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REACH

Potassium aluminium silicate amorphous glass fibres

EC number: 931-219-8 | CAS number: -

Life Cycle description
Uses advised against

Toxicological information

Endpoint summary

Administrative data

Description of key information

Most repeated dose studies carried out on other fibres have used inhalation, this is the most relevant route of exposure due to the fibrous nature of the material, read across to the 90 day sub-chronic AES study using Nota Q low- biopersistance testing to show analgous nature of the substances indicates no adverse effects.  further details on read-across justification can be found in section 7.5.2 repeated dose toxicity: inhalation 90 day sub-chronic overall remarks and attachments
A reproductive toxicity screening study (OECD 421) was carried out using this material administered orally, no toxic effects were seen.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral, other

Remarks:

reproduction\developmental screening

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Fully GLP compliant and audited

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

other: OECD 421

Deviations:

GLP compliance:

yes (incl. QA statement)

Limit test:

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Margate, UK
- Age at study initiation: 10 to 12 weeks old
- Weight at study initiation: Males: 271.2 - 310.4g; Females: 172.1 - 201.7g;
- Fasting period before study: N/A
- Housing: Cages conforming to 'Code of practice for the housing and care of animals used in scientific procedures' (Home Office, London, 1989)
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 40 - 70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 26th January 2010 To: 6th April 2010

Route of administration:

oral: gavage

Vehicle:

other: MC (Methyl cellulose)

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: daily

VEHICLE
- Justification for use and choice of vehicle (if other than water): to ensure homogenous suspension of the substance for dosing as it is insoluble in water
- Amount of vehicle (if gavage): 10ml/kg

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Verification of composition at start and end of sampling carried out by XRF analysis, concentrations verified by gravimetric analysis of start and end samples.

Duration of treatment / exposure:

40 days to 55 days

Frequency of treatment:

daily dosing

Remarks:

Doses / Concentrations:
250mg/kg/day
Basis:
other: nominal conc.

Remarks:

Doses / Concentrations:
25mg/kg/day
Basis:
other: nominal conc.

No. of animals per sex per dose:

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The dose level for the test article was chosen after consultation with the Sponsor and based on the results of previous gavage studies on similar test articles and the physical properties of the test articles. Due to the potential risk of physical interference with gut motility, a high dose of between 50 and 100 mg/rat/day (250 mg/kg/day) was considered to be the limiting dose for this study.
A second dose of 25 mg/kg/day was adminstered to a second group of rats

Positive control:

None used

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily start and end (nominal) of the working day In addition, the animals were observed immediately on return to the home cage after dosing and at 0.5, 1, 2 and 4 hours post dose for signs of reaction to treatment for the first two weeks of dosing. As no signs were observed the animals were observed immediately on return to the home cage after dosing and at 0.5 and 1 hour post dose only from the start of the pairing period until the end of dosing.
- Cage side observations checked; ill health or overt toxicity. Any abnormalities of appearance or behaviour or other signs of reaction to treatment or ill health were recorded

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly, at time of body weight examination Clinical signs for females during the gestation and lactation periods, were recorded more frequently that weekly due to days of body weight recording.

BODY WEIGHT: Yes
- Time schedule for examinations:
MALES : Day -7 (randomisation body weight check)
Weekly
Day of (prior to) necropsy
FEMALES: Day -7 (randomisation body weight check)
Weekly prior to pairing and until confirmation of mating
Days 0, 7, 14 and 20 of gestation
Days 1 and 4 post partum

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
The food consumed by each cage of animals was determined weekly during the pre pairing periods.
Individual food intake of mated females was recorded on Days 0 to 6, 7 to 13 and 14 to 19 of gestation, and on Days 1 to 3 of lactation.

Sacrifice and pathology:

SACRIFICE
- Male animals: All surviving animals after assessment of females and offspring
- Maternal animals: All surviving animals 5 days post-partum

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations, including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues listed below were prepared for microscopic examination and weighed, respectively.
ovaries (with oviducts) testes
uterus epididymides
cervix seminal vesicles
vagina prostate
pituitary coagulating gland
gross lesions animal identification

Statistics:

Stastistical analysis used SAS

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

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
There was one death during the study; the cause of demise was a gavage injury, and not related to Superwool 1400 administration.
There were no clinical observations recorded that were considered to be related to administration with Superwool 1400.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
There was no adverse effect of treatment on mean body weight or body weight gain in males or females. In males and females, there was no effect of treatment on mean food intake.

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
the majority of females mated within one oestrous cycle.
There was no effect of treatment on fertility or fecundity indices

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
Qualitative testis staging did not indicate any abnormalities in the integrity of the various cell types present within the different stages of the spermatogenic cycle.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
There was no effect of treatment on mating, the majority of females mated within one oestrous cycle.
There was no effect of treatment on fertility or fecundity indices.

ORGAN WEIGHTS (PARENTAL ANIMALS)
There was no adverse effect of treatment on adult male or female organ weights.

GROSS PATHOLOGY (PARENTAL ANIMALS)
there was no effect of treatment on adult male or females

HISTOPATHOLOGY (PARENTAL ANIMALS)
Macroscopic findings
Most tissues were macroscopically unremarkable and the findings seen were generally consistent with the usual pattern of findings in rats of this strain and age. There were no macroscopic findings suggestive of effects of the test articles.
Microscopic findings
Microscopic findings were generally infrequent, of a minor nature and consistent with the usual pattern of findings in rats of this strain and age. There were no microscopic findings in treated animals due to effects of the test articles.

Dose descriptor:

NOAEL

Effect level:

> 250 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects

Critical effects observed:

not specified

Conclusions:

Administration of Superwool 1400 by oral gavage to male rats for at least 55 days and to female rats for at least 41 days at 250 mg/kg/day elicited no signs of adverse toxicity.
The no observed adverse effect level (NOAEL) for reproductive and developmental toxicity was considered to be at least 250 mg/kg/day for Superwool 1400

Executive summary:

The objective of the study was to provide a preliminary evaluation of the effects of the test article, Superwool 1400, on the reproductive/developmental toxicity in the rat.

Groups of 10 male and 10 female rats were given 25 or 250 mg/kg/day of Superwool 1400 orally, by gavage, for two weeks prior to pairing, during the pairing period and until Day 4 post-partum for the females and until the day before necropsy in Week 8 for the males. A similar group of 10 males and 10 females were given 1% (w/v) methylcellulose over the same period to act as controls.

There was one death during the study; the cause of demise was a gavage injury, and not related to Superwool 1400 administration.

There were no clinical observations recorded that were considered to be related to administration with Superwool 1400.

Mean body weight gains and food intake were unaffected by administration with Superwool 1400.

Mating data were unaffected by Superwool 1400 administration and there was no effect on mean uterine/implantation data or mean litter data.

Mean organ weights were unaffected by Superwool 1400 administration. At necropsy, macroscopic findings were unremarkable.

There were no microscopic findings or findings in the testis, suggestive of effects due to Superwool 1400 administration.

In conclusion, administration of Superwool 1400 by oral gavage to male rats for at least 54 days and to female rats for at least 41 days at 25 or 250 mg/kg/day elicited no signs of adverse toxicity.

The no-observed-adverse-effect-level (NOAEL) for repeated oral toxicity was considered to be at least 250 mg/kg/day.

Endpoint conclusion

Endpoint conclusion:: no adverse effect observed
Dose descriptor:: NOAEL
: 250 mg/kg bw/day
Study duration:: subacute
Species:: rat

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

reliablilty score of 2 given as this grade 1 study is used for read across purposes. In summary the results from existing 90 day and 2 year inhalation studies for Alkaline Earth Silicate fibres linked to the short term bio-persistence study with the Potassium Alumino Silicate fibres provide reliable evidence as to the lack of toxic potential for Potassium Alumino Silicate fibres. This is supported by the lack of effect on the lungs of the rats used in the biopersistence studies. With this background we do not believe that further animal testing can be justified.

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
bio-durability and physio-chemical properties are very similar for these substances, the fibres both exhibit low biopersistence considered a key component in assessing potential long term toxicity of fibres via inhalation

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
no further information

3. ANALOGUE APPROACH JUSTIFICATION
both fibres pass the IT exoneration testing for low-biopersistence under Note Q

4. DATA MATRIX

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

other: ECB/TM/16/97

Deviations:

yes

Remarks:

only highest dose used, more endpoints were studied and animals were followed up for a longer period

Principles of method if other than guideline:

only highest dose used, more endpoints were studied and animals were followed up for a longer period (12 months rather than 90 days)

GLP compliance:

yes (incl. QA statement)

Limit test:

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland
- Age at study initiation: 9-10weeks
- Weight at study initiation: 110-120g
- Housing: 2 rats per polycarbonate cage
- Diet (e.g. ad libitum): Commerce chow Atromin N 1324 special prepared ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: Two weeks before tube training

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/-2
- Humidity (%): 55 +/- 15
- Air changes (per hr): Not recorded; varied with temperature and humidity controls
- Photoperiod (hrs dark / hrs light): 12h light dark cycle

IN-LIFE DATES: August 15th 1997 (initiation) exposure completed December 14th 1997

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Vehicle:

other: unchanged (no vehicle)

Remarks on MMAD:

MMAD / GSD: Fibre size not calculated as MMAD.
for Fibre A size distribution of aerosol 50% fibres were less than 10.4 microns long, 50% less than 1.25 micron diameter 50% had aerodynamic diameter of less than 4.0 microns.
for Fibre B size distribution of aerosol 50% fibres were less than 11.6 microns long, 50% less than 1.22 micron diameter 50% had aerodynamic diameter of less than 4.0 microns.
For fibre D size distribtion of aerosol 50% fibres were less than 11.0 microns long, 50% less than 1.35 micron diameter 50% had aerodynamic diameter of less than 4.3 microns.

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: flow past system as described in Bernstein DM, Thevenaz P, Fleissner H, Anderson R,Hesterberg TW, Mast R 1995 Evaluation of the oncogenic potential of man-made vitreous fibers: the inhalation model Ann Occup Hyg 1995; 39(5):661-72 except that the aerosol was generated using a pneumatic disperser, static on the aerosol was neutralised using a Nickel 63 radiation source
- Method of holding animals in test chamber: Battelle Tubes
- Air flow rate: 1 litre/min
- Method of particle size determination: samples of the aerosol were collected on membrane filters , these were weighed for gravimetric analysis and fibres counted by SEM, except for Amosite positive control TEM was used.
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples of the aerosol were collected on membrane filters, these were weighed for gravimetric analysis and fibres counted by SEM, except for Amosite positive control where TEM was used.
Fibre A - 644 ± 176 WHO fibres/ml
152 ± 48 fibres longer than 20µm /ml
Mass concentration 71 ± 17.6 mg/m3

Fibre B - 539 ± 159 WHO Fibres/ml
152 ± 40 fibres longer than 20µm /ml
Mass concentration 49.8 ± 8.4 mg/m3

Fibre D - 515 ± 139 WHO Fibres/ml
137 ± 30 fibres longer than 20µm /ml
Mass concentration 58.6 ± 10.4 mg/m3

Further details given below

Duration of treatment / exposure:

total 89 days

Frequency of treatment:

6h/day, 5days/week

Remarks:

Doses / Concentrations:
Fibre A - 644 ± 176 WHO fibres/ml 153 ± 48 fibres longer than 20µm /ml Mass concentration 70 ± 17.6 mg/m3
Basis:
analytical conc.

Remarks:

Doses / Concentrations:
Fibre B 539 ± 159 WHO Fibres/ml 152 ± 40 fibres longer than 20µm /ml Mass concentration 49.8 ± 8.4 mg/m3
Basis:
analytical conc.

Remarks:

Doses / Concentrations:
Fibre D - 515 ± 139 WHO Fibres/ml 137 ± 30 fibres longer than 20µm /ml Mass concentration 58.6 ± 10.4 mg/m3
Basis:
analytical conc.

No. of animals per sex per dose:

57 male

Control animals:

yes, concurrent no treatment

Details on study design:

The EU guideline ECB/TM/16(97) rev. 1 was largely followed except that some animals were allowed to survive for one year after exposure for 90 days to enable any pathology to resolve or develop. Cell proliferation in the terminal bronchioles and in the lung parenchyma was measured by the BrDU method. The dose of fibres in the lung was estimated by counting the fibres in the ashed tissue. RCF fibres were counted by SEM and amosite by TEM Non fibrous aluminosilicate glass content was measured using chemical analysis for the aluminium content of the ash, The dust content of the lung associated lymph nodes was also measured. The integrity of macrophage clearance from the lungs was estimated by thoracic radioactivity measurements after a brief inhalation of tracer particles.
- Dose selection rationale: to ensure comparable dosing of long fibres with positive control
- Rationale for animal assignment (if not random): Randomly assigned by body weight using Datatox system so that mean weight of groups was within 1% of overall mean

Positive control:

amosite asbestos long fibre dose 756 ± 133 WHO fibres/ml
146 ± 28 fibres longer than 20µm /ml
Mass concentration 6.5 ± 0.9 mg/m3

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Up to three months Individual body weights weekly to nearest 0.1g and once every two weeks for the duration of study

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

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: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: Yes
on lung lavage fluid

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: cellular content of lung lavage fluid determined on sacrifice

Sacrifice and pathology:

GROSS PATHOLOGY: No
HISTOPATHOLOGY: Yes (see table)

Other examinations:

clinical chemistry and cellular content, on lung lavage fluid

Fibre and particle content of lungs and lung associated lymph nodes

Statistics:

Differences between groups were considered statistically significant at p <0.05. Data were analysed using analysis variance. if the group means differed significantly by the analysis of variance the means of the treated groups were compared with the means of the control groups based on the Dunnett's test. The analysis of the data was done with SAS software package (version SAS Institute, Cery, NC USA, Release 6.12 on DEC Alpha 2000 4/233).

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):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

in lung lavage fluid

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

small increase in lung weight

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

alvveolar and interstitial deposits of fibre or particle laden macrophages

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
- no clinical abnormalities were observed and no animals died during the study period

BODY WEIGHT AND WEIGHT GAIN
- There was no effect of AES on body weight but exposure to non-fibrous aluminosilicate particles and amosite asbestos resulted in a significant (P<1% - Dunnett’s test) reduction in body weight and a significant increase in lung weight. The body weight reduction with amosite occurred on days 53-91.

CLINICAL CHEMISTRY: LUNG LAVAGE FLUID,
- no effects on LDH or beta-Glucuronidase, small increase in total protein initially but had recovered after 1.5 months.

ORGAN WEIGHTS
- Fibres A & B caused a small increase in lung weight. Fibres A & B, unlike the other three test articles did not cause a significant increase in lung associated lymph node weights.

GROSS PATHOLOGY
- none observed

HISTOPATHOLOGY: NON-NEOPLASTIC
Macroscopic findings - None detected
Microscopic findings
All test materials showed very slight to slight alveolar and interstitial deposits of fibre or particle laden macrophages. This declined by 12 month in the AES exposed group. A summary of fibrosis scores is reported table 9. All other effects were slight or very slight and more intense in RCF and Amosite asbestos.
- Mean Wagner fibrosis grade: Fibre A - 2.2 after 4 days and 3.0 after 12 months
Fibre B - 3.0 after 4 days and 3.0 after 12 months

OTHER FINDINGS
- Cell proliferation in the terminal airways and lung parenchyma was studied using BrdU assay, no lasting effect was observed. The proportion of dividing cells increased after all exposure but for RCF and amosite asbestos this effect was greater in the terminal airway than in the lung parenchyma. The effect of Fibres A & B were only significant immediately after exposure but the effect of amosite persisted for the entire 12 month period of study,

Dose descriptor:

NOAEL

Effect level:

ca. 535 other: WHO f/ml

Based on:

test mat.

Sex:

male

Basis for effect level:

other: overall effects

Critical effects observed:

not specified

Table 3 Terminal Body weights (SD) male rats(g)

Control

Amosite asbestos

Fibre A

Fibre B

Fibre D

Non fibrous aluminosilicate

259.0 (17.4)

235.1

(11.8)

259.3

(8.5)

250.3

(20.9)

251.9

(22.6)

250.0

(8.7)

Table 4 Terminal lung weights

Control

Amosite asbestos

Fibre A

Fibre B

Fibre D

Non fibrous aluminosilicate

1.049 (0.080)

1.214

(0.031)

1.135

(0.13)

1.134

(0.092)

1.188

(0.087)

1.425

(0.096)

Figures in bold

Table 5 Clearance of test substance from the lung Mean (90%CL) days

Material

HALF TIME IN DAYS

Number of fibres

Number of WHO fibres

Number of fibres >20 microns long

Mass

Fibre A

(25-68)

(27-62)

(12-19)

(29-58)

Fibre B

102

(84-120)

(74-106)

(43-58)

(62-85)

Fibre D

338

(286 – 389)

328

(269 – 388)

145

(120 – 170)

145

(120 – 170)

Amosite

402

(270-536)

502

(298-706)

561

(174-948)

444

(295-594)

Non fibrous aluminosilicate glass

(79-102

Half times calculated according to ECB/TM/26 counts less than 5% of initial burden discounted.

Table 6 Lung contents of particle and fibres (LALN = lung associated lymph nodes)

Fibre

Sacrifice

[Months]

WHO

Fibres

[10⁶/lung]

Fibres

(L>20μm)

[10⁶/lung]

Calculated mass

[mg]

Fibres

Particles

Lung

LALN

Lung

LALN

Lung

LALN

Lung

Fibre A

0.1

38.2

0.009

1.760

0.000

0.609

0.000

0.5

19.0

0.011

0.499

0.000

0.289

0.000

1.5

13.9

0.018

0.160

0.000

0.224

0.000

9.8

0.041

0.042

0.000

0.133

0.001

9.2

0.063

0.010

0.000

0.124

0.001

2.5

0.063

0.001

0.000

0.041

0.001

Fibre B

0.1

31.1

0.005

3.82

0.002

0.669

0.000

0.5

20.2

0.008

2.12

0.002

0.420

0.000

1.5

23.0

0.015

1.30

0.003

0.429

0.000

10.4

0.009

0.55

0.001

0.188

0.000

5.0

0.016

0.23

0.001

0.085

0.000

2.0

0.019

0.05

0.000

0.035

0.000

Fibre D

0.1

38.3

4.8

7.90

2.13

1.207

0.239

0.5

36.4

3.1

7.00

0.82

1.161

0.084

1.5

41.1

6.8

7.92

0.37

1.175

0.265

32.2

5.2

6.17

1.11

0.813

0.097

22.8

5.2

3.15

1.08

0.494

0.259

18.2

2.0

1.55

0.32

0.222

0.034

Amosite

0.1

145.7

0.076

14.74

0.005

1.053

0.001

0.5

133.2

0.093

14.19

0.015

0.869

0.002

1.5

139.2

0.082

17.35

0.008

1.012

0.001

110.1

0.206

12.66

0.005

0.846

0.002

93.2

0.135

12.13

0.004

0.700

0.002

88.8

0.149

10.82

0.000

0.619

0.001

Non fibrous aluminosilicate

0.1

4.60

0.5

3.93

1.5

4.05

2.96

1.00

0.33

* For the NF Particulate the mass was determined by chemical analysis

Table 7 Clearance of Tracer particles from alveolar region of lung

Materials

Half time of alveolar tracer clearance (95 CL) days

5 days post exposure

6 months post exposure

Control

(54-58)

(60-73)

Fibre A

(79-98)

(79-95)

Fibre B

(64-75)

(63-72)

Fibre D

435

(343 – 594)

467

(314 – 908)

Nonfibrous aluminosilicate

1202

(778-2641)

infinite

Amosite asbestos

125

(112-140)

(75-89)

All clearance times significantly slower than control at p<0.001

RCF, amosite and AES and the non-fibrous aluminosilicate glass deposited in the lung at concentrations that overloaded lung clearance. But the effect of the non-fibrous materials is much more extreme.

Table 8 CellProliferationindex

Location	Material	Proliferation index (%) at two times after exposure ceased
		At end of exposure		12 months after end of exposure
		Mean	SD	Mean	SD
Terminal bronchiolus	Control	1.20	0.54	0,77	0.17
	Fibre A	2.14	0.66	0.81	0.18
	Fibre B	2.63	0.86	1.09	1.00
	Fibre D	7.02	3.74	0.93	0.07
	Amosite	12.75	2.56	3.47	1.17
	NFP	4.78	1.79	0,94	0.23
Lung parenchyma	control	1.64	0.65	2.65	0.97
	Fibre A	2.19	1.01	2.60	0.25
	Fibre B	2.28	0.59	3.18	0.85
	Fibre D	4.11	1.53	4.36	0.16
	Amosite	4.64	1.17	4.26	0.79
	NFP	4.47	2.18	3.53	1.17

The effects of amosite in the terminal airway are significantly different (p<0.001) throughout the study.

Table 9 Mean Wagner Fibrosis Grades and grade involving at least 4% of lung parenchyma at 4 days and 12 months post exposure

Material	4 days		12 months
	Mean Wagner grade	Grade 4% of total parenchyma	Mean Wagner grade	Grade 4% of total parenchyma
Control	1	-	1.33	-
Fibre A	2.2	-	3.0	-
Fibre B	3.0	-	3.0	-
Fibre D	3.0	-	3.75	0.72
Amosite	4.0	2.16	4.0	2.57
Non fibrous aluminosiliicate	3.0	-	4.0	2.41

Table 10: Biochemicalparametersin lung lavage fluid, normalised to control = 1.

	Months\after end of exposure	LDH	BETA glucuronidase	Total protein
control	ALLTIMES	1.0	1.0	1.0
Fibre A	0	1.31	1.08	1.43
	1.5	1.35	1.13	1.15
	3	1	0.92	1.10
	6	1	1.08	1.07
	12	0.85	0.83	0.99
Fibre B	0	1.42	1.33	1.54
	1.5	1.19	0.96	0.97
	3	0.90	0.75	0.98
	6	1.00	1.00	1.08
	12	1.71	1.17	1.12
RCF	0	3.58	3.92	2.90
	1.5	2.95	2.08	1.95
	3	2.55	2.92	2.05
	6	1.9	1.92	1.67
	12	1.69	1.38	1.52
Amosite	0	2.62	2.93	1.90
	1.5	2.27	1.54	1.45
	3	1.93	2	1.72
	6	1.81	1.75	1.70
	12	1.69	1.38	1.63
NFP	0	10.35	24.25	5.70
	1.5	10.69	14.29	4.37
	3	8.93	23.83	4.09
	6	6.45	15.00	3.09
	12	3.46	3.5	2.18

Figure in bold are significantly different from control p<0.01

Conclusions:

Low biopersistence fibres such as the substance under discussion produce no significant pathological response when inhaled at very high concentrations.

Executive summary:

In this 90 day study two AES fibres were examined alongside RCF and amosite fibres as a positive control. The AES fibres in contrast to the other fibres did not display any significant pathological response and no deterioration of the lung clearance mechanism was observed. The MTD used for this study is in excess of 500 times greater than the recommended exposure levels for AES fibres in EU countries, which is much greater than the normal safety margins applied for workplace substances.

READ ACROSS INFORMATION:

In accordance with REACH Annex XI, paragraph 1.5: Grouping of substances and read across approach, Alkaline Earth Silicate fibres (REACH registration01-2119457644-32-0000)have been identified as an analogue substance where adequate testing already exists.

Man Made Vitreous Fibres (MMVF) are UVCB substances classified as CLP category 1a or 2 carcinogens depending on their content of various elements, both Potassium Alumino Silicate Fibres and Alkaline Earth Silicate Fibres have compositions placing them in category 3. Note Q of Directive 97/69/EC adapting Council Directive 67/548/EEC further exempts these fibres from labelling as carcinogens as they satisfy one or more of the test criteria listed. They share this exemption with many other vitreous fibres in use as insulation products and many examples have been tested by all available routes.

Potassium Alumino Silicate fibres are made using an identical manufacturing process and have the same range of fibre diameters as the well established Alkaline Earth Silicate fibres. It follows that respirable dust is present in the workplace in similar quantities and with similar dimensions. The two substances differ in that the with Alkaline Earth Silicate fibres, Calcium and Magnesium are added to the glass to promote bio-solubility whereas with Potassium Alumino Silicates fibres, the same objective is achieved by the addition of Potassium. The soluble elements are added in sufficient quantity to satisfy the 18% rule inNote Q, which allows the use of in-vivo testing to demonstrate low bio-persistence and exoneration from carcinogen classification.

Alkaline Earth Silicate fibres have been tested by 90 day and 2 year inhalation studies as well as the short term biopersistence tests required in Note Q. Potassium Alumino Silicate fibres have also been tested for their biopersistence after Intratracheal Installation in rats and have satisfied the requirement of having a half life of <40 days. Unless some toxic element were present there is a consensus that fibres with similar bio-persistence will display similar toxicological behaviour when inhaled. The inorganic materials used in the production of Alkaline Earth Silicate Fibres are the oxides of Calcium, Magnesium and Silicon. The inorganic materials used in the production of Potassium Alumino Silicate fibres are the oxides of Potassium, Aluminium and Silicon. All of these are ubiquitous in the environment and are common as the mineral content in foodstuffs. It is therefore not feasible that the chemical difference between these fibres will result in a different toxicological result.

Potassium Alumino Silicate fibres contain a minor addition of Zirconium Oxide. This is also used optionally in the production of Alkaline Earth Silicate fibres. Fibre B in the study report, “Subchronic Inhalation Study with High Temperature Insulation Fibres in Rats” was an Alkaline Earth Silicate fibre containing 5% Zirconia addition. Since fibre B gave very similar results to Fibre A (Alkaline Earth Silicate with no Zirconia addition) it is concluded that 6% addition of Zirconia has no effect on the end points investigated in this study.

The report, “In vitro solubility of Alkaline Earth and Potassium Alumino Silicate Fibres” compares the solubility of these two fibre types in simulated alveolar conditions. Both display similar levels of solubility adding extra confidence to the reliability of read across in inhalation testing.

In summary the results from existing 90 day and 2 year inhalation studies for Alkaline Earth Silicate fibres linked to the short term bio-persistence study with the Potassium Alumino Silicate fibres provide reliable evidence as to the lack of toxic potential for Potassium Alumino Silicate fibres. This is supported by the lack of effect on the lungs of the rats used in the biopersistence studies. With this background we do not believe that further animal testing can be justified.

Endpoint conclusion

Endpoint conclusion:: no adverse effect observed
Dose descriptor:: NOAEC
: 49.8 mg/m³
Study duration:: subchronic
Species:: rat

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

Justification for type of information:

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

other: ECB/TM/16/97

Deviations:

yes

Remarks:

only highest dose used, more endpoints were studied and animals were followed up for a longer period

Principles of method if other than guideline:

only highest dose used, more endpoints were studied and animals were followed up for a longer period (12 months rather than 90 days)

GLP compliance:

yes (incl. QA statement)

Limit test:

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Vehicle:

other: unchanged (no vehicle)

Remarks on MMAD:

Details on inhalation exposure:

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Duration of treatment / exposure:

total 89 days

Frequency of treatment:

6h/day, 5days/week

Remarks:

Doses / Concentrations:
Fibre A - 644 ± 176 WHO fibres/ml 153 ± 48 fibres longer than 20µm /ml Mass concentration 70 ± 17.6 mg/m3
Basis:
analytical conc.

Remarks:

Doses / Concentrations:
Fibre B 539 ± 159 WHO Fibres/ml 152 ± 40 fibres longer than 20µm /ml Mass concentration 49.8 ± 8.4 mg/m3
Basis:
analytical conc.

Remarks:

Doses / Concentrations:
Fibre D - 515 ± 139 WHO Fibres/ml 137 ± 30 fibres longer than 20µm /ml Mass concentration 58.6 ± 10.4 mg/m3
Basis:
analytical conc.

No. of animals per sex per dose:

57 male

Control animals:

yes, concurrent no treatment

Details on study design:

Positive control:

amosite asbestos long fibre dose 756 ± 133 WHO fibres/ml
146 ± 28 fibres longer than 20µm /ml
Mass concentration 6.5 ± 0.9 mg/m3

Observations and examinations performed and frequency:

Sacrifice and pathology:

GROSS PATHOLOGY: No
HISTOPATHOLOGY: Yes (see table)

Other examinations:

clinical chemistry and cellular content, on lung lavage fluid

Fibre and particle content of lungs and lung associated lymph nodes

Statistics:

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):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

in lung lavage fluid

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

small increase in lung weight

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

alvveolar and interstitial deposits of fibre or particle laden macrophages

Histopathological findings: neoplastic:

no effects observed

Details on results:

Dose descriptor:

NOAEL

Effect level:

ca. 535 other: WHO f/ml

Based on:

test mat.

Sex:

male

Basis for effect level:

other: overall effects

Critical effects observed:

not specified

Table 3 Terminal Body weights (SD) male rats(g)

Control

Amosite asbestos

Fibre A

Fibre B

Fibre D

Non fibrous aluminosilicate

259.0 (17.4)

235.1

(11.8)

259.3

(8.5)

250.3

(20.9)

251.9

(22.6)

250.0

(8.7)

Table 4 Terminal lung weights

Control

Amosite asbestos

Fibre A

Fibre B

Fibre D

Non fibrous aluminosilicate

1.049 (0.080)

1.214

(0.031)

1.135

(0.13)

1.134

(0.092)

1.188

(0.087)

1.425

(0.096)

Figures in bold

Table 5 Clearance of test substance from the lung Mean (90%CL) days

Material

HALF TIME IN DAYS

Number of fibres

Number of WHO fibres

Number of fibres >20 microns long

Mass

Fibre A

(25-68)

(27-62)

(12-19)

(29-58)

Fibre B

102

(84-120)

(74-106)

(43-58)

(62-85)

Fibre D

338

(286 – 389)

328

(269 – 388)

145

(120 – 170)

145

(120 – 170)

Amosite

402

(270-536)

502

(298-706)

561

(174-948)

444

(295-594)

Non fibrous aluminosilicate glass

(79-102

Half times calculated according to ECB/TM/26 counts less than 5% of initial burden discounted.

Table 6 Lung contents of particle and fibres (LALN = lung associated lymph nodes)

Fibre

Sacrifice

[Months]

WHO

Fibres

[10⁶/lung]

Fibres

(L>20μm)

[10⁶/lung]

Calculated mass

[mg]

Fibres

Particles

Lung

LALN

Lung

LALN

Lung

LALN

Lung

Fibre A

0.1

38.2

0.009

1.760

0.000

0.609

0.000

0.5

19.0

0.011

0.499

0.000

0.289

0.000

1.5

13.9

0.018

0.160

0.000

0.224

0.000

9.8

0.041

0.042

0.000

0.133

0.001

9.2

0.063

0.010

0.000

0.124

0.001

2.5

0.063

0.001

0.000

0.041

0.001

Fibre B

0.1

31.1

0.005

3.82

0.002

0.669

0.000

0.5

20.2

0.008

2.12

0.002

0.420

0.000

1.5

23.0

0.015

1.30

0.003

0.429

0.000

10.4

0.009

0.55

0.001

0.188

0.000

5.0

0.016

0.23

0.001

0.085

0.000

2.0

0.019

0.05

0.000

0.035

0.000

Fibre D

0.1

38.3

4.8

7.90

2.13

1.207

0.239

0.5

36.4

3.1

7.00

0.82

1.161

0.084

1.5

41.1

6.8

7.92

0.37

1.175

0.265

32.2

5.2

6.17

1.11

0.813

0.097

22.8

5.2

3.15

1.08

0.494

0.259

18.2

2.0

1.55

0.32

0.222

0.034

Amosite

0.1

145.7

0.076

14.74

0.005

1.053

0.001

0.5

133.2

0.093

14.19

0.015

0.869

0.002

1.5

139.2

0.082

17.35

0.008

1.012

0.001

110.1

0.206

12.66

0.005

0.846

0.002

93.2

0.135

12.13

0.004

0.700

0.002

88.8

0.149

10.82

0.000

0.619

0.001

Non fibrous aluminosilicate

0.1

4.60

0.5

3.93

1.5

4.05

2.96

1.00

0.33

* For the NF Particulate the mass was determined by chemical analysis

Table 7 Clearance of Tracer particles from alveolar region of lung

Materials

Half time of alveolar tracer clearance (95 CL) days

5 days post exposure

6 months post exposure

Control

(54-58)

(60-73)

Fibre A

(79-98)

(79-95)

Fibre B

(64-75)

(63-72)

Fibre D

435

(343 – 594)

467

(314 – 908)

Nonfibrous aluminosilicate

1202

(778-2641)

infinite

Amosite asbestos

125

(112-140)

(75-89)

All clearance times significantly slower than control at p<0.001

Table 8 CellProliferationindex

Location	Material	Proliferation index (%) at two times after exposure ceased
		At end of exposure		12 months after end of exposure
		Mean	SD	Mean	SD
Terminal bronchiolus	Control	1.20	0.54	0,77	0.17
	Fibre A	2.14	0.66	0.81	0.18
	Fibre B	2.63	0.86	1.09	1.00
	Fibre D	7.02	3.74	0.93	0.07
	Amosite	12.75	2.56	3.47	1.17
	NFP	4.78	1.79	0,94	0.23
Lung parenchyma	control	1.64	0.65	2.65	0.97
	Fibre A	2.19	1.01	2.60	0.25
	Fibre B	2.28	0.59	3.18	0.85
	Fibre D	4.11	1.53	4.36	0.16
	Amosite	4.64	1.17	4.26	0.79
	NFP	4.47	2.18	3.53	1.17

The effects of amosite in the terminal airway are significantly different (p<0.001) throughout the study.

Table 9 Mean Wagner Fibrosis Grades and grade involving at least 4% of lung parenchyma at 4 days and 12 months post exposure

Material	4 days		12 months
	Mean Wagner grade	Grade 4% of total parenchyma	Mean Wagner grade	Grade 4% of total parenchyma
Control	1	-	1.33	-
Fibre A	2.2	-	3.0	-
Fibre B	3.0	-	3.0	-
Fibre D	3.0	-	3.75	0.72
Amosite	4.0	2.16	4.0	2.57
Non fibrous aluminosiliicate	3.0	-	4.0	2.41

Table 10: Biochemicalparametersin lung lavage fluid, normalised to control = 1.

	Months\after end of exposure	LDH	BETA glucuronidase	Total protein
control	ALLTIMES	1.0	1.0	1.0
Fibre A	0	1.31	1.08	1.43
	1.5	1.35	1.13	1.15
	3	1	0.92	1.10
	6	1	1.08	1.07
	12	0.85	0.83	0.99
Fibre B	0	1.42	1.33	1.54
	1.5	1.19	0.96	0.97
	3	0.90	0.75	0.98
	6	1.00	1.00	1.08
	12	1.71	1.17	1.12
RCF	0	3.58	3.92	2.90
	1.5	2.95	2.08	1.95
	3	2.55	2.92	2.05
	6	1.9	1.92	1.67
	12	1.69	1.38	1.52
Amosite	0	2.62	2.93	1.90
	1.5	2.27	1.54	1.45
	3	1.93	2	1.72
	6	1.81	1.75	1.70
	12	1.69	1.38	1.63
NFP	0	10.35	24.25	5.70
	1.5	10.69	14.29	4.37
	3	8.93	23.83	4.09
	6	6.45	15.00	3.09
	12	3.46	3.5	2.18

Figure in bold are significantly different from control p<0.01

Conclusions:

Low biopersistence fibres such as the substance under discussion produce no significant pathological response when inhaled at very high concentrations.

Executive summary:

READ ACROSS INFORMATION:

Endpoint conclusion

Endpoint conclusion:: no adverse effect observed
Dose descriptor:: NOAEC
: 49.8 mg/m³

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:: no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:: no study available

Additional information

Inhalation and oral routes of exposure are considered the most relveant for fibrous substances and as such have been chosen as suitable endpoints for this substance.

Read across has been used for the inhalation studies as it is felt that the results from existing 90 day and 2 year inhalation studies for Alkaline Earth Silicate fibres linked to the short term bio-persistence study with the Potassium Alumino Silicate fibres provide reliable evidence as to the lack of toxic potential for Potassium Alumino Silicate fibres. This is supported by the lack of effect on the lungs of the rats used in the biopersistence studies. With this background we do not believe that further animal testing can be justified.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
read across to other AES Fibres

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
read across to other AES fibres

Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: ovaries; urogenital: testes

Justification for classification or non-classification

No abnormal effects observed in the short term oral study, or read-across longer term inhalation studies.

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