Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
The study was conducted between 24 April 2019 and 13 May 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2019
Report date:
2019

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Silicon
EC Number:
231-130-8
EC Name:
Silicon
Cas Number:
7440-21-3
Molecular formula:
Si
IUPAC Name:
Silicon
Constituent 2
Chemical structure
Reference substance name:
Magnesium silicate
EC Number:
237-413-2
EC Name:
Magnesium silicate
Cas Number:
13776-74-4
Molecular formula:
H2O3Si.Mg
IUPAC Name:
magnesium(2+) ion oxosilanebis(olate), crystalline
Constituent 3
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:
Silicon dioxide, amorphous
impurity 1
Chemical structure
Reference substance name:
Water
EC Number:
231-791-2
EC Name:
Water
Cas Number:
7732-18-5
Molecular formula:
H2O
IUPAC Name:
Water
impurity 2
Chemical structure
Reference substance name:
Carbon
EC Number:
231-153-3
EC Name:
Carbon
Cas Number:
7440-44-0
Molecular formula:
C
IUPAC Name:
Carbon
impurity 3
Reference substance name:
Metallic impurities (Na and S)
IUPAC Name:
Metallic impurities (Na and S)
Test material form:
solid: particulate/powder
Specific details on test material used for the study:
Identification: Reaction mass of crystalline magnesium silicate and crystalline silicon and synthetic amorphous silicon dioxide
Chemical Name: Reaction mass of Magnesium dioxide(oxo)silane and Silicon dioxide (MgSiO3, Si and SiO2)
Batch: E80-181130-11
Purity: 94 min wt%
Physical state, appearance: Black powder
Expiry Date: 30 November 2019
Storage Conditions: At room temperature, light protected
Stability in Solvent: Not indicated by the Sponsor

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
Animal Information:
Species: Rat
Strain: Wistar Han TM
Source: Envigo RMS B.V., Inc
Sex: Female
Other: Females were nulliparous and non-pregnant
Number of animals for the pre-test: 1 female
Number of animals for the main study: 2 females
Age (beginning of treatment):
Pre-test: 10 - 11 weeks
Main study: 11 - 12 weeks
Bodyweight at Day 0: 201.5 - 243.1 g
Identification: The animals were distributed into the test groups at random. If possible, all animals belonging to the same experimental group were kept in one cage. The animals were individually marked by indelible ink markings on the tail. A colour-coded card was prepared for each project, giving details of the test type, project number, treatment start, dose level, sex and number of animals.
Acclimatization: At least 5 days prior to the start of dosing under test conditions after health examination. Only animals without any visible signs of illness were used for the study.

Husbandry:
Housing:
During the exposure period: single
During the acclimation phase and after the exposure period: groups of up to three rats (of the same sex and dose group)
Cage Type: Makrolon Type IV, with wire mesh top
Bedding: granulated soft wood bedding
Feed: 2018C Teklad Global 18% protein rodent diet (certified), ad libitum
Water: tap water, ad libitum
Environment:
temperature 22 + 2°C
relative humidity approx. 45-65 (except for deviation) (with the aim of 50 – 60%)
artificial light 6.00 a.m. - 6.00 p.m.
Environmental enrichment: provided throughout the study period (e.g., wooden chew blocks, fun tunnels or suitable nesting material)

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
corn oil
Details on dermal exposure:
Test Item Preparation and Analysis:
Formulation:
The different test item concentrations were prepared individually. Homogeneity of the test item in vehicle was maintained during treatment using a magnetic stirrer.
The test item was formulated at a concentration of 200 mg/mL in the vehicle and administered at a constant dose volume of 5 mL/kg body weight. Grinding of the test item in a mortar was used to formulate the test item.
Test item formulations were freshly prepared on the day of dosing, issued at room temperature and administered as soon as possible (within 4 hours of preparation). The formulations were assumed to be stable for this period unless specified otherwise by the Sponsor.
Samples of test substance formulations were not taken for analysis and consequently the homogeneity, concentration and stability of the test item were not determined.

Preparation of Animals:
The day before dose application, the fur was removed from the dorsal region and both flanks of each animal using veterinary clippers. Care was taken to avoid abrading the skin.
Prior to the start of the test the animals were weighed and the individual dose to be administered was adjusted to the animal’s body weight.

Dose Administration:
The test item was applied evenly to an area of clipped skin equivalent to approximately 10% of the total body surface area. The site of application was covered with a gauze dressing backed with semi-occlusive surgical tape.

Dose Levels:
Dose administration was once dermal (topical).
Based on available information on the toxicity of the test item, 2000 mg/kg was chosen as the initial starting dose, since a severe toxicity which may necessitate humane euthanasia was not expected at this dose level.

One single animal was treated as follows:
Dose Level: 2000 mg/kg
Vehicle: Corn oil
Dose Volume: 5 mL/kg

In the absence of mortality or toxicity at a dose level of 2000 mg/kg, 2 additional animals were treated as follows:
Dose Level: 2000 mg/kg
Vehicle: Corn oil
Dose Volume: 5 mL/kg

A total of three animals were therefore treated at a dose level of 2000 mg/kg in the study.

Exposure Period:
The exposure period was twenty-four hours, then the dressings were carefully removed. Residual test item was removed by a cotton wool tissue soaked in corn oil to remove any residual test item.
After removal of the dressings and subsequently for 14 days, the test sites were examined for evidence of primary irritation and scored according to the following scale:

EVALUATION OF SKIN REACTIONS
Erythema and Eschar Formation
No erythema: 0
Very slight erythema (barely perceptible): 1
Well-defined erythema: 2
Moderate to severe erythema: 3
Severe erythema (beef redness) to slight eschar formation (injuries in depth): 4

Edema Formation
No edema: 0
Very slight edema (barely perceptible): 1
Slight edema (edges of area well-defined by definite raising): 2
Moderate edema (raised approximately 1 millimeter): 3
Severe edema (raised more than 1 millimeter and extending beyond the area of exposure): 4

Any other skin reactions, if present were also recorded.















Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
Morbidity/Mortality Inspection and Clinical Observations:
Clinical observations and inspections for morbidity / mortality were performed at least three times within the first six hours after application (i.e., 30 minutes and 1 hour, 2 hours and 4 hours after dosing), thereafter at least once daily for 14 days.
All animals were observed for 14 days after dosing.
The nature and severity, where appropriate, of the clinical signs and the time were recorded at each observation for all individual animals. If applicable, the time of death/humane kill was recorded as precisely as possible. Observations included changes in the skin and fur, eyes and mucous membranes, and respiratory, circulatory, autonomic and central nervous system, and somatomotor activity and behavior pattern. Particular attention was directed to the observation of tremors, convulsions, salivation, diarrhea, lethargy, sleep and coma.

Determination of Body Weight:
Body weights were recorded on Day 0 (prior to dosing), Day 7, and 14, or (if applicable) at death (unscheduled).

Terminal Investigations:
Necropsy:
At the end of the study the animals were killed by CO2 asphyxiation.
A gross necropsy was performed on all animals that died or were humanely killed during the study (if applicable) and at the scheduled end of the in-life part. This consisted of an external examination and opening of the abdominal and thoracic cavities. Any macroscopic abnormalities were recorded.

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths during the study.
Clinical signs:
There were no clinical signs of reaction to treatment throughout the study.
Body weight:
The animals showed expected gains in body weight over the observation period.
Gross pathology:
In the stomach, one animal showed orange spots in the half digested food.
Other findings:
Dermal Reactions:
Animal 3 showed a small red spot and scratch on the skin and animal 2 and 3 showed patchy or no regrowth of fur, respectively. Stained fur and substance residuals were observed in all animals.

Any other information on results incl. tables

Individual Dermal Reactions – 2000 mg/kg b.w.

The Draize Scale was used for scoring primary skin irritation (erythema and edema).

Dose Level (mg/kg)

Animal Number and Sex

Observation

Effects Noted After Initiation of Exposure
(Days)

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000

1
Female

Erythema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Edema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

Fs Sr

Fs Sr

Fs Sr

Fs Sr

Fs Sr

Fs Sr

Fs Sr

0

0

0

0

0

0

0

2
Female

Erythema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Edema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

Fs Sr

Fs Sr

Fs Sr

Fs Sr

Fs

Fs

Fs

0

0

0

0

0

F

0

3
Female

Erythema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Edema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

Fs Sr

Fs Sr

Fs Sr

Fs Sr

Fs*

Fs**

0

0

0

0

0

0

0

Fs stained fur
Sr substance residues
*red spot on skin
**small scratch
F fur grew back patchy
F° fur did not grow back

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Remarks:
Not classified: EU CLP
Conclusions:
The acute median lethal oral dose (LD50) to rats of Reaction mass of crystalline magnesium silicate and crystalline silicon and synthetic amorphous silicon dioxide was demonstrated to be greater than 2000 mg/kg body weight.
Reaction mass of crystalline magnesium silicate and crystalline silicon and synthetic amorphous silicon dioxide is included in Category 5/Unclassified, according to the Globally Harmonised System (GHS).
Executive summary:

Summary:

The study was performed to assess the acute dermal toxicity of Reaction mass of crystalline magnesium silicate and crystalline silicon and synthetic amorphous silicon dioxide to the rat.

Methods:

Initially, one female animal was given a single, 24 hour, semi‑occluded dermal application of the test item to intact skin at a dose level of 2000 mg/kg body weight. Based on the preliminary results of the initial test, a further two female animals were similarly treated. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy.

Results:

Mortality: There were no deaths.

Clinical Observations: There were no signs of systemic toxicity.

Dermal Irritation: Animal 3 showed a small red spot and scratch on the skin and animals 2 and 3 showed patchy or no growth of fur, respectively. Stained fur and substance residuals were observed in all animals.

Body Weight: All animals showed expected gains in body weight.

Necropsy: Animal 2 showed orange spots in the half digested stomach content.

Conclusion:

The acute dermal median lethal dose (LD50) to rats of Reaction mass of crystalline magnesium silicate and crystalline silicon and synthetic amorphous silicon dioxide was found to be greater than 2000 mg/kg body weight. Reaction mass of crystalline magnesium silicate and crystalline silicon and synthetic amorphous silicon dioxide is included in Category 5/Unclassified according to the Globally Harmonised System (GHS).

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