Xylitol

Endpoint summary

Description of key information

Skin: QSAR. Slightly irritating to skin (Primary Irritation index [PII] <2). Reliability = 2

Skin: In vivo rabbit; not irritating when tested as 5 or 10% in topical cream. Reliability = 2

 

Eye: QSAR. Slightly irritating to the eye (Modified maximum average score [MMAS] of 6.66). Reliability = 2

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:

key study

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.

Principles of method if other than guideline:

OECD Toolbox v3.1
Toolbox prediction report is attached in IUCLID

GLP compliance:

no

Species:

other: rabbit; mouse; human

Type of coverage:

other: no data; open; occlusive

Irritation parameter:

primary dermal irritation index (PDII)

Score:

< 2

Remarks on result:

other: slightly irritating

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: Out of Domain

 

(((((("a" and("b" and(not "c")) ) and "d") and "e") and("f" and(not "g")) ) and("h" and(not "i")) ) and("j" and "k") )

 

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 Inclusion rules not met by Skin irritation/corrosion Inclusion rules by BfR

 

Domain logical expression index: "c"

 

Referential boundary: The target chemical should be classified as Acid anhydrides OR Activated N-heterocycles OR Aliphatic alpha-halogen-esters OR Aliphatic iso(thio) cyanates OR Allyl halides, sulfonates OR Alpha-halogenated aldehydes/ketones or thioaldehydes/thio-ketones OR Aromatic amines OR Benzanthrone derivatives OR Disulfides OR Esters of organic sulfonic or sulfuric esters OR Ethylenglycolethers OR Halogenated alkanes  OR Halogenated phenol ethers OR Hydrazines, hydrazonium salts OR Ketones OR Organic silicon halides OR Primary and secondary aliphatic amines OR Quaternary organic ammonium compounds by Skin irritation/corrosion Inclusion rules by BfR

 

Domain logical expression index: "d"

 

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

 

Domain logical expression index: "e"

 

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

 

Domain logical expression index: "f"

 

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

 

Domain logical expression index: "g"

 

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 OR Acylation >> Direct Acylation Involving a Leaving group >> Acyl halides (including benzyl and carbamoyl deriv.) OR Acylation >> Isocyanates and Related Chemicals OR Acylation >> Isocyanates and Related Chemicals >> Ketenes OR Michael addition OR Michael addition >> Polarised Alkenes OR Michael addition >> Polarised Alkenes >> Polarised alkene - pyrazines OR Michael addition >> Polarised Alkenes >> Polarised alkene - pyridines OR Michael addition >> Polarised Alkynes OR Michael addition >> Polarised Alkynes >> Polarised alkyne - pyridine OR Michael addition >> Polarised Alkynes >> Polarised alkyne - pyrimidine OR Michael addition >> Polarised Alkynes >> Polarised alkyne - sulfone OR Michael addition >> Polarized Azo Compounds  OR Michael addition >> Polarized Azo Compounds  >> Azocarbonamides OR SN2 OR SN2 >> Episulfonium Ion Formation OR SN2 >> Episulfonium Ion Formation >> Mustards OR SN2 >> SN2 reaction at a sp2 carbon atom OR SN2 >> SN2 reaction at a sp2 carbon atom >> Polarised alkenes with a halogen leaving group OR SN2 >> SN2 reaction at a sulphur atom OR SN2 >> SN2 reaction at a sulphur atom >> Sulfenyl halides OR SN2 >> SN2 reaction at a sulphur atom >> Sulfoxides of disulfides OR SN2 >> SN2 reaction at a sulphur atom >> Thiosulfonates OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl diazo OR SN2 >> SN2 reaction at sp3 carbon atom >> alpha-Halo ethers OR SN2 >> SN2 reaction at sp3 carbon atom >> alpha-Halobenzyls (and related cyano, sulfate and sulphonate subs. chem.) OR SNAr OR SNAr >> Nucleophilic aromatic substitution OR SNAr >> Nucleophilic aromatic substitution >> Activated halo-benzenes OR SNAr >> Nucleophilic aromatic substitution >> Activated halo-pyridines by Protein binding by OECD

 

Domain logical expression index: "h"

 

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: "i"

 

Referential boundary: The target chemical should be classified as SN2 OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> alpha-haloalkanes by Protein binding alerts for skin sensitization by OASIS v1.1

 

Domain logical expression index: "j"

 

Parametric boundary: The target chemical should have a value of log Kow which is >= -1.77

 

Domain logical expression index: "k"

 

Parametric boundary: The target chemical should have a value of log Kow which is <= -1.22

 

 

Interpretation of results:

GHS criteria not met

Conclusions:

Primary (Dermal) Irritation Index (PII) < 2; Slightly irritating

Executive summary:

A Primary Irritation Index (PII) value of less than 2 was derived by QSAR using the OECD Toolbox. The model was based on in vivo skin irritation data using the five nearest neighbours. The test substance was determined to be slightly irritating to the skin. 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

Reference

Endpoint:

eye irritation: in vivo

Type of information:

(Q)SAR

Adequacy of study:

key study

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.

Principles of method if other than guideline:

OECD Toolbox v3.1
Toolbox prediction report is attached in IUCLID

GLP compliance:

no

Species:

rabbit

Irritation parameter:

overall irritation score

Score:

6.66

Remarks on result:

other: slightly irritating

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(not "c")) ) and "d") and("e" and(not "f")) ) and "g") and("h" and(not "i")) ) and("j" and "k") )

 

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 Inclusion rules not met by Eye irritation/corrosion Inclusion rules by BfR

 

Domain logical expression index: "c"

 

Referential boundary: The target chemical should be classified as Aliphatic glycerol monoethers OR Aliphatic monoalcohols OR Derivatives of alpha amino benzene OR Organic phosphonic acids and their derivatives OR Organic sulphonic salts OR Thiazoles and thiazolidines OR Triphenylphosphonium salts by Eye irritation/corrosion Inclusion rules by BfR

 

Domain logical expression index: "d"

 

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

 

Domain logical expression index: "e"

 

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: "f"

 

Referential boundary: The target chemical should be classified as 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 >> alpha-haloalkanes by Protein binding alerts for skin sensitization 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 OASIS v1.1 ONLY

 

Domain logical expression index: "h"

 

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

 

Domain logical expression index: "i"

 

Referential boundary: The target chemical should be classified as Ethylenglycolethers OR Ketones OR Quaternary organic ammonium compounds by Skin irritation/corrosion Inclusion rules by BfR

 

Domain logical expression index: "j"

 

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

 

Domain logical expression index: "k"

 

Parametric boundary: The target chemical should have a value of log Kow which is <= -0.14

 

Interpretation of results:

GHS criteria not met

Conclusions:

MMAS (modified maximum average score) = 6.66, Slightly irritating

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. 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. This formed the starting set of potential analogues for subsequent evaluation for either skin irritation or eye irritation.

 

Skin Irritation

For skin irritation, a subcategorization on the basis of the skin irritation BfR profiler was then 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 average of 5 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 -2.56, which characterises it as hydrophilic. One of the physicochemical rules as discussed in Rorije E and Hulzebos E (2005) who 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 corrosive/irritating, the weight of evidence based on the available read-across coupled with the low predicted 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 actually assigns the test substance as "not classified". As part of this implementation, the estimated LogKow was found to be less than -3.1, the threshold for “not classified”. Clearly, it can be said that there is uncertainty associated with estimated LogKow values, typically  ± 0.5 log units, as discussed in the QPRF for LogKow. Thus, there is a possibility that the LogKow for the test substance could in fact be sufficiently low enough to trigger the cut off for “not classified for skin irritation”.

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, a subsequent subcategorization was performed using the eye irritation BfR profiler to exclude substances that did contain a feature indicative of eye irritation/corrosive potential. The test 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 average of the 5 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 -2.56, 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 corrosive/irritating, 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 subject to uncertainty, +/- 0.5 log units, as discussed in the QPRF for LogKow, there is a possibility that the true LogKow would 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., 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, 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, 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, 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 classification or non-classification

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