2-propylheptan-1-ol

Skin sensitisation

Administrative data

Endpoint:

skin sensitisation: in chemico

Type of information:

(Q)SAR

Adequacy of study:

supporting study

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
OASIS TIMES v2.27.19.13

2. MODEL (incl. version number)
Skin sensitization with autoxidation; v. 21.26

3. SMILES IDENTIFIERS USED AS INPUT FOR THE MODEL
CCCCCC(CCC)CO

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: In vivo: skin sensitization
- Unambiguous algorithm: refer to QMRF
- Defined domain of applicability:
1. General parametric requirements - includes ranges of variation of log KOW and MW. It specifies in the domain only those chemicals that fall in the range of variation of the MW and log Kow defined on the bases of the correctly predicted training set chemicals. This layer of the domain is applied only on parent chemicals.
2. Structural domain - it is represented by list of atom - centered fragments extracted from the chemicals in the training set. The training chemicals were split into two subsets: chemicals correctly predicted by the model and incorrectly predicted
chemicals. These two subsets of chemicals were used to extract characteristics determining the "good" and "bad" space of the domain. Extracted characteristics were split into three categories: unique characteristics of correct and incorrect chemicals (presented only in one of the subsets) and fuzzy characteristics presented in both subsets of chemicals. Structural domain is applied on parent chemicals, only.
3. Mechanistic domain - in SS model it includes: Interpolation space: this stage of the applicability domain of the model holds only for chemicals for which an additional COREPA model is required. It estimates the position of the target chemicals in the population density plot built in the parametric space defined by the explanatory variables of the model by making use the training set chemicals. Currently, the accepted threshold of population density is 10%.
The mechanistic domain is applied on the parent structures and on their metabolites.

- Appropriate measures of goodness-of-fit and robustness and predictivity:
External Validation: For substances in the applicability domain, a predictivity of 100% was found for 100 industrial chemicals for the distinction of non-sensitizers versus sensitizers of GHS Category 1. The evaluation has been published in W. Teubner, A. Mehling, P.X. Schuster, K.Guth, B. A. Worth, J. Burton, B. van Rawenzwaay, R. Landsiedel: Computer models versus reality: How well do in silico models currently predict the sensitization potential of a substance, Regulatory Toxicology and Pharmacology 67 (2013) 468-485

Statistics for goodness-of-fit: For 875 chemicals, the TIMES-SS model was able to predict correctly 90% of the strong sensitizers, 55% of the weak sensitizers and 77% of the non-sensitizers, i.e., an overall performance of 78 %. Sensitivity: 78 %, Specificity: 77 %

- Mechanistic interpretation:
The TIMES-SS (Tissue Metabolism Simulator for skin sensitization) model integrates a simulator of skin metabolism together with a number of “local” QSAR models for assessing the reactivity of specific alerts. A skin metabolism simulator was developed based on empirical and theoretical knowledge (not enough reported observed skin metabolism data). The transformation probabilities (defining the priority of their execution) were parameterized to reproduce skin sensitization data. The simulator comprises of about 420 transformations, which can be divided into four main types: abiotic transformations, covalent interaction with proteins, Phase I and Phase II reactions. Autoxidation (AU) of chemical is also accounted for. Interactions with skin proteins are grouped into three types: leading to strong or weak skin
sensitization effect and interactions requiring QSAR models to quantify the potency of sensitization of the alerting groups. The QSAR models were developed by the COmmon PAttern Recognition (COREPA) approach [3]. The skin sensitization model predicts skin sensitization effect in three classes: strong, weak and non-sensitizers.
Reliability of alerts in the TIMES-SS model has been also evaluated to provide transparent mechanistic reasoning for predicting sensitization potential. Alert performance was defined as the ratio between the number of correct (positive and negative) predictions and the total number of chemicals within the local training set that triggered the alert. The alert performance was assessed based on the predictions on parents, autoxidation products simulated by the external AU simulator and metabolites as simulated by the skin metabolism simulator embedded in TIMES-SS model. Four different categories of reliability were defined:
High reliability – alert performance higher than 60% and more than 5 chemical in local (transformation/alert) training set
Low reliability – performance less than 60% and more than 5 chemicals in training set
Undetermined reliability – less than 5 chemicals in training set
Undetermined (theoretical) – there are no chemicals supporting the alert in the local training set

5. APPLICABILITY DOMAIN
- Descriptor domain:
Log(Kow): range = [ -13.2 .. 15.4 ]
calculated: 3.71 (In domain)
MOL._WEIGHT: range = [ 30 .. 738 ]Da
calculated: 158Da (In domain)
--> Conclusion: The chemical fulfils the general properties requirements.

- Structural fragment domain: The following ACF are identified: Fragments in correctly predicted training chemicals – 100.00%, Fragments in non-correctly predicted training chemicals – 0.00%, Fragments not present in the training chemicals – 0.00%
--> Conclusion: The chemical is in the interpolation structural space

- Mechanistic domain: Interpolation space
- Similarity with analogues in the training set: not reported

6. ADEQUACY OF THE RESULT
The substance falls in the applicability domain of the model. The model was found to give reliable predictions for industrial chemicals. It is therefore considered to be acceptable for REACH.

The substance is considered to be non skin seniziting.

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: REACH guidance on QSARs R.6, May/July 2008

Principles of method if other than guideline:

TIMES-SS v.2.27.19.13 - Skin sensitization with autoxidation v.21.26 (structure-toxicity and structure-metabolism relationships)

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-propylheptan-1-ol

EC Number:

233-126-1

EC Name:

2-propylheptan-1-ol

Cas Number:

10042-59-8

Molecular formula:

C10H22O

IUPAC Name:

2-propylheptan-1-ol

Results and discussion

In vitro / in chemico

Results

Key result

Remarks on result:

no indication of skin sensitisation

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The registrant considers this predication as valid because TIMES-SS was validated with 100 substances from the registrant's portfolio (Teubner et al., Regulatory Toxicology and Pharmacology 67 (2013) 468–485). All predictions that fullfilled all domain requirements were correct (Specificity 100%).

The QSAR program calculated a negative sensitization potential of the test substance. The substance is in domain of the system.