Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
eye irritation, other
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 405 (Acute Eye Irritation / Corrosion)
Deviations:
not applicable
Principles of method if other than guideline:
The model determines whether the instilled dose of a chemical substance causes cytotoxicity, and thereby responsible for the induction of corneal opacity and/or conjunctival redness. The dose applied and the physico-chemical properties of the test substance are the input data for a series of algorithms to determine the substance concentration in the eye tissue and to establish if this concentration reaches a cytotoxic concentration. This concentration is plotted against the subcooled water solubility of the substance, 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 an eye tissue absorption model which was based on the existing SkinPerm model on the basis that the eye tissue of the eye shares the same permeation properties as the viable epithelium of the skin, i.e., under the conditions required to reach cell burst associated to irritation/corrosion. KREATiS eye irritation/corrosion prediction model was adapted to account for the experimental conditions indicated in the OECD guideline 405 (applied dose) and to account for the physiological differences between the eye and the skin (eye tissue thickness, rabbit eye tear volume and reflex tearing rate). This model, provides the amount of substance which permeates through the eye tissue (comprising the epithelium, the stroma and the endothelium layers) and which is therefore accumulated in the eye tissue. The output of this model is then used to determine the cell burden (CB) value which informs whether the substance is able to cause cytoxicity, therefore leading to eye irritation or corrosion. This cell burden value (mol/kg) is plotted against the subcooled liquid water solubility (SCLS) of the substance and depending on the position of the substance on the plot (already subdivided into corrosive, irritant and non-irritant zones), it will be classified for eye 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 / tissue source

Species:
other: iSafeRat® Eye irritation/corrosion prediction model v1.0 was trained using data from studies performed using rabbits only. Therefore, the model mimics exposure of rabbit eyes to the test substance.
Strain:
other:
Remarks:
Rabbit (See study report)

Test system

Vehicle:
other:
Remarks:
iSafeRat® Eye 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® Eye irritation/corrosion prediction model v1.0 calculations use 100 mg of test substance as the amount applied
Duration of treatment / exposure:
iSafeRat® Eye irritation/corrosion prediction model v1.0 used data from studies that were performed without washing out the test substance or for which the substance was washed out with water or saline 24 h after instillation of the substance.
Observation period (in vivo):
Not applicable
Duration of post- treatment incubation (in vitro):
Not applicable
Number of animals or in vitro replicates:
Not applicable
Details on study design:
WORKING PRINCIPLE OF THE MODEL:
The model determines whether the instilled dose of a chemical substance causes cytotoxicity, and thereby responsible for the induction of corneal opacity and/or conjunctival redness. The dose applied and the physico-chemical properties of the test substance are the input data for a series of algorithms to determine the substance concentration in the eye tissue and to establish if this concentration reaches a cytotoxic concentration. This concentration is plotted against the subcooled water solubility of the substance, 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 an eye tissue absorption model which was inspired from the existing SkinPerm model (2) on the basis that the eye tissue of the eye shares the same permeation properties as the viable epithelium of the skin, i.e., under the conditions required to reach cell burst associated to irritation/corrosion. KREATiS eye irritation/corrosion prediction model was adapted to account for the experimental conditions indicated in the OECD guideline 405 (applied dose) and to account for the physiological differences between the eye and the skin (eye tissue thickness, rabbit eye tear volume and reflex tearing rate). This model, provides the amount of substance which permeates through the eye tissue (comprising the epithelium, the stroma and the endothelium layers) and which is therefore accumulated in the eye tissue. The output of this model is then used to determine the cell burden (CB) value which informs whether the substance is able to cause cytoxicity, therefore leading to eye irritation or corrosion. This cell burden value (mol/kg) is plotted against the subcooled liquid water solubility (SCLS) of the substance and depending on the position of the substance on the plot (already subdivided into corrosive, irritant and non-irritant zones), it will be classified for eye irritation/corrosion.

SCORING SYSTEM:
iSafeRat® Eye 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. Therefore, the model allows to predict the GHS/CLP classification criteria for eye irritation.

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
cornea opacity score
Remarks:
Not applicable/QSAR
Basis:
other:
Time point:
other:
Score:
< 1
Reversibility:
other: not applicable
Remarks on result:
other: iSafeRat eye irritation/corrosion model was trained with substances not-irritant to eyes according to a Draize score for corneal opacity < 1, assuring reversibility of effects if present.
Irritation parameter:
iris score
Remarks:
Not applicable/QSAR model
Basis:
other:
Time point:
other:
Score:
< 1
Reversibility:
other: Not applicable/QSAR model
Remarks on result:
other: iSafeRat eye irritation/corrosion model was trained with substances not-irritant to eyes according to a Draize score for iris < 1, assuring reversibility of effects if present.
Irritation parameter:
conjunctivae score
Remarks:
Not applicable/QSAR model
Basis:
other:
Time point:
other:
Score:
< 2
Reversibility:
other: Not applicable/QSAR model
Remarks on result:
other: iSafeRat eye irritation/corrosion model was trained with substances not-irritant to eyes according to a Draize score for conjuctival redness < 2, assuring reversibility of effects if present.
Irritation parameter:
chemosis score
Remarks:
Not applicable/QSAR model
Basis:
other:
Time point:
other:
Score:
< 2
Reversibility:
other: not applicable/QSAR model
Remarks on result:
other: iSafeRat eye irritation/corrosion model was trained with substances not-irritant to eyes according to a Draize score for chemosis < 2, assuring reversibility of effects if present.

Any other information on results incl. tables

Results foriSafeRat® eye irritation/corrosion v1.0: In the eye irritation/corrosion model’s graph (Figure 1), the test substance Trimethylolpropane Trisorbate, an ester, is located within a non-irritant region (See Figure 1 in study report) in which 20 out of 20 fully validated substances are non-irritant (coloured green). Furthermore, the ester of the training set which is closest to the test substance is non-irritant with a higher cell burden value than the test substance.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Trimethylolpropane Trisorbate is classified as non-irritant to eyes 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 eye irritation/corrosion potential. Therefore, this endpoint prediction can be considered reliable without restrictions (Klimisch score K1).
Executive summary:

The acute eye irritation/corrosion potential of the Trimethylolpropane Trisorbate was predicted using the iSafeRat® eye irritation/corrosion v2.0 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 eye 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. 405, "Acute Eye Irritation/Corrosion" (1), referenced as Method B.5 of Commission Regulation No. 440/2008.

Trimethylolpropane Trisorbate is predicted as non-irritant to eyes 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 eye 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 eye irritation/corrosion endpoint.