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Diss Factsheets

Administrative data

Endpoint:
acute toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because skin contact in production and/or use is not likely
the study does not need to be conducted because the substance does not meet the criteria for classification as acute toxicity or STOT SE by the oral route and no systemic effects have been observed in in vivo studies with dermal exposure (e.g. skin irritation, skin sensitisation)
Justification for type of information:
In accordance with column 2 of Annex VIII section 8.5.3 of REACH Regulation 1907/2006 testing by the dermal route is appropriate if 1) inhalation of the substance is unlikely, 2) skin contact in production and use is likely and 3) the physicochemical and toxicological properties suggest potential for a significant rate of absorption.

Inhalation of Synthetic wollastonite is expected to be the primary route of exposure. An acute inhalation study has been performed on the read-across material Kieselguhr soda ash flux-calcined. As Synthetic wollastonite and Kieselguhr soda ash flux-calcined follow the same exposure routes an acute dermal study was not considered to be necessary. The physiological properties of the substance do not suggest a significant rate of absorption through the skin and no systemic effects or other evidence of absorption were seen in the skin or eye irritation studies. Furthermore the test substance is poorly soluble in water and therefore a limited amount of potential substance is available for absorption via the dermal route. On this basis the short term toxicity test via the dermal route is considered to be scientifically unjustified
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
data waiving: supporting information
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
12-Apr-2010 - 26-Apr-2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
yes (incl. QA statement)
Test type:
fixed concentration procedure
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories B.V. Kreuzelweg 53 5961 NM Horst / Netherlands
- Age at study initiation: Males: 8 weeks; Females: 9 weeks
- Weight at study initiation: Males: 263.9 to 284.3 g ;Females: 182.6 to 198.0 g
- Fasting period before study:
- Housing: Animals were housed in groups of 5 of the same sex in Makrolon® type-IV cages with wire mesh tops and standard softwood bedding
- Diet: Animals had ad libitum access to a pelleted standard Harlan Teklad 2914C rat maintenance diet ( except during the period when the animalsand) batch no. were restrained in exposure tubes.
- Water: Community tap water from Füllinsdorf ad libitum in water bottles, except during the period when they were restrained in exposure tubes
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature : 22 ± 3 °C,
- Humidity: 30 - 70%
- Air changes: 10 - 15 air changes per hour
- Photoperiod 12 hour fluorescent light / 12 hour dark cycle:


Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Inhalation exposure was performed using a flow-past, nose-only exposure system.
- Method of holding animals in test chamber: The animals were confined separately in restraint tubes which were positioned radially around the exposure chamber.
- Source and rate of air: The exposure system ensured a uniform distribution and provided a constant flow of test material to each exposure tube. The flow of air at each tube was 1.0 L/min.
- System of generating particulates/aerosols: A dust aerosol was generated from the test item using a CR 3020 rotating brush aerosol generator connected to a micronizing jet mill. The aerosol generated was then discharged into the exposure chamber through a 63Ni charge neutralizer
- Method of particle size determination: The particle size distribution of the test aerosol was determined three times during exposure using a 7 stage Mercer cascade Impactor (Model 02-130, In-Tox. Products Inc., Albuquerque, New Mexico, U.S.A.). The particle size distribution was measured by gravimetrically analyzing the test item deposited on each stage of the cascade impactor. Mass Median Aerodynamic Diameters (MMAD) and Geometric Standard Deviations (GSD) were calculated on the basis of the results from the impactor, using Microsoft Excel Software . The target range was 1 to 4 μm for the MMAD and between 1.5 and 3 for the GSD.
- Temperature, humidity, pressure in air chamber: The temperature and relative humidity of the test atmosphere was measured continuously during
exposure using a calibrated device. The results were recorded manually and are reported at 30 minute intervals from the start of exposure and additionally at the end of exposure The actual airflow rate through the exposure chamber was recorded at approximately 30 minute intervals from the start of the inhalation exposure.




TEST ATMOSPHERE
- Particle size distribution: Particle size distribution data are presented in table 4
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): MMAD and GSD data are presented in tables 2 and3

Duration of exposure:
4 h
Concentrations:
The mean gravimetric aerosol concentration determined was 2.7 mg/L air
The nominal aerosol concentration was 20.4 mg/L air.

No. of animals per sex per dose:
5 males and 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations for viability were recorded once before exposure on the day of exposure (test day
1), three times during exposure, immediately and 1 h after exposure on test day 1 and twice daily during the observation period. Observations for clinical signs was examined three times during exposure, immediately and 1 h after exposure on test day 1 and once daily during the observation period.The body weight of each animal was recorded on test days 1 (before exposure), 2, 4, 8 and 15 (before necropsy).
- Necropsy of survivors performed: yes
Statistics:
No statistical analysis was performed as only one group was allocated to the study
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 2.6 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Mortality:
All animals survived the scheduled observation period
Clinical signs:
other: Moderately ruffled fur was noted in all animals on test day 1 after the end of the exposure and persisted with a reduced severity degree until test day 2. In addition, a slightly scabbed nose was recorded in all animals on test day 1 after the end of the
Body weight:
From test day 1 to test day 2, marginal to slight body weight loss was noted in five males and four females. Thereafter normal body weight development was recorded in these animals. Marginal body weight loss or stagnation of the body weight gain is not unusual in inhalation studies. Therefore, effects on the body weight were considered to be mainly due to the restraining of the animals in the tubes during the nose-only exposure procedure and not related to treatment with the test item. However, a contribution of a test-item related effect cannot be excluded completely.




Gross pathology:
No macroscopic findings were present at necropsy

Test atmosphere conditions:

Temperature, relative humidity and oxygen concentration during exposure were considered to be satisfactory for this type of study. Data on temperature, relative humidity and oxygen concentration are presented in table 1.

Table 1: Temperature, relative humidity and oxygen concentration

Recording time[hours:min]

O2 concentration [Vol %]

Temperature [°C]

Relative humidity [% RH]

06:30

20.6

22.2

9.2

07:00

20.6

22.3

5.6

07:30

20.7

22.4

5.4

08:00

20.6

22.3

5.7

08:30

20.7

22.3

5.5

09:00

20.6

22.3

5.5

09:30

20.6

22.4

7.2

10:00

20.6

22.3

5.0

10:30

20.7

22.3

5.2

10:39

20.6

22.3

5.1

Mean

St. Dev

N

20.6

0.0

10

22.3

0.1

10

5.9

1.3

10

Gravimetric determination of aerosol concentrations:

The mean gravimetric aerosol concentration determined was 2.7 mg/L air. The aerosol concentration was in general stable during the exposure period. Data on gravimetric aerosol concentrations are presented in table 2.

Table 2: Gravimetric determination of aerosol concentrations

Sampling time [hours:min]

Sampling volume [L]

Amount of test item on the filter [mg]

Gravimetric aerosol concentration [mg/L air]

06:40 – 06:45

4.9

9.592

2.0

06:50 – 06:55

4.9

14.728

3.0

07:40 – 07:45

4.9

14.220

2.9

08:40 – 08:45

4.9

13.151

2.7

09:43 – 09:48

4.9

14.605

3.0

Mean

St. Dev

N

 

2.7

0.4

5

Chemical determination of aerosol concentrations:

The chemically determined aerosol concentration was in general stable during the exposure period. Only one single value at the beginning of the aerosol generation was lower. The remainder of the values were close to the technical limit of approximately 3 mg/L as targeted. The chemical aerosol concentration compared favourably to the gravimetrically determined concentration. This was in accordance with the high purity of the test item. Details on chemically determined aerosol concentrations are presented in table 3.

Table 3: Chemical determination of aerosol concentrations

Sampling time [hours:min]

Sampling volume [L]

Amount of test item on the filter [mg]

Gravimetric aerosol concentration [mg/L air]

06:40 – 06:45

4.9

9.135

1.9

06:50 – 06:55

4.9

13.93

2.9

07:40 – 07:45

4.9

13.60

2.8

08:40 – 08:45

4.9

12.70

2.6

09:43 – 09:48

4.9

14.13

2.9

Mean

St. Dev

N

 

2.6

0.4

5

 

Particle size distribution:

The Mass Median Aerodynamic Diameters (MMAD) obtained from tree gravimetric measurements of particle size distribution during the exposure were similar (MMAD between 2.39 and 2.95 μm). This led to the conclusion that the particle size of the generated aerosol was fairly stable during the whole exposure period. The MMADs were well within the target range of 1 to 4 μm, thus deposition of the particles can be assumed to have occurred in both the upper and the lower respiratory tract. In addition, the Geometric Standard Deviations (GSD) were within the target range of 1.5 to 3. Hence, the particle size distributions obtained were considered to be appropriate for acute inhalation toxicity testing. Data on particle size distribution are presented in table 4.

Table 4: Particle size distribution

Time

Total amount collected [µg]

 

MMAD [µm]

GSD

Corr.Coeff (R )

% < 4 µm

1

--

2

4.6

3

3.0

4

2.13

5

1.6

6

1.06

7

0.715

8

0.325

06:58

1487

19.4

30.3

16.6

13.4

9.8

7.5

0.8

2.2

2.75

2.32

0.964

67.2

07:42

1919

23.4

27.6

16.1

16.3

7.7

4.7

1.4

2.9

2.95

2.47

0.957

63.2

08:42

828

13.9

32.7

16.5

11.6

6.6

12.6

3.7

2.3

2.39

2.35

0.973

72.8

Interpretation of results:
not classified
Conclusions:
In conclusion, the LC50 of Soda-ash flux-calcined kieselguhr obtained in this study was estimated to be greater than 2.6 mg/L air (chemically determined mean aerosol concentration). As the study was conducted up to the maximum attainable concentration and in accordance with Regulation (EC) No. 1272/2008 (EU CLP) the substance is not considered to be classified.
Reason / purpose for cross-reference:
data waiving: supporting information
Reference
Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
The study was performed between 01 June 2010 and 24 June 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
GLP compliance:
yes (incl. QA statement)
Type of study:
mouse local lymph node assay (LLNA)
Species:
mouse
Strain:
CBA
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories UK Ltd, Bicester, Oxon, UK
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: 15 to 23 g
- Housing: Individually housed in suspended solid-floor polypropylene cages furnished with softwood woodflakes
- Diet: 2014 Tekland Global Rodent diet ad libitum
- Water: ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature: 19 to 25°C
- Humidity: 30 - 70 %
- Air changes: Approximately 15 per hr
- Photoperiod: 12 hrs dark / 12 hrs light
Vehicle:
propylene glycol
Concentration:
Groups of four mice were treated with the test material at concentrations of 10%, 5% or 2.5% w/w in propylene glycol
No. of animals per dose:
4 mice per dose
Details on study design:
PRELIMINARY SCREENING TEST:
Using available information regarding the systemic toxicity/irritancy potential of the test material, a preliminary screening test was performed using one mouse. The mouse was treated by daily application of 25 µl of the test material at a concentration of 10% w/w in propylene glycol, to the dorsal surface of each ear for three consecutive days (Days 1, 2, 3). The mouse was observed twice daily on Days 1, 2 and 3 and once daily on Days 4, 5 and 6. Any signs of toxicity or excessive local irritation noted during this period were recorded. The bodyweight was recorded on Day 1 (prior to dosing) and on Day 6

MAIN STUDY:
Groups of four mice were treated with the test material at concentrations of 10%, 5% or 2.5% w/w in propylene glycol. The preliminary screening test suggested that the test material would not produce systemic toxicity or excessive local irritation at the highest suitable concentration. The mice were treated by daily application of 25 µl of the appropriate concentration of the test material to the dorsal surface of each ear for three consecutive days (Days 1, 2, 3). The test material formulation was administered using an automatic micropipette and spread over the dorsal surface of the ear using the tip of the pipette.
A further group of four mice received the vehicle alone in the same manner.

3H-Methyl Thymidine Administration
Five days following the first topical application of the test material or vehicle (Day 6) all mice were injected via the tail vein with 250 µl of phosphate buffered saline (PBS) containing 3H methyl thymidine (3HTdR: 80 µCi/ml, specific activity 2.0 Ci/mmol, ARC UK Ltd) giving a total of 20 µCi to each mouse






Positive control substance(s):
other: Phenylacetaldehyde (90%)
Positive control results:
A group of five animals was treated with 50 µl (25 µl per ear) of Phenylacetaldehyde (90%) as a solution in propylene glycol at a concentration of 2.5% v/v. A further control group of five animals was treated with propylene glycol alone

The Stimulation Index expressed as the mean radioactive incorporation for the treatment group divided by the mean radioactive incorporation of the vehicle control group was 18.43.

Phenylacetaldehyde (90%) was considered to be a sensitiser under the conditions of the test
Key result
Parameter:
SI
Value:
1.13
Test group / Remarks:
4 animals: 2.5 % in propylene glycol
Key result
Parameter:
SI
Value:
0.97
Test group / Remarks:
4 animals: 5 % in propylene glycol
Key result
Parameter:
SI
Value:
0.99
Test group / Remarks:
4 animals: 10 % in propylene glycol

Table 1: Clinical Observations, Bodyweight and Mortality Data – Preliminary Screening Test

Concentration (%w/w) in
propylene glycol

Animal Number

Bodyweight (g)

Day

1

2

3

4

5

6

Day 1

Day 6

Pre-Dose

Post Dose

Pre-Dose

Post Dose

Pre-Dose

Post Dose

10

S-1

19

20

0

0

0

0

0

0

0

0

0

0=      No signs of systemic toxicity

Table 2: Disintegrations per Minute, Disintegrations per Minute/Node and Stimulation Index

Concentration
(%w/w) in
propylene glycol

dpm

dpm/Nodea

Stimulation Indexb

Result

Vehicle

6210.33

776.29

na

na

2.5

7020.81

877.60

1.13

Negative

5

6047.51

755.94

0.97

Negative

10

6135.29

766.91

0.99

Negative

dpm=  Disintegrations per minute

a=      Disintegrations per minute/node obtained by dividing the disintegrations per minute value by 8 (total number of lymph nodes)

b=      Stimulation Index of 3.0 or greater indicates a positive result

na =    Not applicable

Table 3: Individual Clinical Observations and Mortality Data

Concentration
(% w/w) in
propylene glycol

Animal Number

Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Pre-Dose

Post Dose

Pre-Dose

Post Dose

Pre-Dose

Post Dose

Vehicle

1-1

0

0

0

0

0

0

0

0

0

1-2

0

0

0

0

0

0

0

0

0

1-3

0

0

0

0

0

0

0

0

0

1-4

0

0

0

0

0

0

0

0

0

2.5

2-1

0

0

0

0

0

0

0

0

0

2-2

0

0

0

0

0

0

0

0

0

2-3

0

0

0

0

0

0

0

0

0

2-4

0

0

0

0

0

0

0

0

0

5

3-1

0

0

0

0

0

0

0

0

0

3-2

0

0

0

0

0

0

0

0

0

3-3

0

0

0

0

0

0

0

0

0

3-4

0

0

0

0

0

0

0

0

0

10

4-1

0

0

0

0

0

0

0

0

0

4-2

0

0

0

0

0

0

0

0

0

4-3

0

0

0

0

0

0

0

0

0

4-4

0

0

0

0

0

0

0

0

0


0=      No signs of systemic toxicity

Table 4: Individual Bodyweights and Bodyweight Changes

Concentration
(% w/w) in
propylene glycol

Animal Number

Bodyweight (g)

Bodyweight Change (g)

Day 1

Day 6

Vehicle

1-1

20

20

0

1-2

20

21

1

1-3

17

17

0

1-4

18

17

-1

2.5

2-1

18

17

-1

2-2

19

19

0

2-3

19

19

0

2-4

19

19

0

5

3-1

20

20

0

3-2

20

19

-1

3-3

18

18

0

3-4

20

20

0

10

4-1

17

17

0

4-2

21

20

-1

4-3

18

18

0

4-4

20

20

0

Interpretation of results:
not sensitising
Conclusions:
Kieselguhr soda ash flux calcined is not classified as a skin sensitiser in accordance with CLP Regulation (EC) no. 1272/2008

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion