Sebacic acid

Endpoint summary

Description of key information

There were only slightly sensitizing effects observed in Hartley guinea pigs after dermal administration during a pre-GLP skin sensitizing study.

No skin sensitizing effects are predicted by an ECHA-recommended (according to the practical guide: How to use and report (Q)SARs, Ver. 3.1, July 2016) QSAR: TIMES-SS v.2.27.19.13

The substance is not a skin sensitizer in the in vivo or in silico assay.

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:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Principles of method if other than guideline:

Skin sensitisation in guinea pigs, intradermal injection of test substance for induction (seven doses) and challenge.

GLP compliance:

no

Remarks:

pre-GLP

Type of study:

intracutaneous test

Justification for non-LLNA method:

In accordance with Annex VII of EC legislation 1907/2006 in-vivo testing studies apart from murine local lymph node assay (LLNA) meet the regulatory requirements if they were carried out or initiated before 11 October 2016. The described experimental test was performed by an intradermal application during induction and challenge. This reported study is much more sensitising than the epidermal application according to OECD guideline 406 (GPMT method or Buehler test method) and meet the requirements set out in Article 13(3), first subparagraph, and Article 13(4).

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:

7 days, each at an interval of 48 h

Route:

intradermal

Vehicle:

peanut oil

Concentration / amount:

0.1 %

Day(s)/duration:

one injection

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.
The grading system is designed so that the intensity of the skin reaction is represented by a proportionate numerical value and also that any reaction elicited by the vehicle (control substance) is subtracted from the reaction elicited by the test material and vehicle combined. The product of the width and length of the wheal (in mm) is multiplied by the following reaction scores to determine a final grade:
0 = needle puncture ("np")- no wheal
1 = very faint pink ("vfp") - no value for this reaction
2 = faint pink ("fp")
3 = pink P
4 = red ("r")
5 = bright red ("R")
6 = edema - <1 mm in height ( "e")
7 = edema - >1 mm in height ("E")
*8 = necrosis - <1 sq. mm ("n")
*9 = necrosis - >1 sq. mm ("N")
*The product of the width and length of the necrotic area multiplied by 8 or 9 is added to the numerical value of the foregoing reactions that are present and calculated in the same manner.
As a characterization of the sensitizing response which may be expected from exposure to the test material, the final grade was compared with the following categories (Final Grade --> Sensitizing Response): 0-25 --> None; 26-99 --> Mild; 100-200 --> Moderate; >200 --> Severe.
The sensitizing potential of the test material is estimated from the number of animals giving a response with a final grade of at least 25. The scale for this estimation is shown below (Number Sensitized (N=20) --> Sensitizing Potential): 1-3 --> Slight; 4-10 --> Moderate; 11-20 --> Severe.

Reading:

other: overall result

Group:

test chemical

Dose level:

0.05 ml of a 0.1% dilution in peanut oil

No. with + reactions:

3

Total no. in group:

20

Interpretation of results:

GHS criteria not met

Conclusions:

The test substance 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, but positive reactions (final grade per animal >= 25).

Reference 2

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:

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
OC(=O)CCCCCCCCC(O)=O

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: 2.19 (In domain)
MOL._WEIGHT: range = [ 30 .. 738 ] Da
calculated: 202 Da (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.

Qualifier:

according to guideline

Guideline:

other: REACH guidance on QSARs R.6

Version / remarks:

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)
The QSAR is also described in the "Practical guide How to use and report (Q)SARs", Ver. 3.1, July 2016.

GLP compliance:

no

Parameter:

other: Skin sensitization with autoxidation algorithm

Remarks on result:

no indication of skin sensitisation

Remarks:

A

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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not 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 QSAR program OASIS TIMES 2.27.19.13 with its module Skin sensitization with autoxidation v.21.26 calculated a negative sensitization potential of the test substance.

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 rather not required. As the QSAR program additionally calculated a negative sensitization protential, it was concluded that a classification for sebacic acid as skin sensitising is not required.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008, as amended for the thirteenth time in Regulation (EU) No 2018/1480. As a result the substance is not considered to be classified for skin sensitization under Regulation (EC) No. 1272/2008.