Registration Dossier

Diss Factsheets

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Not stated
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
Justification for read-across is warranted given the similarities in toxicity profile and physico-chemical properties for silicon dioxide and magnesium silicate.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1987
Report date:
1987

Materials and methods

Objective of study:
other: deposition and clearance
Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
other: OECD 413
Deviations:
yes
Remarks:
Special modifications as compared with standard study:  Focus upon lung, respiratory  tract, and regional lymph nodes. Post-exposure recovery period up to one year.
Principles of method if other than guideline:
Measurements of Si in lung and lymph nodes within repeated-dose toxicity study: Analytical method for silica determination (Report, part 1, p. 25):
Lung and lymph node tissue were ashed according to the temperature program up to 650 °C in a platinum crucible. Following this, the ash was dissolved in 10 % hydrogen fluoride for 30 min. at 50 °C, and a saturated boric acid solution (silicon standard solution, 1 mg/ml) was added. The Si content of the solution was determined using a Varian ASS flame atomic absorption spectrometer.
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Silicon dioxide
EC Number:
231-545-4
EC Name:
Silicon dioxide
Cas Number:
7631-86-9
Molecular formula:
O2Si
IUPAC Name:
dioxosilane
Details on test material:
- Test material: SIPERNAT 22S
CAS-Name: Silica, precipitated, crystalline-free;
CAS-No.: 112926-00-8

Surface area (Ströhlein): 160 - 195 m2/g
Primary particle size: see Test Condition
- Substance type: inorganic
- Physical state: solid
- Surface area (BET): 192 m2/g (Report p. 64 Specification Certificate)
- Analytical purity: >98 % (SiO2)
- Impurities: 0.8 % Na2O, 0.2 Al2O3
- Particle size: The range of the geometric agglomerate/aggregate size distribution was 1  to about 120 µm for the amorphous silicas 
with a maxima at approx. 10 µm and 100 µm (Report 1987, p. 13)    
- Stability under test conditions: stable
- Storage condition of test material: room temperature
Specific details on test material used for the study:
- Test material: SIPERNAT 22S
CAS-Name: Silica, precipitated, crystalline-free;
CAS-No.: 112926-00-8

Surface area (Ströhlein): 160 - 195 m2/g
Primary particle size: see Test Condition
- Substance type: inorganic
- Physical state: solid
- Surface area (BET): 192 m2/g (Report p. 64 Specification Certificate)
- Analytical purity: >98 % (SiO2)
- Impurities: 0.8 % Na2O, 0.2 Al2O3
- Particle size: The range of the geometric agglomerate/aggregate size distribution was 1  to about 120 µm for the amorphous silicas 
with a maxima at approx. 10 µm and 100 µm (Report 1987, p. 13)    
- Stability under test conditions: stable
- Storage condition of test material: room temperature
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Central Institute for Breeding of Laboratory Animals TNO, Zeist/NL
- Age at study initiation: 4 weeks
- Weight at study initiation: 50 - 70 g
- Fasting period before study: no
- Housing: single during exposure
- Diet: no access during exposure
- Water: no access during exposure
- Acclimation period: 10 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +-2
- Humidity (%): 50 - 70
- Air changes (per hr): 12x/h
- Photoperiod (hrs dark / hrs light): no data

Administration / exposure

Route of administration:
inhalation
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: stainless steel exposure chamber, multitiered (manufactered by Hazelton)
- Exposure chamber volume: 2.3 m3
- Method of holding animals in test chamber: single
- Exposure type: whole body
- Source and rate of air: Aerosol entrance at top of the chamber
- Method of conditioning air: no data
- System of generating particulates/aerosols: Institute´s dust generator with compressed air operating atomizer
- Temperature, humidity, pressure in air chamber: av. 21 - 23 °C, minimum 19.1, max. 25.4 °C /
65 - 75 % rel. humidity, during extreme weather occasionally up to 95.5 % or down to 48 %.
- Air flow rate: approx. 40 m3/h
- Air change rate: 40 / 2.3 = ~17/h
- Method of particle size determination: due to electrostatic charge of the particles not measured:
technical failure of the 10-stage Mercer cascade impactor and the QCM cascade (Report p. 16)
- Treatment of exhaust air: filtered before release


TEST ATMOSPHERE
- Brief description of analytical method used: gravimetrically - Air samples are drawn through glass fiber filters (Sartorius)
and weighed (3 - 4 time per day)
- Samples taken from breathing zone: no data
Duration and frequency of treatment / exposure:
90 day(s)
Doses / concentrations
Remarks:
Doses / Concentrations:
35 mg/m3 (mean analytical values)
No. of animals per sex per dose / concentration:
10 each after exposure (13 weeks) and recovery period (1, 13, 29, 39, and 52 wks):
i.e. 50 m / 50 f animals per group were kept for a recovery period of at most 52 wks 
Control animals:
yes, concurrent no treatment
Positive control reference chemical:
no, but comparative study also including quartz
Details on study design:
- Dose selection rationale: see 7.5.3
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion) of SiO2
- Tissues and body fluids sampled: lung and mediastinal lymph nodes
- Time and frequency of sampling: 1, 13, 29, 39, and 52 weeks post exposure, 10 animals each


Statistics:
The statistical assessment of the findings for the different parameters considered was based on analysis of variance (ANOVA) and Dunnett´s test

Results and discussion

Preliminary studies:
No data

Toxicokinetic / pharmacokinetic studies

Details on absorption:
See overall remarks
Details on distribution in tissues:
See overall remarks
Details on excretion:
See overall remarks
Toxicokinetic parametersopen allclose all
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: ca. 7 wks (males) (from lung)
Test no.:
#2
Toxicokinetic parameters:
half-life 2nd: <7 wks (females) (from lung)

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

Absolute silicon content in lung and mediastinal lymph nodes 1, 13, 29, 39, and 52 weeks post exposure

[Sipernat 22S, 35 mg/m3 (mean analytical value), 13 weeks] [Report, Tab. 59 + 61]

Lung [mg]

Lymph nodes [mg]

Male #1

Female #2

Male

Female

Sipernat 22S

Day 98

0.510 ±0.024 +) (n=10)++)

0.347 ±0.017 (n=10)

0.037 ±0.007 (n=3)

0.034 ±0.002 (n=5)

Day 188

0.127 ±0.011  (n=10)

0.114 ±0.006 (n=7)

0.030 ±0.000 (n=2)

0.050 ±0.004 (n=4)

Day 297

0.049 ±0.004   (n=10)

0.083 (n=1)

0.027 ±0.003 (n=4)

0.030 (n=1)

Day 370

No Si detected

No Si detected

0.030 ±0.000 (n=2)

No Si detected

Day 462

No Si detected

No Si detected

0.030 (n=1)

No Si detected

C ontrol [untreated]

Day 188

0.032 (n=1)

No Si detected

0.030 (n=1)

No Si detected

+) ±SEM (Standard Error of the Mean)

++) n represents the number of animals with Si found,

the total number of animals measured was always 10 per group.


Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results