Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2nd July 2009 to 27th November 2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP Compliant

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009
Report date:
2009

Materials and methods

Objective of study:
other: biopersistence
Test guideline
Qualifier:
according to guideline
Guideline:
other: ECB/TM/27 (rev 7)
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Reference substance name:
potassium alumino silicate fibres
IUPAC Name:
potassium alumino silicate fibres
Constituent 2
Reference substance name:
Potassium aluminium silicate amorphous glass fibres
EC Number:
931-219-8
Molecular formula:
SinO(3n-1)2(n-1) polymeric anions ionically bonded to Al3+ and K2+ cations
IUPAC Name:
Potassium aluminium silicate amorphous glass fibres
Test material form:
solid: fibres
Details on test material:
- Name of test material (as cited in study report): SW1400-EU
- Substance type: fibrous wool
- Physical state: solid
- Analytical purity:>99%
- Stability under test conditions: infinite
- Storage condition of test material: dry sealed container
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany, strain Crl:(WI)BR
- Age at study initiation: approximately 9 weeks
- Weight at study initiation: 194-235g
- Housing: Makrolon cages type III, two rats per cage
- Diet (e.g. ad libitum): commercial chow in pellet form, R/M-H "V 1534", ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 40 - 70
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12hour cycle

IN-LIFE DATES: From: 20-07-2009 to 30-10-2009

Administration / exposure

Route of administration:
intratracheal
Vehicle:
physiological saline
Details on exposure:
VEHICLE
- Choice of vehicle: Saline
- Dose in vehicle: 0.5mg per instillation
- Amount of vehicle : 0.3ml

HOMOGENEITY AND STABILITY OF TEST MATERIAL: suspension of test fibres was prepared fresh each day immediately before the start of the instillation, ultrasonic treatment was used to ensure homogeneity. In the week before starting the treatment of rats, the fibre suspension (identical preparation as for intratracheal instillation) was checked for agglomerates. The tip of the cannula (same as for intratracheal instillation) was observed under a binocular microscope to check if there were accumulations of fibres at the tip. In the sample of the test item no agglomerates were detected by this method.
Duration and frequency of treatment / exposure:
4 doses of 0.5mg/rat at daily intervals by intratracheal instillation
Doses / concentrations
Remarks:
Doses / Concentrations:
4 doses of 0.5mg/rat at daily intervals by intratracheal instillation
Total Dose per Rat 3.5 x 10^7 WHO fibres and 5.4 x 10^6 fibres longer than 20µm
No. of animals per sex per dose / concentration:
35 female
Control animals:
yes, concurrent vehicle
Positive control reference chemical:
not required under EU protocol
Details on study design:
- Dose selection rationale: as required by EU and German protocols
The animals were allocated to two groups on a body weight basis. The animals were weighed, randomized and grouped by the PROVANTIS system (see 5.6). This process ensured that the body weights of all animals were within + 20 % of the group mean and that there was no significant difference between mean body weights of the treatment and the control group at that time
Sacrifice dates 2 days, 14 days, 1 month, 3 months and 6 months
Details on dosing and sampling:
see table 3
Statistics:
The individual toxicological data (body weights, lung weights) of the treatment group were compared to the control group by using Anova and Student’s t-Test with significance levels of 5% and 1%.
The analysis of the data was done with SAS software package (version SAS Institute, Cery, NC USA, Release 9.1 on a Windows XP Server).

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on excretion:
Clearance half-time for fibres more than 20µm long was 38 days

Any other information on results incl. tables

Table7  Analysis of fibres in the lung ash of rats treated with SW1400-EU

               (Means and standard deviations (S.D.) per sacrifice date)

 

Sacrifice date

 

No.

of

rats

 

No. of fibres counted [1/lung]

 

Calculated mass of fibres [µg/lung]

 

Total fibre length [m/lung]

 

No. of particles counted [1/lung]

 

Number of particles [106/lung]

 

Mean

 

S.D.

 

Mean

 

S.D.

 

Mean

 

S.D.

 

Mean

 

S.D.

 

Mean

 

S.D.

2 Days

5

407

5.9

1457

204

893

107

101

2.5

35.9

8.0

14 Days

5

405

3.4

1038

203

678

105

101

1.3

25.3

4.8

1 Month

5

408

6.4

1068

140

626

72

101

1.7

22.4

5.6

3 Months

5

406

3.7

590

177

223

62

101

0.7

6.2

1.5

 

 

 

Sacrifice date

 

No.

of

rats

 

All fibres [106/lung]

 

WHO Fibres

[106/lung]

 

Fibres (L<5µm)

[106/lung]

 

Fibres (5<L<20µm)

[106/lung]

 

Fibres (L>20µm)

[106/lung]

 

Mean

 

S.D.

 

Mean

 

S.D.

 

Mean

 

S.D.

 

Mean

 

S.D.

 

Mean

 

S.D.

2 Days

5

87.8

12.0

52.0

6.6

35.8

6.6

41.4

5.9

10.574

0.752

14 Days

5

69.6

11.0

40.7

6.5

28.9

5.0

32.5

5.1

8.136

1.588

1 Month

5

69.9

8.7

40.6

3.8

29.2

5.8

34.4

3.4

6.213

0.824

3 Months

5

22.6

5.7

15.7

3.7

6.9

2.4

13.5

2.9

2.119

0.759

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: fibre shows low biopersistence characteristics
Clearance of long fibres exonerates from treatment as a carcinogen in Europe.