Potassium aluminium silicate amorphous glass fibres

Basic toxicokinetics

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

Test material information

Constituent 1

Reference substance name:

potassium alumino silicate fibres

IUPAC Name:

potassium alumino silicate fibres

Constituent 2

Reference substance name:

silicon(4+) dialuminium(3+) dipotassium hexaoxidandiide

EC Number:

931-219-8

Molecular formula:

SinO(3n-1)2(n-1) polymeric anions ionically bonded to Al3+ and K2+ cations

IUPAC Name:

silicon(4+) dialuminium(3+) dipotassium hexaoxidandiide

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 [10^6/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 [10^6/lung]		WHO Fibres [10^6/lung]		Fibres (L<5µm) [10^6/lung]		Fibres (5<L<20µm) [10^6/lung]		Fibres (L>20µm) [10^6/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.