Silicic acid, aluminum calcium sodium salt

Endpoint summary

Description of key information

A read-across was made from the registered substance to the results of testing on the similar substance silicic acid, aluminium, sodium salt. The test substance was found to be non-toxic to rats and mice via repeated oral, dietary exposure. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Study period:

21 May - 07 June 1979

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Screening study/limited examination: meets generally accepted scientific standards, sufficiently documented, database insufficient for complete assessment. No study guideline provided. 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.

Qualifier:

no guideline available

Principles of method if other than guideline:

Method: screening/range-finding for 90-d study: Reduced number of animals; no comprehensive examinations in haematology/clinical chemistry/urinalysis/limited histopathology (only high-dose and control group: 3 animals each).

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: no indivual data available / mean weights 179 - 184 g (male); 153 - 156 g (female)
- Fasting period before study: none
- Housing: 5/cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 17 d


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +-1 (Report 74 +-2 °F)
- Humidity (%): 50 +-5
- Air changes (per hr): 10 - 15x
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

oral: feed

Vehicle:

not specified

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): 1x/week
- Mixing appropriate amounts with (Type of food): NIH-07 Rat and Mouse Ration Mash

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

14 d

Frequency of treatment:

continuous

Remarks:

Doses / Concentrations:
0.625%
Basis:
nominal in diet

Remarks:

Doses / Concentrations:
1.25%
Basis:
nominal in diet

Remarks:

Doses / Concentrations:
2.5%
Basis:
nominal in diet

Remarks:

Doses / Concentrations:
5%
Basis:
nominal in diet

Remarks:

Doses / Concentrations:
10%
Basis:
nominal in diet

No. of animals per sex per dose:

5

Control animals:

yes, concurrent no treatment

Details on study design:

Post-exposure period: 1 d (day 15)

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily


BODY WEIGHT: Yes
- Time schedule for examinations: day 0, 7, and 14


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Mean weekly food consumption of each group is given after week 1 and 2 (Tab. 4)
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data


OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes, on 10% of the animals (6/60), 2 female and 1 male each from the control and the 10% group

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Male rats of the highest-dosed group showed a significantly lower bw gain (-39 %), which may be considered to be treatment-related.

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

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:

not specified

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

BODY WEIGHT AND WEIGHT GAIN:  
Male rats of the highest-dosed group showed a significantly lower body weight gain (-39%), which may be considered to be treatment-related.

Dose descriptor:

NOAEL

Remarks:

5% dietary level

Effect level:

ca. 4 750 mg/kg bw/day (nominal)

Sex:

male

Basis for effect level:

other: body weight

Dose descriptor:

NOAEL

Remarks:

10% dietary level

Effect level:

ca. 7 000 mg/kg bw/day (nominal)

Sex:

female

Basis for effect level:

other: overall effects

Critical effects observed:

not specified

Conclusions:

The NOAEL (5% dietary level) was 4750 mg/kg bw/day in male rats (based on body weight). Male rats in the highest-dosed group showed a significantly lower body weight gain (-39%), which may be considered to be treatment-related. The NOAEL (10% dietary level) was 7000 mg/kg bw/day in female rats (based on overall effects). No clinical signs or mortality was recorded. There were no effects reported during gross pathology or histopathological investigation.

Executive summary:

The repeated dose toxicity of the test substance was determined, with no test guideline provided. The method followed involved a screening/range-finding test for 90-day study. The method used a reduced number of animals; there were no comprehensive examinations in haematology/clinical chemistry/urinalysis/limited histopathology (only high-dose and control group: 3 animals each). The study investigated the toxicity of repeated oral exposure of the test substance to male and female rats. Animals were exposed to 0.625 -10% doses, as part of the diet, for 14 days. The NOAEL (5% dietary level) was 4750 mg/kg bw/day in male rats (based on body weight). Male rats in the highest-dosed group showed a significantly lower body weight gain (-39%), which may be considered to be treatment-related. The NOAEL (10% dietary level) was 7000 mg/kg bw/day in female rats (based on overall effects). No clinical signs or mortality was recorded. There were no effects reported during gross pathology or histopathological investigation. The test susbtance is not considered to be toxic to rats via repeated oral exposure. The structure of both silicic acid, aluminium, sodium salt and silicic acid, aluminium, calcium, sodium salt are macromolecular skeletons of silicon and oxygen with the metal cations binding ionically to negatively charged oxygens in the structure. In the silicic acid, aluminium, calcium, sodium salt the metal cations bind ionically to negatively charged oxygens in the structure. The inclusion of calcium salts to the structure of silicic acid, aluminium, sodium salt would not be expected to change the toxicity of the substance.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

4 750 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The results given for this endpoint cover studies on the repeated dose toxicity of the test substance to male and female rats and male and female mice. Both studies provide high NOAELS, in the case of rats the NOAEL in male rats was 4750 mg/kg bw/day based on body weight. At lower doses no adverse effects to body weight were observed. The results consistantly show high NOAELs and no effects observed during gross pathology or histopathology.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

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

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study follows acceptable test methods and sufficient information is available for interpretation. 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.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

No guideline was provided.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

6 week old male (n = 490) and female (n = 490) SPF-bred Wistar rats (Cpb: WU, Wistar random) were purchased from the TNO Central Institute for the Breeding of Laboratory Animals. They were housed singly in stainless-steel wire cages in Hazleton H 1000 inhalation chambers throughout the whole 13 week exposure period. The chambers were kept at 21-23°C, and 65-75% relative humidity, with an air-flow of approximately 40 m^3/hr. The rats were provided ad lib with unfluoridated tap-water and fed the Institute's stock diet for rats. During exposure the rats were deprived of food and water. After the exposure period those rats that were retained for the post-treatment periods were transferred from the inhalation chambers to an animal room and housed in wire-mesh, stainless-steel cages, five males and five females to a cage.

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

MMAD / GSD: Mean primary particle size: 18 nm

Details on inhalation exposure:

The very small primary particles (<6-about 45 nm, calculated as the arithmetic mean of transmission electron micrograph magnifications) form agglomerates and aggregates. Because of the weakness of the bonds and the electrostatic charge of the particles it was impossible to determine the aerodynamic agglomerate/aggregate size distribution in the test atmospheres. The range of the geometric agglomerate/aggregate size distribution was 1 to about 120 µm for the amorphous silicas with maxima at about 10 and 100 µm. Aerosols were generated using the Institute's dust generators, which were composed of a dust feed mechanism and an atomizer operated by compressed air. The concentrations of test material in the test atmospheres were determined by gravimetry. Samples of the test atmospheres were drawn through glass fibre filters (Sartorius SM 13430). The filters were weighed just before and after sampling.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The concentrations of test material in the test atmospheres were determined by gravimetry.

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

6 hours per day, 5 days per week

Remarks:

Doses / Concentrations:
30 mg/m^3
Basis:
nominal conc.

No. of animals per sex per dose:

70 males and 70 females

Control animals:

yes, concurrent no treatment

Details on study design:

There was one test group, one positive control group and one blank control group each containing 70 males and 70 females. The rats were exposed for 6 hr/day, 5 days/week for 13 weeks to 30 mg/m^3. After the exposure period and 13, 26, 39 and 52 weeks after exposure 20, 10, 10, 10 and 20 rats/sex/group, respectively, were killed.

Positive control:

70 males and 70 female rats were exposed to 60 mg/m^3 of quartz.

Observations and examinations performed and frequency:

Clinical observations were made daily. Body weights were recorded weekly during the exposure period and once every 4 weeks thereafter. Haematological and urinary parameters were determined in 10 rats/sex/ group at 13 week intervals. Haematological determinations include cell counts, haemoglobin content, packed cell volume, white-cell counts, differential white-cell counts, prothrombin time, thrombocytes, albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, urea, total protein, creatinine, total bilirubin, calcium, potassium, sodium, inorganic phosphate, cholesterol and glucose. Urinary parameters included appearance, volume, density and pH, analysis for protein, occult blood, glucose and ketones and microscopy of sediment.

Sacrifice and pathology:

From 50% of the rats killed at each stage the following tissues and organs were collected and preserved in 4% aqueous, neutral phosphate buffered formaldehyde solutions: lungs, mediastinal and hylus lymph nodes, trachea, larynx, adrenals, aorta, axillary lymph nodes, brain (brainstem, cerebrum and cerebellum), caecum, co-agulating glands, colon, duodenum, epididymides, eyes, heart, ileum, jejunum, kidneys, liver, mammary glands, mesenteric lymph nodes, nose (nasal cavity), oesophagus, ovaries, pancreas, parathyroids, parotid salivary glands, pharynx, pituitary, prostate, rectum, seminal vesicles, skeletal muscle (thigh), skin/subcutis (flank), spinal cord, spleen, sternum with bone marrow, stomach, sublingual salivary glands, testes, thymus (if identifiable), thyroid, urinary bladder and uterus. The lungs, adrenals, brain, heart, kidneys, liver, spleen, testes and thymus were weighed. The lungs were fixed by intratracheal inflation with the fixative under 10 cm water pressure. Tissues required for microscopic examination were embedded in Paraplast, sectioned at 5 µm and stained with haematoxylin and eosin. Histopathological examin- ation was carried out on all tissues and organs collected at the end of the exposure period, and on the respiratory tract and regional lymph nodes collected after 13, 26, 39 and 52 weeks of observation.

Other examinations:

The collagen and silicon content in the lungs and associated lymph node was also observed from the other 50% of rats killed at each stage.

Statistics:

Body weights were analysed by an analysis of co-variance (Cochran, 1957) followed by the Dunnett's multiple comparison test (Dunnett, 1955). Analysis of variance (Steel and Torrie, 1960) followed by the Dunnett's multiple comparison test were applied to the organ weights, and haematological and biochemical data. Incidences of histopathological changes were analysed by the Fisher exact probability test (Siegel 1956).

Clinical signs:

no effects observed

Description (incidence and severity):

No effects recorded.

Mortality:

no mortality observed

Description (incidence):

No effects recorded.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

At the end of the exposure period, body-weight gain was 5-10% lower in males exposed to the test substance.

Food consumption and compound intake (if feeding study):

not examined

Description (incidence and severity):

Rats did not have access to food during exposure.

Food efficiency:

not examined

Description (incidence and severity):

Rats did not have access to food during exposure.

Water consumption and compound intake (if drinking water study):

not examined

Description (incidence and severity):

Rats did not have access to water during exposure.

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

At the end of the exposure period lung weight had increase. The increases were statistically significant in comparison with the controls.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Most of the rats which were killed at the end of exposure had swollen and spotted lungs with a spongy consistency and/or irregular surface and enlarged lung-associated lymph nodes. These effects had dissapeared after 26 weeks post-exposure.

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Details on results:

The increase in lung weight decreased within 13 weeks post-exposure. Microscopic changes were mainly observed in the lungs. Changes in rats killed at the end of the exposure period comprised slight to severe accumulation of alveolar macrophages, intra-alveolar granular material, cellular debris and polymorphonuclear leucocytes in the alveolar spaces, and increased septal cellularity, seen as an increase in the number of type II pneumocytes and macrophages within the alveolar walls. In general, the most severe changes were found in rats exposed to Aerosil 200 and quartz (positive control), compared with the other amorphous silica substances tested (see the other study records for this endpoint).

Dose descriptor:

NOAEL

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Critical effects observed:

not specified

The test substance induced changes that were similar to those the two pyrogenic silicas tested in the same study (see the other study records for this endpoint), but they were mild and recovery was quick, even though the test material was only slowly cleared from the lungs and lung-associated lymph nodes.

Conclusions:

The test substance was found to induce changes in the lungs after the 13 week exposure period e.g. granulomatous lesions. Silicosis was observed only in the positive control group (exposed to quartz). The changes induced were mild and recovery was quick, even though the test material was only slowly cleared from the lungs and lung-associated lymph nodes.

Executive summary:

The chronic inhalation toxicity of the test substance was determined using male and female Wistar rats, which were exposed to concentrations of 30 mg/m³ of precipitated silica 6 hours per day, five days per week for 13 weeks. Positive controls were exposed to 60 mg/m³ of crystalline silica (quartz), negative controls were exposed to clean air. Clinical signs, body weight, haematology, biochemistry, urinalyses, organ weights, retention of test material in the lungs and regional lymph nodes, collagen content of the lungs, and gross and microscopic pathology were determined in order to disclose possible adverse effects and to study the reversibility, stability or progression of the effects. The test substance induced increases in lung weight, pulmonary lesions and granulomatous lesions. Silicosis was observed only in quartz-exposed animals. The changes induced by the test substance were mild and recovery was quick, even though the test material was only slowly cleared from the lungs and lung-associated lymph nodes. The results of this study revealed that only quartz induced progressive lesions in the lungs resembling silicotic nodules. The structure of both precipitated 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 precipitated silica (silcon dioxide) would not change the toxicity of the substance, or the behaviour of the substance once inhaled.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

subchronic

Species:

rat

Quality of whole database:

The test substance was found to induce changes in the lungs after the 13 week exposure period e.g. granulomatous lesions. Silicosis was observed only in the positive control group (exposed to quartz). Although the test substance was very quickly cleared from the lungs and regional lymph nodes, the changes in these organs were only partly reversed during the post-exposure period in rats exposed to 30 mg/m^3.

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

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

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study follows acceptable test methods and sufficient information is available for interpretation. 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.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

No guideline was provided.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

6 week old male (n = 490) and female (n = 490) SPF-bred Wistar rats (Cpb: WU, Wistar random) were purchased from the TNO Central Institute for the Breeding of Laboratory Animals. They were housed singly in stainless-steel wire cages in Hazleton H 1000 inhalation chambers throughout the whole 13 week exposure period. The chambers were kept at 21-23°C, and 65-75% relative humidity, with an air-flow of approximately 40 m^3/hr. The rats were provided ad lib with unfluoridated tap-water and fed the Institute's stock diet for rats. During exposure the rats were deprived of food and water. After the exposure period those rats that were retained for the post-treatment periods were transferred from the inhalation chambers to an animal room and housed in wire-mesh, stainless-steel cages, five males and five females to a cage.

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

MMAD / GSD: Mean primary particle size: 18 nm

Details on inhalation exposure:

The very small primary particles (<6-about 45 nm, calculated as the arithmetic mean of transmission electron micrograph magnifications) form agglomerates and aggregates. Because of the weakness of the bonds and the electrostatic charge of the particles it was impossible to determine the aerodynamic agglomerate/aggregate size distribution in the test atmospheres. The range of the geometric agglomerate/aggregate size distribution was 1 to about 120 µm for the amorphous silicas with maxima at about 10 and 100 µm. Aerosols were generated using the Institute's dust generators, which were composed of a dust feed mechanism and an atomizer operated by compressed air. The concentrations of test material in the test atmospheres were determined by gravimetry. Samples of the test atmospheres were drawn through glass fibre filters (Sartorius SM 13430). The filters were weighed just before and after sampling.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The concentrations of test material in the test atmospheres were determined by gravimetry.

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

6 hours per day, 5 days per week

Remarks:

Doses / Concentrations:
30 mg/m^3
Basis:
nominal conc.

No. of animals per sex per dose:

70 males and 70 females

Control animals:

yes, concurrent no treatment

Details on study design:

There was one test group, one positive control group and one blank control group each containing 70 males and 70 females. The rats were exposed for 6 hr/day, 5 days/week for 13 weeks to 30 mg/m^3. After the exposure period and 13, 26, 39 and 52 weeks after exposure 20, 10, 10, 10 and 20 rats/sex/group, respectively, were killed.

Positive control:

70 males and 70 female rats were exposed to 60 mg/m^3 of quartz.

Observations and examinations performed and frequency:

Clinical observations were made daily. Body weights were recorded weekly during the exposure period and once every 4 weeks thereafter. Haematological and urinary parameters were determined in 10 rats/sex/ group at 13 week intervals. Haematological determinations include cell counts, haemoglobin content, packed cell volume, white-cell counts, differential white-cell counts, prothrombin time, thrombocytes, albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, urea, total protein, creatinine, total bilirubin, calcium, potassium, sodium, inorganic phosphate, cholesterol and glucose. Urinary parameters included appearance, volume, density and pH, analysis for protein, occult blood, glucose and ketones and microscopy of sediment.

Sacrifice and pathology:

From 50% of the rats killed at each stage the following tissues and organs were collected and preserved in 4% aqueous, neutral phosphate buffered formaldehyde solutions: lungs, mediastinal and hylus lymph nodes, trachea, larynx, adrenals, aorta, axillary lymph nodes, brain (brainstem, cerebrum and cerebellum), caecum, co-agulating glands, colon, duodenum, epididymides, eyes, heart, ileum, jejunum, kidneys, liver, mammary glands, mesenteric lymph nodes, nose (nasal cavity), oesophagus, ovaries, pancreas, parathyroids, parotid salivary glands, pharynx, pituitary, prostate, rectum, seminal vesicles, skeletal muscle (thigh), skin/subcutis (flank), spinal cord, spleen, sternum with bone marrow, stomach, sublingual salivary glands, testes, thymus (if identifiable), thyroid, urinary bladder and uterus. The lungs, adrenals, brain, heart, kidneys, liver, spleen, testes and thymus were weighed. The lungs were fixed by intratracheal inflation with the fixative under 10 cm water pressure. Tissues required for microscopic examination were embedded in Paraplast, sectioned at 5 µm and stained with haematoxylin and eosin. Histopathological examin- ation was carried out on all tissues and organs collected at the end of the exposure period, and on the respiratory tract and regional lymph nodes collected after 13, 26, 39 and 52 weeks of observation.

Other examinations:

The collagen and silicon content in the lungs and associated lymph node was also observed from the other 50% of rats killed at each stage.

Statistics:

Body weights were analysed by an analysis of co-variance (Cochran, 1957) followed by the Dunnett's multiple comparison test (Dunnett, 1955). Analysis of variance (Steel and Torrie, 1960) followed by the Dunnett's multiple comparison test were applied to the organ weights, and haematological and biochemical data. Incidences of histopathological changes were analysed by the Fisher exact probability test (Siegel 1956).

Clinical signs:

no effects observed

Description (incidence and severity):

No effects recorded.

Mortality:

no mortality observed

Description (incidence):

No effects recorded.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

At the end of the exposure period, body-weight gain was 5-10% lower in males exposed to the test substance.

Food consumption and compound intake (if feeding study):

not examined

Description (incidence and severity):

Rats did not have access to food during exposure.

Food efficiency:

not examined

Description (incidence and severity):

Rats did not have access to food during exposure.

Water consumption and compound intake (if drinking water study):

not examined

Description (incidence and severity):

Rats did not have access to water during exposure.

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

At the end of the exposure period lung weight had increase. The increases were statistically significant in comparison with the controls.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Most of the rats which were killed at the end of exposure had swollen and spotted lungs with a spongy consistency and/or irregular surface and enlarged lung-associated lymph nodes. These effects had dissapeared after 26 weeks post-exposure.

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Details on results:

The increase in lung weight decreased within 13 weeks post-exposure. Microscopic changes were mainly observed in the lungs. Changes in rats killed at the end of the exposure period comprised slight to severe accumulation of alveolar macrophages, intra-alveolar granular material, cellular debris and polymorphonuclear leucocytes in the alveolar spaces, and increased septal cellularity, seen as an increase in the number of type II pneumocytes and macrophages within the alveolar walls. In general, the most severe changes were found in rats exposed to Aerosil 200 and quartz (positive control), compared with the other amorphous silica substances tested (see the other study records for this endpoint).

Dose descriptor:

NOAEL

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Critical effects observed:

not specified

The test substance induced changes that were similar to those the two pyrogenic silicas tested in the same study (see the other study records for this endpoint), but they were mild and recovery was quick, even though the test material was only slowly cleared from the lungs and lung-associated lymph nodes.

Conclusions:

The test substance was found to induce changes in the lungs after the 13 week exposure period e.g. granulomatous lesions. Silicosis was observed only in the positive control group (exposed to quartz). The changes induced were mild and recovery was quick, even though the test material was only slowly cleared from the lungs and lung-associated lymph nodes.

Executive summary:

The chronic inhalation toxicity of the test substance was determined using male and female Wistar rats, which were exposed to concentrations of 30 mg/m³ of precipitated silica 6 hours per day, five days per week for 13 weeks. Positive controls were exposed to 60 mg/m³ of crystalline silica (quartz), negative controls were exposed to clean air. Clinical signs, body weight, haematology, biochemistry, urinalyses, organ weights, retention of test material in the lungs and regional lymph nodes, collagen content of the lungs, and gross and microscopic pathology were determined in order to disclose possible adverse effects and to study the reversibility, stability or progression of the effects. The test substance induced increases in lung weight, pulmonary lesions and granulomatous lesions. Silicosis was observed only in quartz-exposed animals. The changes induced by the test substance were mild and recovery was quick, even though the test material was only slowly cleared from the lungs and lung-associated lymph nodes. The results of this study revealed that only quartz induced progressive lesions in the lungs resembling silicotic nodules. The structure of both precipitated 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 precipitated silica (silcon dioxide) would not change the toxicity of the substance, or the behaviour of the substance once inhaled.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

subchronic

Species:

rat

Quality of whole database:

The test substance was found to induce changes in the lungs after the 13 week exposure period e.g. granulomatous lesions. Silicosis was observed only in the positive control group (exposed to quartz). Although the test substance was very quickly cleared from the lungs and regional lymph nodes, the changes in these organs were only partly reversed during the post-exposure period in rats exposed to 30 mg/m^3.

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: dermal

Data waiving:

exposure considerations

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

Dermal exposure is not considered to be a key exposure pathway during production and use of the substance. A repeated dose inhalation report is provided as it is considered more likely that inhalation exposure of the substance will occur. This is in accordance with REACH Annex VIII, Column 2.

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: dermal

Data waiving:

exposure considerations

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

Dermal exposure is not considered to be a key exposure pathway during production and use of the substance. A repeated dose inhalation report is provided as it is considered more likely that inhalation exposure of the substance will occur. This is in accordance with REACH Annex VIII, Column 2.

Additional information

The results given for this endpoint cover studies on the repeated dose toxicity of the test substance to male and female rats and male and female mice. Both studies provide high NOAELS, in the case of rats the NOAEL in male rats was 4750 mg/kg bw/day based on body weight. At lower doses no adverse effects to body weight were observed. The results consistantly show high NOAELs and no effects observed during gross pathology or histopathology. The results from the repeated dose oral testing on the substance silicic acid, aluminium, sodium salt, which is similar to the registered substance are outlined below:

NOAEL (5% dietary level) for male rats, based on body weight = 4750 mg/kg bw/day

NOAEL (10% dietary level) for female rats, based on overall effects = 7000 mg/kg bw/day

NOAEL (5% dietary level) for male mice, based on overall effects and food consumption = 15000 mg/kg bw/day

NOAEL (5% dietary level) for female mice, based on overall effects and food consumption = 25000 mg/kg bw/day.

The structure of both silicic acid, aluminium, sodium salt and silicic acid, aluminium, calcium, sodium salt are macromolecular skeletons of silicon and oxygen with the metal cations binding ionically to negatively charged oxygens in the structure. In the silicic acid, aluminium, calcium, sodium salt the metal cations bind ionically to negatively charged oxygens in the structure. The inclusion of calcium salts to the structure of silicic acid, aluminium, sodium salt would not be expected to change the toxicity of the substance. Therefore read-across between the two substances is considered justified. The registered substance is not considered to be toxic to mice or rats via repeated oral exposure.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
This study was conducted according to standard methods.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
The study was conducted according to accepted methodology and included in a peer reviewed academic journal.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
The study was conducted according to accepted methodology and included in a peer reviewed academic journal.

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: lung

Justification for classification or non-classification

The NOAELs found in the study on mice and rats were high and no significant clinical signs were recorded. In addition, no mortality was recorded and no effects were seen during gross pathology.