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EC number: 251-649-3
CAS number: 33704-61-9
Skin sensitisation: skin sensitiser (1B) based on testing in an OECD TG 429
Respiratory sensitisation: The substance is not a respiratory sensitiser in absence of human data.
LLNAA Local Lymph Node Assay (OECD TG 429) was performed to determine the sensitising potential of Cashmeran in mice. Groups of 5 mice were treated with the undiluted Cashmeran or Cashmeran at concentrations of 50% or 25% v/v in acetone/olive oil 4:1.α-Hexylcinnamaldehyde, freshly prepared as a 25% v/v dilution in acetone/olive oil 4:1, was used as positive control. Clinical observations and bodyweights were recorded and lymph node proliferation was determined using 3HTdR incorporation. The number of radioactive disintegrations per minute (dpm) reflect the proliferation response of lymph node cells, and were 2295.90, 6168.85, 8413.63, and 8073.27 mean dpm/animal for the 0%, 25%, 50%, and 100% concentration groups, respectively. This corresponds with a lymph node proliferation of 2.69, 3.66 and 3.52, respectively, for the Cashmeran-treated groups, calculated as the Stimulation Index (SI). A limited dose effect concentration is derived. No mortality and no signs of systemic toxicity were observed. No effects on bodyweight (gain) were observed. An EC3 value (the concentration of test item expected to cause a 3 -fold increase in 3HTdR incorporation) of 33% was calculated. Under the conditions of this study, a maximum SI of 3.66 was calculated. Considering the SI threshold of 3 as stated in Annex I of 1272/2008/EC, the substance needs to be classified as sensitiser for concentrations ≥ 33%. Based on the absence of effects at the lowest concentration tested, a NOEC of 25% could be established.
In a human Repeated Insult Patch test according to a modified Shelanski - Shelanski human patch test method, 120 human subjects (male/female) were treated on the (cleaned) upper back to 10% (w/w) of the test article in EtOH:DEP (1:3) with an occlusive patch for 24 hours (0.2 ml on 3.63 m2 patch). This was repeated 9 times on Monday, Wednesday and Friday during the induction period. Sites were graded for dermal irritation 24 hours after removal of the patches on Tuesday and Thursday and 48 hours after removal on Saturday. After a 2-week rest period challenge patches were applied on untreated test sites for 24 hours. Dermal irritation was evaluated 0, 24 and 48 hours after removal of the patches. An extra assessment was done after 96 hours in case of reactions. Six volunteers discontinued study participation for reasons unrelated to the test material. In the remaining 106 human volunteers no adverse skin reactions were observed after repeated induction (9 times) followed by one challenge patch. Therefore it can be concluded that the test article does not induce sensitization up to that 10% concentration, under the conditions of this test.
Three in vitro tests were performed with the test substance (SENS-IS, h-CLAT and KeratinoSens), a consise summary of each test is given below.
SENS-ISIn a non-GLP study, the aim was to assess the potential of the test products to specifically induce the expression of irritation and/or sensitzation biomarkers in an in vitro 3D skin model SENS-IS test. The test is based on analysis by RT-PCR of two sets of genes, the test item and the controls are tested in at least two experiments (with different batched of EpiSkin models). For each experiment, the controls were used according to the protocol and the experiment was analysed if the controls were correctly classified. The results were assessed using evaluation and acceptance criteria. Test item was tested pure, dissolved in OO at 50% v/v and 10% v/v. For all three tested concentration, the test item was found to be positive for irritation. The test item was found to be positive for sensitization at pure and 50% v/v concentrations, negative for 10%v/v. The test performed in 10% DMSO was negative. It was concluded that the test substance is a weak sensitizer.
h-CLATThe potential of test substance to induce the cell membrane markers CD86 and CD54 expression was evaluated in the Human Cell Line Activation Test (h-CLAT) (OECD 442E in accordance with GLP). A non-GLP pre-test was performed to determine suitable concentrations. The CV75 value (i.e. a concentration showing 75% of THP-1 cell survival (25% cytotoxicity) was determined for the main experiments to be 54 μg/mL (experiment 1) and 51 μg/mL (experiment 2), respectively. After 24 hours of exposure to test substance, CD54 expression was induced in THP-1 cells affording at least 50% viability in at least two independent experiments. The CD86 expression was induced in the borderline range in experiment 1, only. From this it was to be concluded that test substance 6,7-Dihydro-1,1,2,3,3-pentamethyl-4(5H)-indanone induces dendritic cell activation.
Keratino SensThe skin sensitisation potential of test substance was assessed in a high throughput cell based in vitro test with KeratinoSens Cells. The experiment was designed to determine the maximum induction (Imax), the concentration for maximal gene induction (Cimax), the EC1.5 value, and mean IC50 for the test substance. The test substance was tested in three valid assays, each including a set of 4 plates (3 for gene induction, 1 for cytotoxicity assessment) and a valid positive control was included. Test results were evaluated with Evaluation and acceptance criteria. The EC1.5 value for the test item was (µM) was >2000, the mean IC50 (µM) MTT was 107.56 and therefore the substance was predicted to be non-sensitizer.
The substance is not a respiratory sensitiser in absence of human data indicating such effects. In addition, the respiratory sensitisation is assessed using the integrated evaluation strategy for respiratory sensitisation data in the ECHA guidance (R7A, Fig. 7.3-4, 2017).
1) The substance is a skin sensitiser;
2) The substance does not belong to the di-isocyanates;
3) The substance has no structural alerts or is structurally related to chemicals causing respiratory sensitisation as presented in Table R.7.3-1 in the ECHA guidance of 2008 or those provided in the following document: http://ec.europa.eu/health/scientific_committees/docs/annex6_respiratory.pdf. Therefore, the substance is not considered to be a respiratory sensitiser.
There are no standard tests for assessing respiratory sensitisation. This endpoint can still be assessed using the ITS strategy in the REACH guidance. Following this strategy Cashmeran is not a respiratory sensitiser.
Based on the available information, the substance needs to be classified for skin sensitisation as Skin Sens. 1B, H317 based on the criteria of EU-CLP (1272/2008 and its amendments).
Based on the available information, the substance does not need to be classified for respiratory sensitisation based on the criteria of EU-CLP (1272/2008 and its amendments).
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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