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Description of key information

Key value for chemical safety assessment

Skin sensitisation

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

To assess sensitisation potential of reaction mass of isomers of: C7 -C9 -alkyl 3 -(3,5 -di-tert-butyl-4hydroxyphenyl) propionate the following sensitisation studies on the related substances were used:

A Dermal Sensitisation Study in Guinea Pigs conducted with Butyl 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoate (CAS No. 52449 -44 -2) (Modified Buehler Design)

In the present GLP sensitisation study performed according to the EPA sensitisation guideline OPTTS 870.2600, 10 Hartley-derived albino guinea pigs per sex were treated with 100% w/v test substance (Patterson, 2000; Report No. 3263.247). Scores of zero in all test animals were obtained in the challenge phase at all time points examined. 1-chloro-2,4-dinitrobenzene (DNCB) served as positive control substance. Following challenge with DNCB, all DNCB test animals were noted to have a substantially stronger dermal response than was observed in the corresponding DNCB control animals. Group mean dermal scores were also noted to be higher in the DNCB test animals as compared to those of the DNCB control animals. Based on the results of this study, the test material is not considered to be a contact sensitizer in guinea pigs. The results of the DNCB positive control study demonstrated that a valid test was performed and indicated that the test design would detect potential contact sensitizers.

Skin Sensitisation to the Guinea- Pig (Magnusson & Kligman) conducted with Butyl 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoate (CAS No. 52449-44-2)

The GLP OECD guideline study was performed to assess the skin sensitisation potential of test material using guinea pigs with the maximisation method described by Magnusson and Kligman (Coleman, 2000; Report No. 040/002777/SS).According to the study protocol, 20 young healthy female animals were used for the test group. 10 animals served as control group.The dose levels for the study were chosen on the basis of a preliminary study in compliance with the guidelines. The main study consisted of two phases: induction and challenge.

During the induction phase, the test material was administered to test animals by intradermal injection at concentrations of 1% (v/v) in Alembicol D (which served as vehicle) or 1% v/v in a 50:50 mixture of Freund's complete adjuvant and Alembicol D. This concentration was the highest concentration that caused irritation but did not adversely affect the animals. One week later, neat test material was administered topically to the same skin area of test animals and was left for 48 hours occlusively covered. During the induction phase, the control animals were treated similarly to the test animals with the exception that the test substance was omitted from the intradermal injections and topical application. The dermal reactions to the intradermal injections were recorded after 24 hours following the injections and the reactions to the induction topical application were recorded after removal of the bandages. During the challenge phase, the control and test animals were treated topically two weeks after the topical induction application using test material, as supplied and 50% v/v in Alembicol D. The challenge sites were evaluated approximately 24 and 48 hours after removal of the patches.

There were no positive controls included in the present study. However, the sensitivity of test system is checked periodically at the test facility. In such a positive control study, conducted short before the main study, positive control substance hexyl cinnamic aldehyde (HCA) produced evidence of skin sensitisation (delayed contact hypersensitivity) in nine of the ten animals tested, thus confirming the sensitivity and reliability of the experimental technique.

After challenge exposure to the test material, there were no dermal reactions seen in any of the test or control animals at all time points examined. The test material did not produce evidence of skin sensitisation (delayed contact hypersensitivity) in any of the twenty test animals. The test material is not considered to have the potential to cause skin sensitisation.

 

Local Lymph Node Assay in the Mouse conducted with (Benzenepropanoic acid, 3,5 -bis(1,1 -dimethylethyl)-4 -hydroxy-,2 -ethylhexylester (CAS No. 144429 -84 -5)

A study was performed to assess the skin sensitisation potential of the test material in the CBA/Ca strain mouse following topical application to the dorsal surface of the ear (Local Lymph Node Assay) (Sanders, 2007; Report No. 0525/0756). The method was designed to meet the requirements of the OECD guideline 429 and EU Method B.42. Following a preliminary screening test, three groups, each of five animals, were treated with 50 µL (25 µL per ear) of the undiluted test material or the test material as a solution in acetone/olive oil 4:1 at concentrations of 25% or 50% v/v. A further group of five animals was treated with acetone/olive oil 4:1 alone. A stimulation index of less than 3 was recorded for the three concentrations of the test material. In a positive control study, which is routinely conducted at the test facility, two concentrations of a-Hexylcinnamaldehyde, Tech, 85% induced a more than threefold increase in 3HTdR incorporation compared to control values. The study demonstrated an appropriate performance of the assay and competency of the laboratory to successfully conduct the assay. The test material was considered to be a non-sensitiser under the conditions of the test.

Prediction of skin sensitisation potential by the OECD QSAR Toolbox

The chemical benzenepropanoic acid, 3,5-bis(1,1-dimethylethyl)-4-hydroxy-, C7-9-branched alkyl esters (CAS 125643-61-0) was evaluated by the QSAR OECD Toolbox software for its skin sensitisation potential. The prediction was based on the measured values of chemicals assigned into the category. The experimental data for the related chemicals butyl 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoate (CAS 52449 -44 -2) and benzenepropanoic acid, 3,5-bis(1,1-dimethylethyl)-4-hydroxy-,2-ethylhexylester(CAS 144429 -84 -5) were added in the software manually and together with data of other structurally similar analogues were used for the read-across.

The target chemical was classified as "Phenols, Esters" by the profiling method "Aquatic toxicity classification by ECOSAR ". Therefore, at first the chemicals with the same classification were searched. 122 chemicals (inclusive manually added data of two chemicals) were assigned into the category. There were several chemicals in the category for which data were available for the investigated endpoint. These chemicals were scanned for their differences to the target and thereafter the category was refined eradicating chemicals with different characteristics relevant for skin sensitisation. In this manner, the chemicals were eliminated which were structurally dissimilar to the target (the threshold was set at 50 -60%). The same chemicals were different regarding their bioavailability potential (by Lipinski Rule OASIS). The selected 4 neighbour chemicals which were used for read-across represent the same class of chemicals and exhibit negative skin sensitisation potential.

 

Prediction of skin sensitisation potential by the TOXTREE modelling tool (v2.1.0)

The chemical structure of the C9 -representative of the reaction mass of isomers was assessed by the Toxtree (v.2.1) modelling tool for its skin sensitisation potential. The chemical nonyl-3(3,5 -ditert-butyl-4 -hydroxyphenyl)propanoate is estimated to be negative for skin sensitisation potential. The test substance is not an electrophile reactive. No structural alerts are identified for the possibility of nucleophilic substitution, Schiff base formation or addition-elimination reactions. There are no functional groups which can act as Michael acceptors.

 


Migrated from Short description of key information:
The sensitisation studies available for the related substances of reaction mass of isomers of: C7 -C9 -alkyl 3 -(3,5 -di-tert-butyl-4hydroxyphenyl) propionate do not indicate sensitisation potential of test material. In both a Modified Buehler Test and a Maximisation Test, no dermal reactions at any time point examined were observed in the test animals after challenge exposure to the test material. In the Local Lymph Node Assay, a stimulation index of less than 3 was recorded for all concentrations tested. Opposite to this, the positive control substances which are routinely tested at the test facilities induced a clear positive response in all three sensitisation studies, confirming the sensitivity of the assays and reliability of experimental techniques. Furthermore, skin sensitisation potential of the target substance was predicted negative by the OECD QSAR Toolbox and Toxtree modelling tool.

Justification for selection of skin sensitisation endpoint:
The most recent study available.

Justification for classification or non-classification

The overall weight of evidence allows to conclude that the target chemical is not skin sensitizer. In accordance to Directive 67/548/EEC and EU CLP (Regulation (EC) No. 1272/2008), this substance does not meet the criteria for classification and labelling as a skin sensitizer.