Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
skin irritation / corrosion, other
Remarks:
QSAR result
Type of information:
(Q)SAR
Adequacy of study:
key study
Study period:
October 14th, 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
1. SOFTWARE
iSafeRabbit models for skin and eye irritation by KREATiS

2. MODEL (incl. version number)
iSafeRat skin irritation/corrosion prediction model v1.0

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
CC=CC=CC(=O)OCC(CC)(COC(=O)C=CC=CC)COC(=O)C=CC=CC

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
see documents under 'Attached justification' below

5. APPLICABILITY DOMAIN
see documents under 'Attached justification' below

6. ADEQUACY OF THE RESULT
If the substance falls within the applicability domain of the model, the result is expected to be reliable.

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 404 (Acute Dermal Irritation / Corrosion)
Deviations:
not applicable
Principles of method if other than guideline:
The model determines whether the applied dose of a chemical substance causes cytotoxicity, and thereby be responsible for the induction of erythema and/or oedema. The dose applied and the physico-chemical properties of the test substance are the input data to a series of algorithms to determine the substance concentration in the viable epidermis and to establish if this concentration reaches a cytotoxic concentration for the keratinocytes. These concentrations are plotted against the logarithm of subcooled water solubility of the substance (Log SCLS). As shown in the figure 1, the plot is subdivided into corrosive, irritant and non-irritant zones. The substance will fall into one of these zones, thereby allowing a classification.
The parameters given in Table 1 were provided as the input data into a skin absorption model, which was based on the existing SkinPerm model (4). The Kreatis model was adapted for the experimental conditions indicated in the OECD guideline 404 (exposure period, applied dose, semi-occlusive dressing). This model provides the amount of substance which passes through the stratum corneum and that permeates into the viable epidermis. The output of this model was then used to determine the cell burden value (CB) which informs whether the substance was able to cause any cytotoxicity, therefore leading to dermal irritation or corrosion. This cell burden value is plotted against the (Log SCLS) of the substance and depending on its position on the plot (already subdivided into corrosive, irritant and non-irritant zones), it will be classified for skin irritation/corrosion.
GLP compliance:
no
Remarks:
Not applicable/QSAR models

Test material

Constituent 1
Chemical structure
Reference substance name:
2,4-Hexadienoic acid, 1,1’-[2-ethyl-2-[[(1-oxo-2,4-hexadien-1-yl)oxy]methyl]-1,3-propanediyl] ester
EC Number:
950-112-7
Cas Number:
347377-00-8
Molecular formula:
C24H32O6
IUPAC Name:
2,4-Hexadienoic acid, 1,1’-[2-ethyl-2-[[(1-oxo-2,4-hexadien-1-yl)oxy]methyl]-1,3-propanediyl] ester
Test material form:
solid
Details on test material:
Physical state: solid

Test animals

Species:
other: iSafeRat® Skin irritation/corrosion prediction model v2.0 was trained using data from studies performed using rabbits only. Therefore, the model mimics exposure of the rabbit skin to the test substance.
Strain:
other:
Remarks:
Rabbit (See study report)

Test system

Type of coverage:
other: iSafeRat® Skin irritation/corrosion prediction model v1.0 was trained using data from studies performed with a semi-occlusive patch only. Data from occlusive coverage was only included when the outcome was not-irritant to skin.
Preparation of test site:
other:
Remarks:
iSafeRat® Skin irritation/corrosion prediction model v1.0 was trained using data from studies using shaved rabbits only. Therefore, the model mimics exposure over shaved rabbit skin.
Vehicle:
other:
Remarks:
iSafeRat® Skin irritation/corrosion prediction model v1.0 was trained using data from studies performed using neat substances only. Therefore, the model mimics studies performed with the unchanged test substance (no vehicle).
Controls:
not required
Amount / concentration applied:
iSafeRat® Skin irritation/corrosion prediction model v1.0 calculations use 500 mg of test substance as the amount applied
Duration of treatment / exposure:
iSafeRat® Skin irritation/corrosion prediction model v1.0 mimics a 4 h exposure period
Observation period:
not applicable
Number of animals:
not applicable
Details on study design:
WORKING PRINCIPLE OF THE MODEL:
The model determines whether the applied dose of a chemical substance causes cytotoxicity, and thereby responsible for the induction of erythema and/or oedema. The dose applied and the physico-chemical properties of the test substance are the input data to a series of algorithms to determine the substance concentration in the viable epidermis and to establish if this concentration reaches a cytotoxic concentration for the keratinocytes. These concentrations are plotted against the logarithm of subcooled water solubility of the substances (Log SCLS). As shown in the figure 1 (see study report), the plot is subdivided into corrosive, irritant and non-irritant zones. The substance will fall into one of these zones, thereby allowing a classification.
The parameters given in Table 1(see study report) were provided as the input data into a skin absorption model, which was based on the existing SkinPerm model. The Kreatis model was adapted for the experimental conditions indicated in the OECD guideline 404 (exposure period, applied dose, semi-occlusive dressing). This model provides the amount of substance which passes through the stratum corneum and that permeates into the viable epidermis. The output of this model was then used to determine the cell burden value (CB) which informs whether the substance was able to cause any cytotoxicity, therefore leading to dermal irritation or corrosion. This cell burden value is plotted against the (Log SCLS) of the substance and depending on its position on the plot (already subdivided into corrosive, irritant and non-irritant zones), it will be classified for skin irritation/corrosion.

SCORING SYSTEM:
iSafeRat® Skin irritation/corrosion prediction model v1.0 was trained using data from studies that used the Draize scoring method. From these studies the substances were validated as Category 1, Category 2 and No category chemicals according to GHS/CLP classification criteria.

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
erythema score
Remarks:
Not applicable/QSAR model
Basis:
other:
Time point:
other:
Score:
< 2.3
Reversibility:
other: Not applicable/QSAR model
Remarks on result:
other: iSafeRat skin irritation/corrosion model was trained with substances not-irritant to skin according to a Draize score for erythema < 2.3, assuring reversibility of effects if present.
Irritation parameter:
edema score
Remarks:
Not applicable/QSAR model
Basis:
other:
Time point:
other:
Score:
< 2.3
Reversibility:
other: Not applicable/QSAR model
Remarks on result:
other: iSafeRat skin irritation/corrosion model was trained with substances not-irritant to skin according to a Draize score for edema < 2.3, assuring reversibility of effects if present.

Any other information on results incl. tables

Results for iSafeRat® skin irritation/corrosion v1.0: The test substance Trimethylolpropane Trisorbate, an ester, is located within a non-irritant output region of the model (see Figure 1 in study report), in which 22 out of 22 fully validated substances are non-irritant. Furthermore, the ester of the training set which is closest to the test substance is non-irritant with a higher cell burden value and higher SCLS than the test substance. Therefore, Trimethylolpropane Trisorbate is concluded to be non-irritant to skin.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Trimethylolpropane Trisorbate is classified non-irritant to skin according to Regulation (EC) No. 1272/2008 (CLP) and to GHS. The test substance falls within the applicability domain of the model and was hence reliably predicted for its acute skin irritation/corrosion potential. Therefore, this endpoint prediction can be considered reliable without restrictions (Klimisch score K1).
Executive summary:

The acute skin irritation/corrosion potential of Trimethylolpropane Trisorbate was predicted using the iSafeRat® skin irritation/corrosion v1.0 local model for esters. This QSAR model has been validated to be compliant with the OECD recommendations for QSAR modeling (OECD, 2004) and predicts the skin irritation/corrosion potential that would be expected when testing the substance under experimental conditions in a laboratory study following the Guideline for Testing of Chemicals No. 404, "Acute Dermal Irritation/Corrosion" (1), referenced as Method B.4 of Commission Regulation No. 440/2008 (2).

Trimethylolpropane Trisorbate is predicted to be non-irritant to skin according to Regulation (EC) No. 1272/2008 (CLP) and to GHS. The test substance falls within the applicability domain of the model and was hence reliably predicted for its acute skin irritation/corrosion potential. Therefore, this endpoint prediction can be considered reliable without restrictions (Klimisch score K1).

This study is considered as acceptable and satisfies the requirement for acute skin irritation/corrosion endpoint.