Fumes, silica

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: oral

Remarks:

combined repeated dose and carcinogenicity

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: acceptable well documented study report which meets basic scientific principles read-across to synthetic amorphous silica

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

GLP compliance:

not specified

Species:

other: mice and rats

Strain:

other: B6C3F1 mice and Fisher rats

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Funabashifarm Animal Co. Ltd, Japan
- Age at study initiation: mice 4 weeks, rats 3 weeks
- Weight at study initiation: male-mice 21.0-27.3 g, female-mice 16.0-19.9 g; male-rats 117-150 g, female-rats 92.0- 126 g
- Fasting period before study:
- Housing: in wire-mesh cages, separated according to sex, 5 mice per cage, 2 rats per cage
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum): tap water ad lipidum
- Acclimation period: 1 week for mice; 2 weeks for rats


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23.1+-1
- Humidity (%): 50+-10
- Air changes (per hr): air-conditioned
- Photoperiod (hrs dark / hrs light): artifical fluorescent lighting daily for a continuous 14-hour period

Route of administration:

oral: feed

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:


DIET PREPARATION
- Rate of preparation of diet (frequency): prepared weekly
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:


VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle:
- Amount of vehicle (if gavage):
- Lot/batch no. (if required):
- Purity:

Duration of treatment / exposure:

93 weeks for mice and 103 weeks for rats

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
0, 1.25, 2.5, 5%
Basis:
nominal in diet

Remarks:

Doses / Concentrations:
0, 2500, 5000, 10000 mg/kg bw/day (for mice)
Basis:
nominal in diet

Remarks:

Doses / Concentrations:
0, 625, 1250, 2500 mg/kg bw/day (for rats)
Basis:
nominal in diet

No. of animals per sex per dose:

mice and rats were dined into dosage groups of 10 animals each

Control animals:

yes

Observations and examinations performed and frequency:

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


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

BODY WEIGHT: Yes
- Time schedule for examinations: with mice 0, 5, 15, 30, 50, 81 and 93 weeks after feeding; with rats 0, 5, 15, 30, 50, 81 and 103 weeks after feeding


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: Yes / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: 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 AND COMPOUND INTAKE (if drinking water study): Yes / No / No data
- Time schedule for examinations:


OPHTHALMOSCOPIC EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:


HAEMATOLOGY: Yes
- Time schedule for collection of blood: 6, 12 and 21 months for mice and 6, 12 and 24 months for rats
- Anaesthetic used for blood collection: Yes (identity) / No / No data
- Animals fasted: Yes / No / No data
- How many animals: 89/160 male mice and 105/158 female mice; 118/161 male rats and 123/161 female rats
- Parameters checked in table [No.?] were examined: erythrocytes (RBC), hemoglobin (Hb), leucocytes (WBC) and hematocrit (Ht)


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 6, 12 and 21 (mice) or 24 (rats) months
- Animals fasted: Yes / No / No data
- How many animals: 89/160 male mice and 105/158 female mice; 118/161 male rats and 123/161 female rats
- Parameters checked in table [No.?] were examined: aspartate transaminase (AST), alanine transaminase (ALT), serum inorganic phosphorus (IP), total protein (TP), albumin (ALB), lactic dehydrogenase (LDH), alkali phosphatase (ALP), total bilirubin (TB), total cholesterol (T-Cho), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglyceride (TG), blood urea nitrogen (BUN), uric acid (UA), creatine (Cre), and calcium (CA) on serum separated from the blood after clotting


URINALYSIS: No
- 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
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Statistics:

The mean and standard deviations of various measured parameters were calculated for each dose group. The significant difference between the control and the compound-treated groups was tested by Student's t-analysis variance test (P<0.05*; P<0.01**). The chi-square test of significance (P<0.05) by Mantel-Hanszel was employed to compare the survival date exclusive of sacrificed specimens. Prevalence rates were cited as percentages of tumor groups and non-tumor groups in cases of post-mortem examination. The significance of differences between the two means of prevalence was tested by Fisher's exact test for fourfold tables. The percentages of the frequencies of tumor in specific tissues were analysed by the Cochrane-Armitage test for linear trend in proportion with continuity correction.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

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:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY:
Most of the mice remained in good health, appeared to be active, and showed normal behavior throughout the treatment. No significant difference in survival rates for each group was observed.
In rats, no physical or behavioral signs of pharmacologic effects were observed during the treatment. In male rats over a perioid of 48 weeks, the mean survival rates in treated groups was greatest in the 5%, followed by the control and 1.25 or 2.5% dosage groups. However, the variations were not significant between the control and treated groups. While the female survival rates of 5%, 2.5%, and 1.25% groups were 0.875, 0.80, and 0.65 respectively, these were not statisticall and significantly different from the values observed in the control group.

BODY WEIGHT AND WEIGHT GAIN:
In mice, during the initial 61-week period, the control and treated groups grew at essentially the same rate. No significant variation in body weight were observed throughout this study between the control and treated groups of 1.25% and 2.5% dosages. However, at the end of the initial 10-week period, the 5% dosage group showed lower growth rate as compared to the control group. At 81 weeks, an increase in food consumption in the control groups was evident in the treated male groups of 2.5% and 5% dosages. Increased food consumption in the treated group of 5% dosage was accompanied by decreased body weight.
In rats, no consistent compound- or dose-related changes in growth rates were evident.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
In mice, the mean cumulative intake of SYLOID at the end of 93 weeks in the 1.25, 2.5 and 5% dietary levels was 38.45, 79.78 and 160.23 g/mouse in males, and 37.02, 72.46 and 157.59 g/mouse in females, respectively.
In rats, the mean cumulative intake of SYLOID at the end of 103 weeks for the 1.25, 2.5 and 5% dietary levels was 143.46, 179.55 and 581.18 g/rat in males, and 107.25, 205.02 and 435.33 g/rat in females, respectively.


FOOD EFFICIENCY

HAEMATOLOGY:
In mice, the mean HCT and MCV at 12 months in female mice showed a somewhat lower level in comparison with the normal group. However, there was no evidence of dose-related alteration of hematological profiles at the end of the 12- and 21-month treatments.
In rats, occasional erratic variations in hematologic profiles were observed in the treated groups: high WBC at 24 months in male groups of 1.25% dosage, and low RBC, HGB, and HCT at 24 months in the female 2.5% dosage group. The very high value for WBC in male rats of the 1.25% group looks as if it has one or two values, perhaps because of technical errors. However, no significance can be attached to the difference.

CLINICAL CHEMISTRY: In rats, no biologically meaningful changes in TA, ALB, AST, ALT, ALP, T-BL and LDH were observed, although transient differences reaching statistical significance were frequently present. No noteworthy changes related to compound ingestion were observed in any parameters of renal analyses, such as BUN, CRE and UA.

ORGAN WEIGHTS: No noted atrophy or hypertrophy of the organs in each group was sex- or dose-related.


GROSS PATHOLOGY


HISTOPATHOLOGY: NON-NEOPLASTIC:
In mice, non-neoplastic lesions were observed in the subcutis, lungs, kidneys, and liver in the treated groups. These were considered to be of no toxicological significance.

HISTOPATHOLOGY: NEOPLASTIC (if applicable):
In mice, tumours attributed to the treatment of Syloid were found in the hematopoietic organs, particularly malignant lymphoma/leuiemia, which occurred in 7/20 (35%) in the female groups of the 2.5% dosage groups (not scientifically significant). In the lungs, the frequency of adenoma/adenocarcinoma was 1/16 (6.25%) for the control, 2/17 (11.8%) for the 1.25%, 3/14 (21.4%) for the 2.5% and 3/16 (18.8%) for the 5% dosage groups of males. The incidence of the lung adenomas in females was greater than that of males. However, none of these findings were sex- or dose-related. In the liver, the correlation of hyperplasic nodules/hepato cellular carcinoma/hemangioma/fibrosarcoma in the treated groups, as compared with the control group, was relatively low.
In rats, the incidence of tumors was the greatest in the genital organs, next in the skin. The other organs showed relatively low incidence.
The occasional presence of some neoplasms did not reveal any consistent, dose-related trends in any group.


HISTORICAL CONTROL DATA (if applicable)

Dose descriptor:

NOAEL

Remarks:

the highest dose tested

Effect level:

10 000 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: for mice; Syloid

Dose descriptor:

NOAEL

Remarks:

the highest dose tested

Effect level:

2 500 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: for rats; Syloid

Critical effects observed:

not specified

Conclusions:

Proper dietary administration of micronized silica (Syloid 244) was proven to be generally safe with no long-term effects.

Executive summary:

Food grade micronized silica gel (SYLOID®) was given in a feed to B6C3F1 mice and Fisher rats at dose levels of 0, 1.25, 2.5, and 5% (≈ 0, 2,500, 5,000, 10,000 mg/kg/day for mice and 0, 625, 1,250, 2,500 mg/kg/day for rats) and) for 93 and 103 weeks, respectively (Takizawa et al. 1988). Measurements: physical examinations and observations, clinical chemistry, post-mortem examination. There were no biological or any other meaningful alterations in body weight, food consumption or physical features of the exposed animals. No significant dose-related effects were seen at any dose level upon clinical laboratory examinations. The pathological examinations revealed no gross or microscopic changes in the tissues examined. The occasional presence of some neoplasms did not reveal any consistent, dose-related trends in any group.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

2 500 mg/kg bw/day

Study duration:

chronic

Species:

rat

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

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

Qualifier:

according to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

GLP compliance:

not specified

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):

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

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

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.

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.

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

Critical effects observed:

not specified

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).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

15 mg/m³

Study duration:

subchronic

Species:

monkey