N,N'-hexane-1,6-diylbis[3-(3,5-di-tert-butyl-4-hydroxyphenylpropionamide]

Skin sensitisation

Administrative data

Endpoint:

skin sensitisation, other

Remarks:

QSAR analysis with OASIS TIMES

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.

Justification for type of information:

1. SOFTWARE
TIMES-SS 2.27.19.13

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

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
CC(C)(C)c1cc(CCC(=O)NCCCCCCNC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
QMRF attached

5. APPLICABILITY DOMAIN
The structure falls to 88.89% within the domain of the model

6. ADEQUACY OF THE RESULT
The result (negative) is used in a weight of evidence approach in combination with a negative prediction by the OECD toolbox and based on structures with similar functional groups.

Data source

Reference

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: REACH guidance on QSAR R.6

Principles of method if other than guideline:

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

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

N,N'-hexane-1,6-diylbis[3-(3,5-di-tert-butyl-4-hydroxyphenylpropionamide]

EC Number:

245-442-7

EC Name:

N,N'-hexane-1,6-diylbis[3-(3,5-di-tert-butyl-4-hydroxyphenylpropionamide]

Cas Number:

23128-74-7

Molecular formula:

C40H64N2O4

IUPAC Name:

N,N'-hexane-1,6-diylbis[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propanamide]

Results and discussion

In vivo (LLNA)

Results

Parameter:

other:

Remarks on result:

no indication of skin sensitisation based on QSAR/QSPR prediction

Any other information on results incl. tables

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 sensitization potential of the test substance. The substance is not entirely in domain of the system.