Fumes, silica

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

chronic toxicity: inhalation

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: read-across to synthetic amorphous silica

Data source

Reference

Reference Type:

other: proceedings

Title:

Chronic effects of inhaled amorphous silicas in animals.

Author:

Groth, D. H., Moorman, W. J., et al.

Year:

1981

Bibliographic source:

Proc. of Symposium on Health Effects of Synthetic Silica Particulates, Marbella, Spain. ASTM STP 732, Dunnom, D.D (Ed), American Society for Testing and Materials, 1981, pp. 118-143.

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Automatically generated during migration to IUCLID 6, no data available

IUPAC Name:

Automatically generated during migration to IUCLID 6, no data available

Details on test material:

- Name of test material (as cited in study report): silica gel, precipitated silica, fume silica
- Molecular formula (if other than submission substance):
- Molecular weight (if other than submission substance):
- Smiles notation (if other than submission substance):
- InChl (if other than submission substance):
- Structural formula attached as image file (if other than submission substance): see Fig.
- Substance type:
- Physical state:
- Analytical purity:
- Impurities (identity and concentrations):
- Composition of test material, percentage of components:
- Isomers composition:
- Purity test date:
- Lot/batch No.:
- Expiration date of the lot/batch:
- Radiochemical purity (if radiolabelling):
- Specific activity (if radiolabelling):
- Locations of the label (if radiolabelling):
- Expiration date of radiochemical substance (if radiolabelling):
- Stability under test conditions:
- Storage condition of test material:
- Other:

Test animals

Species:

other: rat, guinea pig and monkey

Strain:

other: Sprague-Dawley rats, Hartley guinea pigs, and Cynomolgus monkeys

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Laboratory Supply Company, Inc., Indianapolis, Ind. (rats), Sweetwater Farms, Hillsboro, Ohio (guine pigs), Primate Imports Corp., Long Island, N.Y. (monkeys)
- Age at study initiation: adult monkeys
- Weight at study initiation: 300-380 g (rats), 400-800 g (guinea pigs), 2300-5400 g (monkeys)
- Fasting period before study:
- Housing: all three species individually housed during the exposures, rats and guine pigs two to four animals per cage at all other times
- Diet (e.g. ad libitum): standard laboratory pellet diets (Rodent Laboratory Chow, Guinea Pig Chow, and Monkey Chow-Jumbo from Ralston Purina, St. Louis, Mo.); monkeys were given fresh fruit (oranges, bananas, or apples) twice a week
- Water (e.g. ad libitum): tap water ad libidum
- Acclimation period: rats and guinea pis were quarantined for two weeks, monkeys for one month


ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):

Administration / exposure

Route of administration:

inhalation: dust

Type of inhalation exposure:

whole body

Remarks on MMAD:

MMAD / GSD: Amount of particles <4.7 μm: 65% (pyrogenic silica), 62% (silica gel), 46% (precipitated silica)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: stainless steel inhalation chamber 60 in. long by 57 in. wide by 57 in. high (160ft3)
- Method of holding animals in test chamber: stainless and galvanized steel open wire-mesh cages were used as exposure cageing to provide adequate distribution of the dust aerosols within the exposure chambers
- Source and rate of air:
- Method of conditioning air:
- System of generating particulates/aerosols: Silica gel and precipitated silica dust aerosols were generated by Wright dust feed mechanisms, which were affixed to each exposure chamber. Fume silica was generated with a modified fluidized bed.
- Temperature, humidity, pressure in air chamber:
- Air flow rate: dynamic flow conditions with tangential airfeed manifolds maintained at 40 L/min with a pressure pf -0.254 cm H2O
- Air change rate:
- Method of particle size determination:
- Treatment of exhaust air:


TEST ATMOSPHERE
- Brief description of analytical method used:
- Samples taken from breathing zone: yes/no


VEHICLE (if applicable)
- Justification for use and choice of vehicle:
- Composition of vehicle:
- Type and concentration of dispersant aid (if powder):
- Concentration of test material in vehicle:
- Lot/batch no. of vehicle (if required):
- Purity of vehicle:

Duration of treatment / exposure:

up to 18 months

Frequency of treatment:

5.5-6 hours/day, 5 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
15 mg/m3
Basis:

No. of animals per sex per dose:

80 rats/dose, 20 guinea pigs/dose, 10 monkeys/dose

Control animals:

yes

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes / No / No data
- Time schedule:
- Cage side observations checked in table [No.?] were included.


DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:


BODY WEIGHT: Yes / No / No data
- Time schedule for examinations:


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data


WATER CONSUMPTION: Yes / No / No data
- Time schedule for examinations:


OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood:
- Anaesthetic used for blood collection: Yes (identity) / No / No data
- Animals fasted: Yes / No / No data
- How many animals:
- Parameters checked in table [No.?] were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
- Animals fasted: Yes / No / No data
- How many animals:
- Parameters checked in table [No.?] were examined.


URINALYSIS: Yes / No / No data
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.


NEUROBEHAVIOURAL EXAMINATION: No

OTHER: Pulmonary function in monkeys was tested prior the study.

Sacrifice and pathology:

Autopsies on rats were performed after 3, 6 and 12 months of exposure, and on guinea pigs and monkeys after 10 to 18 months of exposure.

Statistics:

Multivariate one-way analyses of covariance between the control and each exposed group were calculated. The dependent variables (pulmonary functions) were placed into two groups for this analysis. The ventilatory mechanisms group included resistance at low frequency (RLLF), compliance at low frequency (CLLF), forced expiratory flow at 25 percent vital capacity (FEF25), forced expiratory flow at 10 percent vital capacity (FEF10%), closing volume (CV), nitrogen washout (N2), and volume of isoflow (VISFL). The lung volume group included forced vital capacity (FVC), inspiratory capacity (IC), residual volume (RV), and total lung capacity (TLC). If the multivariate analysis indicated a significant difference, then each response variable was analyzed individually by adjusted univariate analysis.

Results and discussion

Results of examinations

Body weight and weight changes:

not examined

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:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Details on results:

CLINICAL SIGNS AND MORTALITY

BODY WEIGHT AND WEIGHT GAIN

HAEMATOLOGY
No statistically significant changes.

CLINICAL CHEMISTRY
No statistically significant changes in rats and guinea pigs. Alkaline phosphatase levels in fume silica monkeys were elevated compared to controls (however, elevation did not correlate with pathology and was probably not the result of exposure).

ORGAN WEIGHTS

GROSS PATHOLOGY

HISTOPATHOLOGY: NON-NEOPLASTIC
The most significant finding was the deposition of large quantities of amorphous silica in macrophages in the lungs and tracheal lymph nodes of exposed monkeys. Regardless of the type of amorphous silica to which they were exposed, the lungs of each monkey contained large numbers of macrophage and mononuclear cell aggregates. The size of cell aggregates varied from 40 to 600 μm in diameter and they were found in the walls of respiratory bronchioles, alveolar ducts, around venules and arterioles, and occasionally in alveolar walls distant from the aforementioned structures. More and larger aggregates appeared in the lungs exposed to precipitated silica, slightly fewer and smaller ones in the lungs exposed to fumed silica, and considerably fewer and smaller ones in the lungs exposed to silica gel. Relatively few or no macrophages containing particles of amorphous silica were found in the lungs and lymph nodes of the guinea pigs and rats. Fumed silica induced early nodular fibrosis in the lungs of the monkeys, 5– 50% of the aggregates contained collagen in varying amounts in six of the nine monkeys exposed to fumed silica. In three of the monkeys, little or no collagen was present in the aggregates.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)

HISTORICAL CONTROL DATA (if applicable)

OTHER FINDINGS
Lung-function studies indicated statistically significant differences in lung volume and ventilatory mechanics between the monkeys exposed to fumed silica and the control group. In addition, monkeys exposed to precipitated silica demonstrated significantly lower lung volumes compared with controls, while monkeys exposed to silica gel had significant changes in ventilatory performance and mechanical properties.

Effect levels

Dose descriptor:

LOAEL

Effect level:

15 mg/m³ air

Sex:

male

Basis for effect level:

other: rat, monkey; for respirable particles (<4.7 μm) about 6 to 9 mg/m³

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Executive summary:

In a chronic inhalation study of Groth et al. (1981), rats, guinea pigs, and monkeys were exposed by inhalation for up to 18 months to fume, gel and precipitated synthetic amorphous silica. The concentration used was 15 mg/m³and the exposure was performed 5.5 to 6 h/day, 5 days/week. Exposure with monkeys showed the most significant findings: deposition of amorphous silica in macrophages in the lungs and tracheal lymph nodes, induction of early nodular fibrosis in the lungs, and differences in lung volume and ventilatory mechanics measurements between exposed and controls. LOAEL for amorphous silica was 15 mg/m³(total dust).