical changes observed during the observation period are as follows: 1. Mild depression 2. Faecal stains 3. Blue sample-like stains on coats 4. Blue mucoid faeces on cage paper 5. Blue-sample-like stains on fur
Body weight:
other body weight observations
Remarks:
All animals gained bodyweight (mean bodyweight gain: 59 g (S.D. = 11 g).
Gross pathology:
Gross necropsies performed at the end of the study revealed no gross pathological changes.
Interpretation of results:
GHS criteria not met
Conclusions:
LD50 (male rats) > 10000 mg/kg
According to the EC-Regulation 1272/2008 and subsequent regulations, the test item is not classified as acute toxic via the oral route.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The key study fulfils the requirements for acute oral toxicity under REACH (Regulation (EC) 1907/2006)

Acute toxicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
According to the ECHA Guidance Read-Across Assessment Framework (RAAF, March 2017), the read-across hypothesis for systemic effects is based on the assumption that different compounds give rise to the same common moieties (“(Bio)transformation to common compound(s)”) to which the organisms are exposed.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target substance Cobalt aluminate blue spinel is a complex inorganic colored pigment (CICP) and considered to be a UVCB under REACH, following the sector specific guidance for complex inorganic colored pigments (Eurocolour, 2017). Cobalt and aluminium expressed as the respective oxides are the main contributing elements. It is noted, that during the manufacture of CICPs chemical bonds of the raw materials are broken, and atoms are homogeneously and ionically interdiffused to form a specific crystalline matrix. Therefore, metals and oxygen atoms occupy specific places within the crystalline lattice, and individual oxides do not exist.
A detailed characterisation of the target substance is given in the attached justification document, Table 1..
The source substance Cobalt zinc aluminate blue spinel is also a complex inorganic colored pigment (CICP) and considered to be a UVCB under REACH, following the sector specific guidance for complex inorganic colored pigments (Eurocolour, 2017). It consists of almost the same contributing elements (Cobalt, zinc and aluminium expressed, as oxides are the main constituent). It is noted, that during the manufacture of CICPs chemical bonds of the raw materials are broken, and atoms are homogeneously and ionically interdiffused to form a specific crystalline matrix. Therefore, metals and oxygen atoms occupy specific places within the crystalline lattice, and individual oxides do not exist.
A detailed characterisation of the sourcesubstance is given in the attached justification document, Table 2.
The common characteristic of the target substance and the source substance is that both substances crystallise in the spinel structure, which forms a strong and inert crystal lattice. Both substances consist of almost the same chemical constituents. Furthermore, both show a similar, very low solubility in different artificial and aqueous media which is used for (eco)toxicological predictions.

3. ANALOGUE APPROACH JUSTIFICATION
Upon uptake of the target substance, the toxicological units will be liberated in the ionic form similar to the source substance, which also liberates the toxicological units, cobalt, aluminium and zinc, respectively. Upon solvation in body-fluids such as gastric juice, the toxic units become indistinguishable. The sole relevant modifier of systemic toxicity is the “solubility” of the cations in the respective body-fluid. The target substance also releases trivalent chromium ions which are not known to show signs of systemic toxicity (EFSA, 2014).
The target as well as the source substance show a very low solubility in different artificial and aqueous media demonstrating the inertness of the substances. The source substance shows slightly higher bioaccessibility for cobalt without showing any signs of systemic or local toxicity in various studies (acute inhalation, sub-acute oral toxicity, skin/eye irritation and sensitisation). The target substance shows no systemic or local toxicity in an acute oral toxicity study and skin and eye irritation studies.
Particle size information of the substance influences the deposition behaviour in the respiratory tract and potential toxic effects. Based on particle size distribution data, trends in deposition and potency of effects can be assessed for locally acting substances.
When comparing the particle size and the MMAD obtained in an acute inhalation toxicity study and dustiness study of the two substances one can assume that the deposition behaviour of the source pigment is higher compared to the target substance. This is further emphasised by the results of the MPPD model, where about 4 % of inhaled material is predicted to be deposited in the pulmonary region (PU) for the source pigment, whereas only 0.3% is predicted to be deposited in the pulmonary region (PU) for the target pigment. Most of the material of both pigments deposited in the tracheobronchial (TB) and the extrathoracic region (Head) and may be assumed to be cleared to the GI tract (i. e., by mucociliary escalation and subsequent swallowing). Regarding the deposition in the deep lung the source substance shows a higher deposition in the PU region compared with the target substance. Furthermore, taking into account that the source substance shows slightly higher bioaccessibility in artificial lung fluids (ALF and GMB) read-across can be considered to be conservative.

4. DATA MATRIX
A data matrix is presented in Appendix 1 of the read-across document (attached in IUCLID section 13.2).

A detailed read-across justification is provided in the read-across document (attached in IUCLID section 13.2) .
Reason / purpose for cross-reference:
read-across source
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.06 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: Standard deviation: 0.07 mg/L air. The LC50 cut-off value is 'unclassified'.
Interpretation of results:
GHS criteria not met
Conclusions:
LC50 (rats; 4 hours) > 5.06 mg/L air (actual concentration)
According to the EC-Regulation 1272/2008 and subsequent regulations, the test item is not classified as acute toxic via the inhalation route.
Furthermore, no signs of respiratory tract irritation were observed.
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2010-07-01 to 2010-08-17
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
Version / remarks:
2009-09-07
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
signed 2009-11-12
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: Males: 50 days; Females: 64 days
- Weight at study initiation: Males: 252 - 262 g; Females: 222 - 242 g
- Fasting period before study: Feeding was discontinued approx. 16 hours before exposure
- Housing: During the 14-day observation period the animals are kept by sex in groups of 3 animals in MAKROLON cages (type III plus); Granulated textured wood (Granulat A2, J. Brandenburg, 49424 Goldenstedt, Germany) was used as bedding material for the cages.
- 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 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.

ENVIRONMENTAL CONDITIONS
- Temperature: 22°C±3°C (maximum range)
- Relative humidity: 55%±15% (maximum range)
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- 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).

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.

- Method of particle size determination: An analysis of the particulate 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).
The 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 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.

- Treatment of exhaust air: The exhaust air was drawn through gas wash-bottles.

- Temperature, humidity, oxygen, carbon dioxide, air flow: 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 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 (22.9°C ± 0.2°C) and humidity (53.2% ± 1.3%) were measured once every hour with a climate control monitor (testo 175-HZ data logger).

TEST ATMOSPHERE - The inhalation chamber was equilibrated for at least 15 minutes (t95 approximately 8 minutes).
- 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). The correct loading of the filter was checked by the airflow via the rotameter and by a positive weight increase of the filter after the sampling period of 1 minute.
- Samples taken from breathing zone: yes

TEST ATMOSPHERE (if not tabulated)
- MMAD: 2.633 µm (GSD: 2.62)
Analytical verification of test atmosphere concentrations:
yes
Remarks:
see above ("Details on inhalation exposure")
Duration of exposure:
4 h
Remarks on duration:
Exposition started by locating the animals’ noses into the exposure chamber after equilibration of the chamber concentration for at least 15 minutes.
Concentrations:
5.06 +/- 0.07mg/L air (actual concnetration)
5.0 mg/L air (nominal concentration)
No. of animals per sex per dose:
3 male rats and 3 female rats
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: During and following exposure, observations were made. 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). 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.
- Necropsy of survivors performed: Yes
Necropsy of all animals was carried out and all gross pathological changes were recorded.
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: 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.
Changes in weight were calculated and recorded when survival exceeded one day.
Statistics:
not applicable
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.06 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: Standard deviation: 0.07 mg/L air. The LC50 cut-off value is 'unclassified'.
Mortality:
No mortality occurred.
Clinical signs:
other: Moderate ataxia (0 - 60 min), slight to moderate tremor (0 min - 3 hours) and slight dyspnoea (0 min - 3 hours) were observed in all 3 male and 3 female rats.
Body weight:
All animals gained the expected body weight throughout the study period.
Gross pathology:
No pathological findings were made.
Other findings:
No data
Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this study, the 4-hour inhalation LC50 of Pigment Al-Co-Zn is >5.06 mg/L air, and hence, the LC50 cut-off value 'unclassified'.
According to the EC Regulation 1272/2008 and subsequent regulations, the test material is not classified for acute inhalation toxicity.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The study fulfils the requirements for acute inhalation toxicity under REACH (Regulation (EC) 1907/2006).

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

Acute oral toxicity

Reference Doyle (1987) will be used as key study for acute oral toxicity and will be used for classification.

The LD50 was determined to be greater than 10000 mg/kg bw. Thus, according to regulation (EC) 1272/2008 and subsequent amendments the substance is not classified.

Specific target organ toxicant (STOT) - single exposure: oral

The classification criteria according to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – single exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value, oral for a Category 1 classification (C≤ 300 mg/kg bw) and at the guidance value, oral for a Category 2 classification (2000 mg/kg bw≥C > 300 mg/kg bw). No classification required.

Acute inhalation toxicity

The reference Haferkorn (2010) is used as read across in order to cover this endpoint and will be used for classification. Read across is made to cobalt zinc aluminate blue spinel. Male and female rats were exposed to 5.06 mg/L air (limit test, observation period 14 days) for 4 hours. No mortality occurred. The LC50 is > 5.06 mg/L air.

The classification criteria according to regulation (EC) 1272/2008 as acutely toxic are not met since the ATE is above 5.0 mg/L, hence no classification required. Hence, cobalt aluminate blue spinel will also not be classified.

Specific target organ toxicant (STOT) - single exposure: inhalation

The classification criteria according to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – single exposure, inhalation (dust/mist/fume) are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value, inhalation (dust/mist/fume) for a Category 1 classification (C≤ 1 mg/L/4h). Based on the outcome of the limit test on acute inhalation toxicity (0 animals of 6 animals died at a concentration of 5.06 mg/L/4h and no systemic or local effects were observed) it can safely be assumed that no classification for Category 2 (5.0 ≥C > 1.0 mg/L/4h) is required.