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Diss Factsheets

Administrative data

acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
according to guideline
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
Test type:
standard acute method
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
Test materials used in this dossier are all considered to fall under the definition of nano-materials according to the European Commission Recommendation 2011/696/EU as the synthesis and manufacturing of this pigment always yields particulate material with a fine particle size distribution.
Specific details on test material used for the study:
- Lot/Batch No.: 19695
- Analytical purity: ca. 98%
- Physical state: solid
- Storage condition of test material: room temperature

Test animals

Details on test animals or test system and environmental conditions:
- Source: strain: SPF Wistar/Chbb: THOM; breeding facility: Dr. K. Thomae GmbH, D-7950 Biberach, FRG)
- Age at study initiation: 8 - 9 weeks
- Weight at study initiation: 251 g (males) and 172 g (females)
- Housing: cages type D III of Becker, without bedding, 5 animals per cage
- Diet (e.g. ad libitum): KLIBA rat/mouse laboratory diet 24-343-4 10 mm pellets, Klingentalmühle AG, CH-4303 Kaiseraugst, Switzerland, ad libitum
- Water (e.g. ad libitum): ad libitum

- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Air changes (per hr): fully air-conditioned rooms
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure:
nose/head only
other: Aerosil
Details on inhalation exposure:
- Exposure apparatus: Head-nose inhalation system INA 20 (glass-steel construction, BASF Aktiengesellschaft)
- Exposure chamber volume: ca. 55 L
- Method of holding animals in test chamber: the animals were restrained in tubes and their snouts projected into the inhalation chamber
- Source and rate of air: 1500 L/h, supply air
- Method of conditioning air: The exposure system was placed in an air-conditioned laboratory. Temperatures in the exposure system were 19-25 °C
- System of generating particulates/aerosols: A dust aerosol air mixture was generated by means of a dosing-wheel dust generator (Gericke/BASF).
- Method of particle size determination: Stack Sampler Mark III (Andersen)

- Brief description of analytical method used: The preweighed filter was placed into the filtration equipment. By means of a vacuum compressed air pump a volume of the dust aerosol was drawn through the filter. The dust concentration in mg/l was calculated from the difference between the preweight of the filter and the weight of the filter after sampling, with reference to the sample volume of the inhalation atmosphere. The concentration was corrected for the amount of the added excipient.
- Samples taken from breathing zone: yes

- Composition of vehicle (if applicable): 1 wt% of Aerosil

TEST ATMOSPHERE (if not tabulated)
- MMAD (Mass median aerodynamic diameter): 3.0 µm (GSD: 3.6)
Analytical verification of test atmosphere concentrations:
gravimetric determination
Duration of exposure:
4 h
5.2 mg/L
No. of animals per sex per dose:
Control animals:
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The body weight of the animals was checked before the beginning of the test, after 7 days and at the end of the observation period. Clinical findings were recorded several times during exposure and at least once an each workday in the observation period. A check for dead animals was made daily.
- Necropsy of survivors performed: yes
The statistical evaluation of the concentration/effect relationship was carried out on the basis of the binomial test (Wittig, H.: Mathematische Statistik 1974, pp. 32 - 35).

Results and discussion

Effect levels
Dose descriptor:
Effect level:
> 5.2 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
not determinable due to absence of adverse toxic effects
None of the animals died during the observation period
Clinical signs:
other: Irregular, accelerated and/or intermittent respiration, flight behaviour and discoloured fur. From day 7 of the observation period onward, no abnormalities, except discoloured fur, were detected in the animals.
Body weight:
The body weight gain of male and female rats in the test group, compared with a historical control collective, was not affected by the substance over the total observation period.
Gross pathology:
No pathologic findings were noted.

Any other information on results incl. tables

Results of analytical measurements:

Sample No Analyt. Conc. (mg/l)
1 5.01
2 5.5
3 5
4 5.32
Mean 5.26
mean corrected for 1 % additive 5.22
mean rounded 5.2
standard deviation of the mean 0.2
Nominal concentration 16.8

Particle size analysis:

Cascade Impactor
Stage EACD 50% [µm] [mg] percentage distribution [%] cummulative distribution [%]
pre-impactor 26.6 0.97 4 96
0 29.5 0.79 3.3 92.7
1 18.2 2.67 11.1 81.6
3 8.5 2.69 11.2 70.5
4 5.5 6.58 27.2 43.3
5 2.8 4.45 18.4 24.9
7 1.2 6.01 24.9 -
backup filter < 1.2
Sum 24.15

The MMAD 50% = 3.0 µm (geometrical standard deviation =3.6) was calculated from the results of the particle size analysis.

A respirable dust aerosol fraction that might reach the alveolar region of 82% was obtained from the results of the particle size analysis.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
The LC50 was concluded to be greater than 5.2 mg/L.
Executive summary:

In an inhalation toxicity study according to OECD guideline 403, Wistar rats (5/sex) were exposed to the test article as dust for 4 hours at a measured concentration of 5.2 mg/L followed by a 14-day observation period. Cascade impactor measurements resulted in a particle size distribution with a mass median aerodynamic diameter (MMAD) of 3 µm (GSD: 3.6), which is well within the respirable range. None of the animals died during the study period. Clinical signs included irregular, accelerated and/or intermittent respiration, flight behaviour and discoloured fur. From day 7 of the observation period onward, no abnormalities, except discoloured fur, were detected in the animals. The body weight gain of male and female rats in the test group, compared with a historical control collective, was not affected by the substance over the total observation period. No pathologic findings were noted during gross pathology. The LC50 determined on the basis of the study results was >5.2 mg/L.