Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
skin sensitisation, other
Remarks:
calculation
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
Justification for type of information:
1. SOFTWARE

OASIS TIMES v.2.27.19
Name: Skin sensitization with autoxidation
Developer: Laboratory of Mathematical Chemistry, University "Prof. Assen Zlatarov, " 1
Yakimov Str., Bourgas 8010, BULGARIA

2. MODEL (incl. version number)

Skin sensitization with autoxidation v.21.26

3. SMILES USED AS INPUT FOR THE MODEL

CCC(C)(O)C=C

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL

See attached QMRF

5. APPLICABILITY DOMAIN

i. Parameter domain:
Log(Kow):
range = [ -13.2 .. 15.4 ]
calculated: 1.58 (In domain)
MOL._WEIGHT:
range = [ 30 .. 738 ]Da
calculated: 100Da (In domain)
CONCLUSION:
The chemical fulfils the general properties requirements
ii. 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
iii. Mechanistic domain:
Interpolation space
Domain result: N/A

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2014

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 Skin sensitization with autoxidation
Model version: v. 21.26
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
3-methylpent-1-en-3-ol
EC Number:
213-044-2
EC Name:
3-methylpent-1-en-3-ol
Cas Number:
918-85-4
Molecular formula:
C6H12O
IUPAC Name:
3-methylpent-1-en-3-ol
Details on test material:
- Name of test material (as cited in study report): 3-methyl-1-Penten-3-ol
Specific details on test material used for the study:
SMILES: CCC(C)(O)C=C

Results and discussion

In vitro / in chemico

Results
Key result
Parameter:
other: QSAR
Remarks on result:
other: QSAR calculation in domain; negative

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 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 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 in domain of the system.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met