Silicic acid, aluminum calcium sodium salt

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study was conducted at the request of CEFIC-ASASP, Brussels, and followed adapted OECD Testing Guidelines for acute, subacute and subchronic inhalation toxicity. The study is included in the peer reviewed Food and Chemical Toxicology Journal. Read-across from the results on the test substance has been made to the registered substance based on the similar structure of the two substances.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2007

Report date:

2007

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

The study was conducted in order to compare results with those of 90-day, subchronic inhalation studies. The study was designed to provide evidence that short-term (five-day) exposure can provide comparable prediction of toxicity to those of 90-day studies. There are no references made to specific testing guidelines in the report (with the exception of the animal procedures which were carried out according to OECD 412, and GLP guidelines). The study appears to utilise adapted versions of OECD 412 and 413, based on a comparison of the published study and the relevant OECD test guidelines.

GLP compliance:

not specified

Remarks:

There is no specific mention of GLP compliance (with the exception of the animal procedures which were carried out according to GLP).

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Silicon dioxide

EC Number:

231-545-4

EC Name:

Silicon dioxide

Cas Number:

7631-86-9

Molecular formula:

O2Si

IUPAC Name:

silicon dioxide (amorphous)

Constituent 2

Reference substance name:

Pyrogenic silica (pyrogenic amorphouse)

IUPAC Name:

Pyrogenic silica (pyrogenic amorphouse)

Constituent 3

Reference substance name:

Cab-O-Sil M5

IUPAC Name:

Cab-O-Sil M5

Constituent 4

Reference substance name:

112945-52-5

EC Number:

601-216-3

Cas Number:

112945-52-5

IUPAC Name:

112945-52-5

Test material form:

aerosol dispenser: not specified

Remarks:

migrated information: aerosol

Details on test material:

Specifications of the synthetic amorphous silica (SAS):

Characteristic: Cab-O-Sil M5
CAS No.: 7631-86-9/112945-52-5
Form: Pyrogenic amorphous
Specific surface area: 200 m^2/g
Hydrophilic/hydrophobic: Hydrophilic
Agglomerate size: ca. 100 µm
Primary particle shape: Spherical
pH: Not given
SiO2 content: >99.7%

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

Young adult, Wistar (Crl:(WI)WU BR) rats were purchased from Charles River Deutschland (Sulzfeld, Germany). The animals were acclimatised for at least 5 days before the start of the study. They were kept under conventional laboratory conditions in suspended, stainless steel cages fitted with wire mesh floor and front, two, three or five rats per cage and received powdered RM3 rodent diet and unfluoridated tap water ad libitum. The animal rooms were ventilated with about 10 air changes per hour and were maintained at a temperature of 22°C ± 2°C and a relative humidity of at least 30% and not exceeding 70% other than during room cleaning. All animal procedures were approved by the TNO Committee on Animal Welfare and carried out according to OECD 412 and OECD GLP guidelines.

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

clean air

Remarks:

Filtered, ambient air

Details on inhalation exposure:

Electromagnetically driven, miniature dust feeders (Institute's design) were used that released periodically (with periods in the range of 2-8 or 6-12 s) small lumps of test material to low velocity eductors in which the test material were aerosolised. Separate aerosol generators were used for each unit. All test materials were delivered using a slip stream of filtered ambient air. The eductors were operated with compressed humidified air, using mass flow controllers. At the entrance of each exposure unit, the generated aerosol was diluted with measured amounts of humidified air.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

The concentration of the test material in the test atmosphere was determined by gravimetric analysis. The actual concentrations were calculated by dividing the amount of test material present on each fibre glass filter by the volume of the sample taken

Duration of exposure:

5 d

Concentrations:

1, 5 and 25 mg/m^3

No. of animals per sex per dose:

10 male rats

Control animals:

yes

Details on study design:

Only male rats were used in this study because of a slightly higher sensitivity in male rats when compared to female rats in initial experiments with a similar substance (see 'Acute toxicity: inhalation_read-across_precipitated silica'). The exposure groups consisted of 10 males each, the control groups II consisted of 12 males each. Positive controls were exposed to 25 mg/m^3 crystalline silica (quartz dust), negative controls were exposed to clean air.

During exposure, the rats were individually restrained in Battelle tubes and each tube was then placed into one of the inhallation units for head/nose-only exposure to the test atmosphere. Each unit had a volume of approximately 50 l, with an exposure air flow of 51 l/min. Daily mean temperature of the test atmospheres was between 21.9°C and 25.5°C with standard deviations between 0.1°C to 1.2°C; daily mean relative humidity was between 29% and 51% with standard deviations of 1-2%. Rats were exposed for 6h/day for five consecutive days.

Statistics:

Body weight data were analysed by one-way analysis of co-variance (ANCOVA) using pre-exposure (day 0) weights as the covariate. Total cell counts, absolute differential cell counts and biochemical parameters in (bronchoalveolar lavage fluid) BALf, silicon content in the lungs and lymph nodes, and weights of these organs were analysed by one-way analysis of variance (ANOVA).

Results and discussion

Effect levels

Sex:

male

Dose descriptor:

other: NOAEL

Effect level:

1 mg/m³ air

Based on:

test mat.

Exp. duration:

5 d

Remarks on result:

other: No serious treatment-related changes were observed in animals of the low exposure group directly after exposure. The level of 1 mg/m^3 was therefore considered a NOAEL for this substance.

Mortality:

No treatment-related mortality was observed during the study period.

Clinical signs:

other: No treatment-related clinical signs were observed during the study period.

Body weight:

A slight, though statistically significant (1-2 g) body weight loss was observed in all groups exposed to pyrogenic silica the day after the last exposure. Due to the absence of a concentration-response relationship, this finding was not considered to be test compound-related.

Gross pathology:

There were no treatment-related gross lesions at necropsy.

Other findings:

Microscopic examination revealed substance-related changes in the lungs and tracheobronchial lymph nodes. Most histopathological changes were observed at 25 mg/m^3, and to a lesser degree at 5 mg/m^3, and none at 1 mg/m^3. Directly after the exposure period, the histopathological changes in the lungs that were observed consisted of increased intra-alveolar accumulation of macrophages and granulocytes and bronchial/bronchiolar hypertrophy. All of the noted changes were very slight to slight. No changes were observed in the tracheobronchial lymph nodes.

Any other information on results incl. tables

Of the three SAS substances which were tested (see the additional study records for this endpoint) pyrogenic silica produced the most pronounced changes in markers of lung inflammation but these were almost completely reversible within the three month recovery period. These results are similar to those of other studies that had 90-day exposure periods e.g. Reuzelet al. (1991). SAS induced changes were generally most apparent the day after the last exposure and disappeared relatively fast within three months post-exposure. In contrast, the quartz (i.e. the positive control) induced pulmonary changes were minimal at the end of the five day exposure period but progressed clearly thereafter with slight changes one month post-exposure and overt changes three months after the last exposure. Clearance of the pyrogenic silica from the lungs during the post-exposure period was rapid as amounts of silicon were mostly below the detection limit one month after exposure. In contrast, quartz dust was not cleared at all during the three month post-exposure period. It appeared that the vast majority of the pyrogenic silica was dissolved rapidly in the lung fluid and removed via the mucocilliary escalator within three months post-exposure.

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The study gave a NOAEL of 1 mg/m^3 for pyrogenic silica. No treatment-related deaths or clinical signs were observed during the study, therefore the substance is not classified as an acute inhaltion toxin according to EU CLP criteria.

Executive summary:

The acute inhalation toxicity of the test substance was determined in accordance with adapated OECD Guidelines for Testing of Chemicals (possibly 412 and 413 based on the method information provided). Male Wistar rats were exposed nose-only to concentrations of 1, 5 and 25 mg/m³ of pyrogenic silica 6 hours per day for five consecutive days. Positive controls were exposed to 25 mg/m³ of crystalline silica (quartz dust), negative controls were exposed to clean air. Animals were necropsied the day after the last exposure, or one or three months later. All exposures were tolerated without serious clinical effects, changes in body weight or food intake. Silicon was found in the lungs one day after exposure to 25 mg/m³ of pyrogenic silica but was cleared three months later. Some effects were seen in the lungs at the highest exposure concentration, however, these effects were transient and reversible during the three month recovery period. No adverse reactions were seen at the 1 mg/m³ exposure level, therefore 1 mg/m³ was assigned as the NOAEL for this substance. The substance is not classified as an acute inhaltion toxin according to EU CLP criteria. The structure of both pyrogenic silica (silicon dioxide) and silicic acid, aluminium, calcium, sodium salt are macromolecular skeletons of silicon and oxygen. In the silicic acid, aluminium, calcium, sodium salt the metal cations bind ionically to negatively charged oxygens in the structure. The inclusion of the metal cations to the structure of pyrogenic silica (silcon dioxide) would not change the toxicity of the substance, or the behaviour of the substance once inhaled.