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Description of key information

Skin Irritation: Primary Irritation Index (PII) value of <2 was derived by QSAR using the OECD Toolbox
Eye Irritation: MMAS (modified maximum average score) of 6.66 was derived by QSAR using the OECD Toolbox

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The scientific validity of the (Q)SAR model has been established in accordance with the OECD Principles for (Q)SAR Model Validation. This study is used to provide a weight of evidence for the hazard endpoint that is sufficient for the purpose of classification and labelling and/or risk assessment. Another study on this endpoint is included.
Justification for type of information:
QSAR prediction: migrated from IUCLID 5.6
Reference:
Composition 0
Principles of method if other than guideline:
OECD Toolbox v3.1
Toolbox prediction report is attached in IUCLID
GLP compliance:
not specified
Test material information:
Composition 1
Species:
other: Rabbit; Human
Type of coverage:
other: no data; occlusive
Irritation parameter:
primary dermal irritation index (PDII)
Score:
< 2

The prediction was based on dataset comprised from the following descriptors: "Primary Irritation Index"

Estimation method: Takes average value from the 5 nearest neighbours

Domain  logical expression:Result: In Domain

 

(("a" and "b") and("c" and "d") )

 

Domain logical expression index: "a"

 

Referential boundary:The target chemical should be classified as Neutral Organics by Aquatic toxicity classification by ECOSAR ONLY

 

Domain logical expression index: "b"

 

Referential boundary:The target chemical should be classified as Discrete chemical by Substance Type

 

Domain logical expression index: "c"

 

Parametric boundary:The target chemical should have a value of log Kow which is >= -3.9

 

Domain logical expression index: "d"

 

Parametric boundary:The target chemical should have a value of log Kow which is <= -1.55

 

Interpretation of results:
slightly irritating
Remarks:
Migrated information expert judgement Criteria used for interpretation of results: expert judgment
Conclusions:
This study and the conclusions which are drawn from it fulfil the quality criteria (validity, reliability, repeatability).

Primary (Dermal) Irritation Index (PII): <2; Slightly irritating based on expert judgement
Executive summary:

A Primary Irritation Index (PII) value less than 2 was derived by QSAR using the OECD Toolbox. The model was based on in vivo rabbit skin irritation using the five nearest neighbours. The test substance was determined to be slightly irritating to the skin based on expert judgement. Supporting documentation is provided in the attached prediction report..

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The scientific validity of the (Q)SAR model has been established in accordance with the OECD Principles for (Q)SAR Model Validation. This study is used to provide a weight of evidence for the hazard endpoint that is sufficient for the purpose of classification and labelling and/or risk assessment. Other studies on this endpoint are included.
Justification for type of information:
QSAR prediction: migrated from IUCLID 5.6
Reference:
Composition 0
Principles of method if other than guideline:
OECD Toolbox v3.1
Toolbox prediction report is attached in IUCLID
GLP compliance:
not specified
Test material information:
Composition 1
Species:
other: Rabbit
Irritation parameter:
overall irritation score
Score:
1.86
Remarks on result:
other: MMAS (modified maximum average score)

The prediction was based on dataset comprised from the following descriptors: MMAS

Estimation method: Takes average value from the 5 nearest neighbours

Domain  logical expression:Result: Out of Domain

 

(("a" and "b") and("c" and "d") )

 

Domain logical expression index: "a"

 

Referential boundary:The target chemical should be classified as Neutral Organics by Aquatic toxicity classification by ECOSAR ONLY

 

Domain logical expression index: "b"

 

Referential boundary:The target chemical should be classified as Discrete chemical by Substance Type

 

Domain logical expression index: "c"

 

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.65

 

Domain logical expression index: "d"

 

Parametric boundary:The target chemical should have a value of log Kow which is <= -0.621

 

Interpretation of results:
slightly irritating
Remarks:
Migrated information expert judgement Criteria used for interpretation of results: expert judgment
Conclusions:
This study and the conclusions which are drawn from it fulfil the quality criteria (validity, reliability, repeatability).

MMAS (modified maximum average score) = 1.86, Slightly irritating based on expert judgement
Executive summary:

A MMAS (modified maximum average score) of 1.86 was derived by QSAR using the OECD Toolbox. The model was based on in vivo rabbit eye irritation using the five nearest neighbours. The test substance was determined to be slightly irritating to the eye based on expert judgement. Supporting documentation is provided in the attached prediction report.

 

Additional information

General Discussion

Skin and eye irritation are endpoints where there has been significant progress in developing in vitro alternatives which minimises the need for any in vivo testing. Some efforts have been made in estimating irritation potential quantitatively through chemical class specific QSARs where the chemical determining features have focused on hydrophobicity (often modelled by log Kow), reactivity (dipole or pKa) and size (molecular weight MW or volume) (Gallegos-Saliner et al, 2008; Barratt, 1996).

One of the most significant efforts was undertaken by the German Bundesinstitut für Risikobewertung (BfR) who devised a set of physicochemical rules and structural alerts to identify potential skin and eye irritant/corrosive chemicals (Gerner et al, 2004; Hulzebos et al, 2005; Tsakovska et al, 2006; Rorije & Hulzebos, 2005). The system was developed in order to support regulatory decision making for hazard assessment of chemicals, and is based on the combined use of two predictive approaches:

1. Physicochemical property limits (physicochemical exclusion rules) to identify chemicals with no skin irritation/corrosion or eye irritation/corrosion potential.

2. Structural alerts (inclusion rules) to identify chemicals with skin irritation/corrosion or eye irritation/corrosion potential.

The rules were subsequently encoded into Toxtree v2.5 and hence into the OECD Toolbox to facilitate the evaluation of substances for their irritation/corrosion characteristics as well as to permit the grouping of substances for read-across.

The OECD Toolbox was used as a convenient source of irritation data for substances related to the test substance. A pragmatic grouping was devised on the basis of neutral organic chemicals using the ECOSAR aquatic chemical classes SAR profiler. This enabled a reasonable number of substances to be gathered that possessed no features that would be suggestive of reactivity. The test substance contains no reactive groups and is categorised as a neutral organic based on this profiler. The set of substances was subsequently subcategorised to remove substances that alerted for skin sensitisation based on the available protein binding alerts.

 

Skin Irritation

For skin irritation, a subcategorisation on the basis of the skin irritation BfR profiler was undertaken to exclude substances that did contain a feature indicative of skin irritation/corrosive potential. The test substance as the target substance did not contain any alerts indicative of irritation/corrosion potential. Based on the resulting set of analogues, a qualitative read-across was performed on the basis of the available  in vivo skin irritation data. The read-across based on the nearest neighbours resulted in an estimated primary irritation index of <2. The estimate is said to be out of domain on account of the LogKow of the test substance being lower than any of the analogue substances. The test substance has an estimated LogKow of -2.91, which characterises it as hydrophilic. One of the physicochemical rules as discussed in Rorije E and Hulzebos E (2005) evaluated the threshold of LogKow <-3.1 proposed by Gerner et al, (2004) as sufficient for the purposes of classifying a substance as not a skin corrosive or irritant. The cut off is based on the training set of substances evaluated by the BfR and on measured LogKow values. Given this threshold of highly hydrophilic substances being not corrosives/irritants, the weight of evidence based on the available read-across coupled with the low LogKow value supports the expectation that the test substance is unlikely to be a skin irritant. Furthermore a prediction made using the BfR for skin irritation as implemented in Toxtree v2.5 computes an estimated LogKow that is less than -3.1, hence the rule is satisfied and Toxtree assigns the test substance as not classified. Given the uncertainty associated with LogKow estimates and the reported estimated LogKow being able to vary ± 0.5 log units (as discussed in the QPRF for LogKow), there is a possibility that the LogKow could be low enough to trigger the cut off for “not classified”.

Accordingly, the test substance is not expected to be a skin irritant on the basis of the read-across, and the low estimated LogKow as detailed by the BfR exclusion rules.

 

Eye Irritation

For eye irritation, the subcategorisation performed was based on the eye irritation BfR profiler to exclude substances that did contain a feature indicative of eye irritation/corrosive potential. The test substance as the target substance did not contain any alerts indicative of irritation/corrosion potential. Based on the resulting set of analogues, a qualitative read-across was performed on the basis of the available in vivo eye irritation data. The read-across based on the nearest neighbours resulted in an estimated MMAS of 6.6. The estimate is said to be out of domain on account of the LogKow of The test substance being lower than any of the analogue substances. The test substance has an estimated LogKow of -2.91, which characterises it as hydrophilic. One of the physicochemical rules as discussed in Tsakovska et al (2006) evaluated the threshold of LogKow <-3.1 proposed by Gerner et al, (2005) as sufficient for the purposes of classifying a substance as not an eye corrosive or irritant. The cut off is based on the training set of substances evaluated by the BfR and on measured LogKow values. Given this threshold of highly hydrophilic substances being not corrosives/irritants, the weight of evidence based on the available read-across coupled with the low LogKow value supports the expectation that the test substance is unlikely to be an irritant.

Furthermore a prediction made using the BfR for eye irritation as implemented in Toxtree v2.5 computes an estimated LogKow that is less than -3.1, hence the rule is satisfied and Toxtree assigns the test substance as not classified. Given the uncertainty associated with LogKow estimates and the reported estimated LogKow being able to vary ± 0.5 log units (as discussed in the QPRF for LogKow), there is a possibility that the LogKow could be low enough to trigger the cut off for “not classified”.

Accordingly, the test substance is not expected to be an eye irritant on the basis of the read-across, and the low estimated LogKow as detailed by the BfR exclusion rules.

 

Literature references

Barratt MD (1996). Quantitative Structure-Activity Relationships for Skin Irritation and Corrosivity of Neutral and Electrophilic Organic Chemicals. Toxicology in Vitro 10: 247-256.

Gallegos Saliner A et al (2008). A review of (Q)SAR models for skin and eye irritation and corrosion. QSAR & Comb Sci. 27: 49-59.

Gerner I, Liebsch M, and Spielmann H (2005). Assessment of the eye irritating properties of chemicals by applying alternatives to the Draize rabbit eye test: the use of QSARs and in vitro tests for the classification of eye irritation. Alternatives to Laboratory Animals 33, 215-237.

Gerner I, Walker JD, Hulzebos E, and Schlegel K (2004). Use of physicochemical property limits to develop rules for identifying chemical substances with no skin irritation or corrosion potential. QSAR Comb Sci 23:726-733.

Hulzebos E, Walker JD, Gerner I and Schlegel K (2005). Use of structural alerts to develop rules for identifying chemical substances with skin irritation or skin corrosion potential. QSAR Comb. Sci. 24: 332-342.

Rorije E and Hulzebos E (2005). Evaluation of (Q)SARs for the Prediction of Skin Irritation/Corrosion Potential: Physico-chemical exclusion rules. Final report for ECB contract IHCP.B430206. European Chemicals Bureau, Joint Research Centre, Ispra, Italy. Available at: http://ihcp.jrc.ec.europa.eu/our_labs/predictive_toxicology/information-sources/qsar-document-area/Evaluation_of_Skin_Irritation_QSARs.pdf)

Tsakovska I, Netzeva T, and Worth A (2005). Evaluation of (Q)SARs for the prediction of Eye Irritation/Corrosion Potential: Physicochemical exclusion rules EUR 21897 EN. Available at: http://ihcp.jrc.ec.europa.eu/our_labs/predictive_toxicology/doc/Evaluation_of_Eye_Irritation_QSARs.pdf)

Justification for selection of skin irritation / corrosion endpoint:
No studies were available. Therefore, a QSAR analysis was performed.

Justification for selection of eye irritation endpoint:
No studies were available. Therefore, a QSAR analysis was performed.

Effects on skin irritation/corrosion: slightly irritating

Effects on eye irritation: slightly irritating

Justification for classification or non-classification

The test substance is not expected to be either a skin or eye irritant on the basis of the weight of evidence of QSAR data. Therefore, no classification is required for skin or eye irritation according the EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.