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Administrative data

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

Referenceopen allclose all

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:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Remarks:
The scientific validity of the (Q)SAR model has been established in accordance with the OECD Principles for (Q)SAR Model Validation.
Justification for type of information:
QSAR prediction
Principles of method if other than guideline:
OECD Toolbox v3.1
Toolbox prediction report is attached in IUCLID
GLP compliance:
not specified
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:
GHS criteria not met
Conclusions:
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..

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:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Remarks:
The scientific validity of the (Q)SAR model has been established in accordance with the OECD Principles for (Q)SAR Model Validation.
Justification for type of information:
QSAR prediction
Principles of method if other than guideline:
OECD Toolbox v3.1 OECD Guideline 404
Toolbox prediction report is attached in IUCLID
GLP compliance:
not specified
Species:
rabbit
Type of coverage:
other: occlusive; semiocclusive; no data
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(not "d")) ) and("e" and "f") )

Domain logical expression index: "a"

Referential boundary:The target chemical should be classified as Inclusion rules not met by Skin irritation/corrosion Inclusion rules by BfR 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"

Referential boundary:The target chemical should be classified as No alert found by Protein binding alerts for skin sensitization by OASIS v1.1

Domain logical expression index: "d"

Referential boundary:The target chemical should be classified as Acylation OR Acylation >> Acyl transfer via nucleophilic addition reaction OR Acylation >> Acyl transfer via nucleophilic addition reaction >> Isocyanates and isothiocyanates OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> N-acylamides OR Acylation >> Ester aminolysis or thiolysis OR Acylation >> Ester aminolysis or thiolysis >> Activated alkyl or aryl esters OR Michael addition OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-carbonyl compounds with polarized double bonds OR Radical OR Radical >> Free radical formation OR Radical >> Free radical formation >> Hydroperoxides OR SN2 OR SN2 >> Interchange reaction with sulphur containing compounds OR SN2 >> Interchange reaction with sulphur containing compounds >> Thiols and disulfide compounds OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Activated alkyl esters OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> alpha-activated haloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> alpha-haloalkanes OR SN2 >> Nucleophilic substitution on benzylic carbon atom OR SN2 >> Nucleophilic substitution on benzylic carbon atom >> alpha-activated benzyls OR SN2 >> Nucleophilic substitution on heterocyclic sulfenamides OR SN2 >> Nucleophilic substitution on heterocyclic sulfenamides >> Heterocyclic sulfenamides OR SN2 >> Ring opening SN2 reaction OR SN2 >> Ring opening SN2 reaction >> Epoxides, Aziridines and Sulfuranes OR SNAr OR SNAr >> Nucleophilic aromatic substitution on activated halogens OR SNAr >> Nucleophilic aromatic substitution on activated halogens >> Activated haloarenes by Protein binding alerts for skin sensitization by OASIS v1.1

Domain logical expression index: "e"

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

Domain logical expression index: "f"

Parametric boundary:The target chemical should have a value of log Kow which is <= -1.86

 

Interpretation of results:
GHS criteria not met
Conclusions:
Primary (Dermal) Irritation Index (PII): <2; Slightly irritating
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..

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

Eye irritation

Link to relevant study records

Referenceopen allclose all

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:
results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Remarks:
The scientific validity of the (Q)SAR model has been established in accordance with the OECD Principles for (Q)SAR Model Validation.
Justification for type of information:
QSAR prediction
Principles of method if other than guideline:
OECD Toolbox v3.1
Toolbox prediction report is attached in IUCLID
GLP compliance:
not specified
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:
GHS criteria not met
Conclusions:
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.

 

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:
results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Remarks:
The scientific validity of the (Q)SAR model has been established in accordance with the OECD Principles for (Q)SAR Model Validation.
Justification for type of information:
QSAR prediction
Principles of method if other than guideline:
OECD Toolbox v3.1
Toolbox prediction report is attached in IUCLID
GLP compliance:
not specified
Species:
rabbit
Irritation parameter:
overall irritation score
Score:
5.86
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(not "d")) ) and("e" and(not "f")) ) and("g" and(not "h")) ) and "i") and("j" and(not "k")) ) and("l" and "m") )

 

Domain logical expression index: "a"

 

Referential boundary:The target chemical should be classified as Inclusion rules not met by Skin irritation/corrosion Inclusion rules by BfR 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"

 

Referential boundary:The target chemical should be classified as Inclusion rules not met by Eye irritation/corrosion Inclusion rules by BfR

 

Domain logical expression index: "d"

 

Referential boundary:The target chemical should be classified as Aliphatic esters of chloro formic acid OR Aliphatic glycerol monoethers OR Aliphatic monoalcohols OR Derivatives of 2-halogen benzoic acids and corresponding alkali salts OR Derivatives of alpha amino benzene OR Halogen benzenes with substituents containing carboxylic acid groups OR Organic phosphonic acids and their derivatives OR Organic sulphonic salts OR Pyrrolidones OR Substituted indoles OR Subststituted pyrazoles OR Thiazoles and thiazolidines OR Thiazolones OR Triphenylphosphonium salts by Eye irritation/corrosion Inclusion rules by BfR

 

Domain logical expression index: "e"

 

Referential boundary:The target chemical should be classified as No alert found by Protein binding by OASIS v1.1

 

Domain logical expression index: "f"

 

Referential boundary:The target chemical should be classified as Acylation OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> Acyl halide of carboxylic acids OR Acylation >> Direct acylation involving a leaving group >> N-acylamides OR Acylation >> Direct acylation involving a leaving group >> N-acylsulphonamides OR Michael addition OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-carbonyl compounds with polarized double bonds OR SN2 OR SN2 >> Interchange reaction with sulphur containing compounds OR SN2 >> Interchange reaction with sulphur containing compounds >> Thiols and disulfide compounds OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Activated alkyl esters OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> alpha-haloalkanes OR SN2 >> Ring opening SN2 reaction OR SN2 >> Ring opening SN2 reaction >> Epoxides, Aziridines and Sulfuranes by Protein binding by OASIS v1.1

 

Domain logical expression index: "g"

 

Referential boundary:The target chemical should be classified as No alert found by Protein binding by OECD

 

Domain logical expression index: "h"

 

Referential boundary:The target chemical should be classified as Acylation OR Acylation >> Direct Acylation Involving a Leaving group OR Acylation >> Direct Acylation Involving a Leaving group >> Acetates by Protein binding by OECD

 

Domain logical expression index: "i"

 

Referential boundary:The target chemical should be classified as Acidic [0,10) AND Basic [0,10) by Ionization at pH = 7.4

 

Domain logical expression index: "j"

 

Referential boundary:The target chemical should be classified as Group 14 - Carbon C AND Group 16 - Oxygen O by Chemical elements

 

Domain logical expression index: "k"

 

Referential boundary:The target chemical should be classified as Group 15 - Nitrogen N OR Group 16 - Sulfur S by Chemical elements

 

Domain logical expression index: "l"

 

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

 

Domain logical expression index: "m"

 

Parametric boundary:The target chemical should have a value of log Kow which is <= 0.128

 

Interpretation of results:
GHS criteria not met
Conclusions:
MMAS (modified maximum average score) = 5.86, Slightly irritating based on expert judgement
Executive summary:

A MMAS (modified maximum average score) of 5.86 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.

 

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:
results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Remarks:
The scientific validity of the (Q)SAR model has been established in accordance with the OECD Principles for (Q)SAR Model Validation.
Justification for type of information:
QSAR prediction
Principles of method if other than guideline:
OECD Toolbox v3.1
Toolbox prediction report is attached in IUCLID
GLP compliance:
not specified
Species:
rabbit
Irritation parameter:
overall irritation score
Score:
6.66
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

 

Interpretation of results:
GHS criteria not met
Conclusions:
MMAS (modified maximum average score) = 6.66, Slightly irritating based on expert judgement
Executive summary:

A MMAS (modified maximum average score) of 6.66 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.

 

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

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.

Justification for classification or non-classification

The test substance is not expected to be a skin or eye irritant and is not classified according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.