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Description of key information

iSafeRat® Skin irritation/corrosion, KREATIS, 2019 :

Not-irritant to skin (UN GHS/CLP no-category)

iSafeRat® Eye irritation/corrosion, KREATIS, 2019 :

Not-irritant to eyes (UN GHS/CLP no-category)

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
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.
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
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)
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.
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.

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.

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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
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.
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
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)
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.
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.

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.

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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

A QSAR prediction (KREATiS, 2019) was performed to assess the both skin and eye irritation/corrosion of the test substance. This QSAR model has been validated to be compliant with the OECD recommendations for QSAR modeling (OECD, 2004) and predicts the:

Eye irritation/corrosion that would be expected when testing the substance under experimental conditions in a laboratory 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. The predicted toxicological endpoint is the eye irritation/corrosion according to Regulation (EC) No. 1272/2008 (CLP) and to GHS.

The irritation/corrosion to eyes was determined using a validated QSAR model for the chemical family of esters. The QSAR model is based on a validated data set of 20 chemicals, from eye irritation/corrosion experimental studies following the OECD TG 405 performed using rabbits. For these studies the irritation/corrosion lesions were evaluated using the Draize scale and the substances were classified according to UN GHS/CLP classification system.

As discussed in the QMRF for this model, the calculated cell burden (mol/Kg) as a function of the SCLS (mol/L) of compounds can be linked to the cell burden leading to cytotoxicity and therefore the clinical signs of eye irritation/corrosion of corneal opacity, conjunctival redness, chemosis and iritis.

The test substance is predicted to be not-irritant to eyes, based on existing experimental validated studies for eye irritation/corrosion following the OECD TG 405.

 

Skin irritation/corrosion that would be expected when testing the substance under experimental conditions in a laboratory 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).

The irritation/corrosion to skin was determined using a validated QSAR model for the chemical family of esters. The QSAR model is based on a validated data set of 22 chemicals, from skin irritation/corrosion experimental studies following the OECD TG 404 performed using rabbits. For these studies the irritation/corrosion lesions were evaluated using the Draize scale and the substances were classified according to UN GHS/CLP classification system.

As discussed in the QMRF for this model, the calculated cell burden (mol/Kg) as a function of the SCLS (mol/L) of compounds can be linked to the cell burden leading to cytotoxicity and therefore the clinical signs of skin irritation/corrosion of erythema and oedema.

The test substance is predicted to be not-irritant to skin, based on existing experimental validated studies for skin irritation/corrosion following the OECD TG 404.

The test substance is inside the applicability domain for both iSafeRat® eye/skin irritation/corrosion models. Therefore, the prediction for both skin and eye irritation/corrosion are considered reliable without restrictions (Klimisch score K1).

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008.

Self classification:

Based on the available predictions:

- No additional self-classification is proposed regarding skin and eye irritation/corrosion according to the CLP and to the UN GHS.

- No data was available regarding respiratory irritation.