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Diss Factsheets

Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

short-term repeated dose toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Range-finding study considering OECD 413, section: Range-finding study. Read-across to silicon.

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
no guideline followed
Principles of method if other than guideline:
Range-finding study conducted with silicon, considering OECD test guideline 413, section: Range-finding study
GLP compliance:
Study conducted in compliance with the principles of GLP, however no inspections by QAU staff were done

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Test material form:
aerosol dispenser: not specified
migrated information: aerosol
Details on test material:
- Name of test material (as cited in study report): Jetmilled Silgrain

- Physical state: Grey-brown powder
- Analytical purity: > 99.5% Si
- Lot/batch No.: J-257
- Expiration date of the lot/batch: Dec 13, 2018

- Storage condition of test material: Room temperature, at a dark place
- Other:
Particle size distribution: d10=1.3, d50=3, d90=7.4 (laser diffraction)
BET surface area 4.5-5.1 m2/g

Test animals

Details on test animals or test system and environmental conditions:

- Diet (e.g. ad libitum): standard laboratory pellet diets, commercial chow in pellet form used, identified as ssniff "V1534", purchased from ssniff Spezialdiäten GmbH, Soest, Germany
- Water (e.g. ad libitum): tap water ad libidum
- Acclimation period: Rats exposed to the test item by nose-only inhalation. For a period of 2 - 3 weeks prior to exposure animals will be trained to become accustomed to nose-only tubes.

- Source: Wistar rats, strain Crl:WI (Han), purchased from Charles River Deutschland (Sulzfeld, Germany)
- Age at study initiation: approximately 8 weeks
- Weight at study initiation: males approximately 235 grams, females approximately 175 grams
- Fasting period before study: no
- Housing: Makrolon® (polycarbonate) cages type III, two rats per cage.Lignocel BK 8-15' absorbing softwood bedding material, changed twice a week or more often if necessary.
- Diet: commercial chow in pellet form: Ssniff "V1534", purchased from ssniff Spezialdiäten GmbH, Soest, Germany ad libitum
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: The animals were first allowed to adjust and become acclimatized to the environment for one day. During 2-3 weeks prior to exposure start, all rats were trained to the 6-h restraint in nose-only tubes.

- Temperature (°C): 22 ± 2 C
- Humidity (%): 55% ± 15%
- Photoperiod (hrs dark / hrs light): 12 h light/dark

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
clean air
Remarks on MMAD:
MMAD / GSD: MMAD approximately 2.4 µm.
Details on inhalation exposure:
- Exposure apparatus: The test item was administered to the test animals by nose-only inhalation, using a flow-past nose-only inhalation exposure system.

- Method of holding animals in test chamber: The rat nose is located at the front end of a tube being connected to a cylinder delivering the aerosol. Through the thin pipes, the aerosol was supplied to each rat nose individually and exhaled air was drawn off immediately by a cylinder surrounding the aerosol delivering cylinder.
The exposure tubed were arranged around a cylinder capable to take up 16 tubes per platform. The position of exposuretubes of tats at the cylinder was changed daily to minimize exposure differences due to geometry.

- System of generating particulates/aerosols: The particulate sample aerosols were generated by dispersing the dry powder. Dispersion was achieved by a feeding system and a high-pressure, high-velocity pressurized air dispersion nozzle. For each nose-exposure unit, the aaerosols were generated by a high-pressure pneumatic disperser, fed with the silicon powder under computerized control.

- Temperature, humidity, pressure in air chamber: 22° C + 2° C for temperature and 55 % + 15 % for relative humidity

- Air flow rate: laminar airflow to each rat of approximately 1 l/min
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
The actual aerosol concentrations were measured daily using a photometer (gravimetric analysis of filter samples). The mean concentrations were very close to the target concentrations, being 3.83 mg/m3 in the 4 mg/m3-group, 20.03 mg/m3 in the 20 mg/m3-gropu and 101.81 mg/m3 in the 100 mg/m3 group.
Duration of treatment / exposure:
2 weeks
Frequency of treatment:
6 h/day, 5 days/week
Doses / concentrations
Doses / Concentrations:
4, 20 and 100mg/m3
nominal conc.
No. of animals per sex per dose:
10 animals/sex/dose in all groups except the 100 mg/m3 group having 15 animals/sex/dose.
Control animals:
Details on study design:
- Rationale for animal assignment: The animals were allocated to groups based on body weight, in order to ensure that all animals in the groups had body weights deviating not more than approximately 20% from the mean weight of that group (male/female) at that time.

- No satellite groups.
Positive control:


Observations and examinations performed and frequency:
- Time schedule: once per week

- Time schedule for examinations: thrice per week.

- 5 males and 5 females per group on day 1 after the end of exposure.
- Macrophages, neutrophils, eosinophils and lymphocytes counted.
- LDH, B-glucuronidase and total protein measurements.

-chemical analysis to verify the retention of silicon in the lungs and lung-associated lymph nodes.
Sacrifice and pathology:
by an overdose of carbon dioxide. Rats scheduled for bronchoalveolar lavage sacrificed following a lethal narcosis using Narcoren.

- 5 animals per group and sex at day 1 after the end of exposure.
- All animals of all groups: histopathology of lung lobes, including bronchi and the lung-associated lymph nodes, trachea, larynx, pharynx and the nasal cavities.
- Histopathological examination of other organs only if needed, e.g. as indicated by macroscopical findings
Data analyzed using analysis of variance. Differences between groups considered statistically significant at p < 0.05.
The means of the treated groups were compared with the means of the control groups using Dunnett's test (if the group means differed significantly by the analysis of variance).

Results and discussion

Results of examinations

Clinical signs:
no effects observed
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Lung weight increased at 100 mg/m3
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
Very slight to sight (multi)focal alveolar accumulation of particle-laden macrophages were observed in all examined silicon-exposed animals.

Mild adverse effects were observed only in the 100 mg/m3 group: alveolar granulocyte infiltration and interstitial mononuclear cell infiltration.

Aggregates of particle-leaden macrophages were observed within the bronchus-associated lymphoid tissue in animals of the 20 mg/m3 and 100 mg/m3 groups.

Very slight to slight accumulation of particle-laden macrophages in the lung-associated lymph nodes was observed in the 20 mg/m3 and 100 mg/m3 groups.

BAL-fluid analyses showed increased levels of LDH and total protein in males and females exposed to 20 mg/m3 and 100 mg/m3 silicon. B-glucuronidase levels were increased in the 100 mg/m3 group. Cell counts showed increased amounts of macrophages and neutrophils in the samples of 20 mg/m3 and 100 mg/m3-exposed males and females. In addition, macrophages were induced in the 20 mg/m3 male rats, and in female and male rats exposed to 100 mg/m3.

The authors of the study report identified 4 mg/m3 silicon as a NOAEC for this study.

Effect levels

Dose descriptor:
Effect level:
4 mg/m³ air (nominal)
Basis for effect level:
other: local lung effects

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Exposure to silicon particles via inhalation during 14 days resulted in mild, local, adverse effects only at the highest dose tested (100 m/m3). Bronchoalveolar-lavage fluid analysis showed silicon-exposure related, dose-dependent increases in lactate dehydrogenase, beta-glucuronidase and total protein concentrations. Also the concentration of leukocytes, macrophages and neutrophils incrreased upon exposure. No systemic effects were observed.
Executive summary:

A 14-day nose-only inhalation study with silicon particles was performed by Fraunhofer ITEM in Wistar rats (Fraunhofer ITEM 2012). One aim of the study was to identify appropriate aerosol concentrations to be used in a subsequent 90-day inhalation study. Male and female rats were exposed to 4, 20 and 100 mg/m3of silicon particles (MMAD 2.6 µm), 5 days/week, 6 h/day during two weeks. No effects indicating systemic toxicity were observed at any doses. The lung weights were increased in animals of the high dose group at the end of the exposure period. Bronchoalveolar lavage fluid analyses showed dose-related effects in the 20 and 100 mg/m3groups. (Multi)focal alveolar accumulation of particle-laden macrophages was observed in animals of all groups. Furthermore, alveolar granulocyte infiltration and interstitial mononuclear cell infiltration were observed at 100 mg/m3. All observed effects were very slight or slight.

The NOAEC for silicon was 4 mg/m3and the LOAEC 20 mg/m3. On the basis of this study, a dosing scheme of 1, 4 and 16 mg/m3was proposed for the 90-day inhalation study.