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Description of key information

The test substance is assumed to be not skin sensitising, as deduced from a QSAR calculation and data on the structural analog isotridecanol

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in chemico
Remarks:
other: Calculation
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The QSAR result meets the conditions listed in REACH (EC 1906/2006) ANNEX XI 1.3.
Qualifier:
according to
Guideline:
other: REACH guidance on QSARs R.6, May/July 2008
Principles of method if other than guideline:
TIMES-SS 2.27.13 - Skin sensitization v. 18.21 with autoxidation (structure-toxicity and structure-metabolism relationships)
GLP compliance:
no
Type of study:
other: Calculation QSAR
Remarks on result:
no indication of skin sensitisation

TIMES-SS model aims to encode structure toxicity and structure metabolism relationships

through a number of transformations simulating skin metabolism and interaction of the

generated reactive metabolites with skin proteins. The skin metabolism simulator mimics

metabolism using 2D structural information. The autoxidation (abiotic oxidation) of

chemicals is also accounted for. A training set of diverse chemicals was compiled and their

skin sensitization potency assigned to one of three classes. These three classes were Strong,

Weak or Non sensitizing. The skin sensitization model was built as a composite of the

following submodels: 1. Skin metabolism Simulator: This mimics the metabolic fate of

parent chemical controlled by skin enzymes and thus the potential formation of protein

adducts with reactive agents. 2D structural information of parent chemicals is used to model

metabolism. Metabolic pathways are generated based on a set of hierarchically ordered

principal transformations including spontaneous reactions, enzyme-catalyzed Phase I and

Phase II drug metabolism reactions, and reactions with protein nucleophiles. The formation

of macromolecular immunogens was used to identify probable structural alerts in parent

chemicals or their metabolites. 2. COREPA (COmmon Pattern Recognition approach) 3D

QSARs for intrinsic reactivity of compounds having substructures associated with activity.

These models depend on both the structural alert and the rate of skin sensitization. Steric

effects around the active site, molecular size, shape, solubility, lipophilicity and electronic

properties are taken into account. These models generally may involve combinations of

molecular parameters or descriptors, which trigger (“fire”) the alerting group. A quantitative

structure-activity relationship (QSAR) system for estimating skin sensitization potency has

been developed which incorporates skin metabolism and considers the potential of parent

chemicals and/or their activated metabolites to react with skin proteins. The autoxidation

(abiotic oxidation) of chemicals is also accounted for. A training set of diverse chemicals was

compiled and their skin sensitization potency assigned to one of three classes. These three

classes were Strong, Weak or Non sensitizing.

The applicability domain of TIMES-SS model consists of the following layers:

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 (from 30 to 737 Da, in this study) and log Kow (from -13.2 to 15.4, in this study)

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 the 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. The target structure is also partitioned into atom-centered

fragments and when they present in the list of extracted atom-centered fragments from

the training set chemicals and satisfy the accepted thresholds the chemical is

categorized as belonging to the structural domain. The default thresholds for

classifying of chemicals to the structural domain of the current skin sensitization

model are:

· All extracted fragments to belong to the "good" domain ("Correct" = 100%)

· All fuzzy fragments are considered as part of the "good" domain

· No fragments belonging to "bad" domain ("Incorrect" = 0%)

· No unique fragment ("Unknown" = 0%)

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. The accepted threshold of population density in the

current study is 10%. Chemicals with values below 10% are "Out of domain".

"N/A" is assigned when this type of sub-domain is not relevant to the structure and

will be not accounted in the total domain. "Unknown" is referred for the cases

when some parameters could not be calculated by any reason or for chemicals with

equivocal predictions (not reaching the probability threshold of the COREPA

model and reported in TIMES as Can't predict).

The mechanistic domain is applied on the parent structures and on their metabolites.

In order to belong to the model domain a target structure must meet the requirements of all the

domain layers.

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 sensitizing potential of the test substance. The substance is in domain of the system.

Interpretation of results:
GHS criteria not met
Conclusions:
The QSAR program calculated a negative sensitizing potential of the test substance. The substance is in domain of the system.
Endpoint:
skin sensitisation: in chemico
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Read-across based on mechanistic considerations and structural similarity
Qualifier:
no guideline available
Principles of method if other than guideline:
Analogue substances are primarily sought based on mechanistic considerations, i.e. structural alerts for protein binding. The group of mechanistic analogues may then be subcategorized by organic functional groups or empirically based on chemical elements or structural similiarity.
GLP compliance:
no
Key result
Remarks on result:
no indication of skin sensitisation

The substance is considered a non sensitizer based on read across to the following substances:

 CAS Number  Substance Name
 3913-02-8

 2-butyloctan-1-ol

 3452-97-9

 3,5,5-trimethylhexan-1-ol

      

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

QSAR predictions for the target substance with either OASIS Times or the OECD toolbox both gave negative predictions for the skin sensitizing potential of C13-C15, alcohols, branched and linear. This matches the expectations for this group of chemical. For a substance to be a skin sensitizer it has to have the ability to react with proteins in the skin to form a covalent bond by reactions such as Michael-type reactions, SN2 reactions, SNAr reactions, acylation reactions and Schiff-base formation. However, as the only reactive group present is an alcohol, these reactions are not expected to occur.

This is supported by the short summary available of an intradermal assay in guinea pigs performed with CAS 27458 -92 -0 (BIBRA 1988). A group of 20 guinea pigs received an unspecified number of intradermal injections of a 1% mixture of the test substance (70% branched chain primary isomers of tridecanol and 30% pentadecanol) in liquid paraffin. One week later a 5% solution was topically applied (probably covered, 48 hr). A topical challenge with 0.1% of the same mixture in liquid paraffin (probably covered, 48 hr) given 2 weeks later produced no reactions.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the available information the substance does not need to be classified for skin sensitisation, as in accordance with EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation No. 1272/2008.