Disodium sebacate

Endpoint summary

Description of key information

In a pre-guideline/pre-GLP skin sensitisation study in guinea pig sebacic acid challenged animals showed mild responses to sensitization. The substance was characterized with a slight sesitization potential. The OASIS TIMES QSAR Models predicts no sensitization poential for sebacic acid.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

Skin sensitisation in guinea pigs via intradermal injection of the test substnace for induction (seven doses) and challenge.

GLP compliance:

not specified

Remarks:

pre-GLP

Type of study:

intracutaneous test

Justification for non-LLNA method:

The LLNA was not established at that time.

Species:

guinea pig

Strain:

Hartley

Sex:

male

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Sweetwater Farms

Route:

intradermal

Vehicle:

peanut oil

Concentration / amount:

0.1%

Day(s)/duration:

15 days

Adequacy of induction:

other: 7 injections of the test substance evenly distributed over 15 days

No.:

#1

Route:

intradermal

Vehicle:

peanut oil

Concentration / amount:

0.1 %

Day(s)/duration:

48 h

Adequacy of challenge:

other: injection of the test substance

No. of animals per dose:

20

Details on study design:

Twenty male albino guinea pigs were used to test the sensitizing potential of the materials. The sensitization test was started on a Monday when the guinea pigs were weighed and closely clipped on the scapular areas. The material (0.05 mL of a 0.1% dilution in peanut oil) was injected intradermally into the upper right scapular area of each pig. A similar injection of peanut oil alone into the upper left scapular area served as a control site. Readings were made 24 and 48 hours later. Doses of 0.1 mL of the same dilutions (freshly prepared) were injected into the clipped dorsal lumbo-sacral areas of the guinea pigs on the following Wednesday, Friday, Monday, etc., until seven doses were administered. Care was taken to insure that the repeated doses were not injected into the same site. The guinea pigs were rested for three weeks (incubation period), weighed and given a challenge dose of 0.05 mL of the 0.1% dilution of the test material into the lower right scapular area. A control injection of the vehicle alone was also administered into the lower left scapular area at this time. The reactions were read after 24 and 48 hours.

Key result

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

0.1 %

No. with + reactions:

3

Total no. in group:

20

Remarks on result:

other: No. of sensitized animals were not given in the report. Highest number of sensitized animals in the corresponding category was chosen.

Sebacic acid caused a mild sensitization response (final grades per animal: 26 -99) and was categorized as a substance with "slight" sensitization potential. According to the applied scoring system, this refers to 1 - 3 animals out of 20 with mild reactions (final grade per animal > 26, according to the corresponding grading system).

Interpretation of results:

study cannot be used for classification

Reference 2

Endpoint:

skin sensitisation, other

Remarks:

calculation

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

accepted calculation method

Qualifier:

according to guideline

Guideline:

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

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

Type of study:

other: Calculation QSAR

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 ategorized 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.

Interpretation of results:

GHS criteria not met

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

In a pre-GLP sensitisation study guinea pigs were intradermally treated with sebacic acid (1x 0.05 ml, then 7x 0.1 ml of a 0.1 % peanut oil solution) at the scapular region and after an incubation period of 3 weeks, the animals were challenged with 0.05 ml of a 0.1 % peanut oil solution) at the lumosacral area. Readings were done 24 and 48 h after the very first and the challenge injection. Sebacic acid caused a "mild" sensitization response and was categorized as a substance with "slight" sensitization potential (1 -3 animals out of 20 with mild sensitization response).

The intradermal application during induction and challenge in the reported study is much more sensitising than the epidermal application according to OECD guideline 406. An only mild sensitization response in 1 - 3 animals out of 20 (<= 15 %) was observed after this severe application procedure without adjuvans. Therefore, according to current standard, a classification is not required.

As the QSAR program OASIS TIMES additionally calculated a negative sensitization protential, it was concluded that a classification for sebacic acid as skin sensitising is not required according to Annex I of Directive 1272/2008 (EU-GHS).

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The available data are reliable and suitable for classification purposes under Regulation 1272/2008. In an experimental study with sebacic acid a slight sensitization potential was reported. The method used in the cited study is much more sensitive than the epidermal application according to OECD Guideline 406 (17.07.1992). As a result the substance is not considered to be classified for sensitisation under Regulation (EC) No. 1272/2008, as amended for the ninth time in (EC) No. 2016/1179. This is confirmed by the QSAR Model OASIS TIMES, which gave a negative prediction regarding skin sensitization for sebacic acid.