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EC number: 243-424-3 | CAS number: 19910-65-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Description of key information
Key value for chemical safety assessment
Skin sensitisation
Link to relevant study records
- Endpoint:
- skin sensitisation: in vitro
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- April 15-19, 2018
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 442D (In Vitro Skin Sensitisation: ARE-Nrf2 Luciferase Test Method)
- Version / remarks:
- February 2015
- Deviations:
- no
- GLP compliance:
- yes
- Type of study:
- activation of keratinocytes
- Justification for non-LLNA method:
- Non animal test method -OECD approved. Activation of keratinocytes by the Induction of Antioxidant-
Response-Element Dependent Gene Activity and Cytotoxicity (Using MTT) in the Keratinocyte ARE
Reporter Cell Line provides an in vitro procedure used for supporting the discrimination between skin
sensitizers and non sensitizers in accordance with the UN GHS.
According to REACH, In vivo methods can only be used if the in chemico or in vitro test methods are
not adequate for the substance or cannot be used for classification and risk assessment - Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
-Source and lot/batch No of test material: Sponsor Lot No. 17121B3105
-Expiration date of the lot/batch:27 November 2018
Purity test date:10 February 2018
Purity:99.3%
Appearance:Clear colorless non-viscous liquid
Storage condition of test material:-15to -25 degrees celcius - Details on the study design:
- Test system
The Induction of Antioxidant-Response-Element Dependent Gene Activity and Cytotoxicity (Using
MTT)
in the Keratinocyte ARE-Reporter Cell Line KeratinoSens skin sensitization assay is a
high-throughput cell based in vitro test to screen for the skin sensitization potential of chemicals.
The KeratinoSens cells (Givaudan, Switzerland) were propagated as a reporter cell line. The
KeratinoSens cells are transfected HaCaT keratinocytes that include a 56-base-pair insertion
containing
the ARE sequence from the AKR1C2 gene, a SV40 promoter, the luciferase gene in the vector pGL4
from Promega, and a stable insertion allowing for cells to be selected in the presence of Geneticin
(G418).
The signalling pathway with the repressor protein Keap1 and the transcription factor Nrf2, which binds
to the antioxidant / electrophile response element (ARE / EpRE), was shown to be a valuable cellular
endpoint to detect skin sensitizers in vitro. The induction of luciferase directly indicates the activation
of ARE dependent genes.
Cytotoxicity of a test article was assessed using cell MTT (3-[4,5 - dimethylthiazol-2-yl] - 2,5 - diphenyl
tetrazolium bromide). Cytotoxicity was determined by measuring the relative conversion of MTT
in test article-treated cultures compared to the solvent control at 570nm absorbance.
Experimental Design
The experimental design of this study consisted of three definitive assays to determine the maximal
induction (Imax), the concentration for maximal gene induction (CImax), the EC1.5 value (concen
tration for a statistically significant induction of 50% above solvent controls),
and a mean IC50 (concentration leading to 50% viability as compared to solvent controls) for the test
articles. For each
definitive assay, the KeratinoSens cells were cultured in quadruplicate plates for 24 hours, treated
with the test articles for 48 hours, and assessed for luciferase induction (3 plates) and cytotoxicity
(1 plate). The procedures that were performed in this assay were a modification of the procedures
previously described by Natsch, et al. (2008) and were performed similar to those procedures perfo
rmed by the Institute for In Vitro Sciences, Inc. in the KeratinoSens ring-study .
The Induction of Antioxidant-Response-Element Dependent Gene Activity and Cytotoxicity (Using M
TT) in the Keratinocyte ARE- Reporter Cell Line KeratinoSens Assay was performed to determine the
skin sensitization potential of the test articles, supplied by AkzoNobel.
The laboratory phase of this study was conducted from 15 to 19 April 2018 at the Institute for In
Vitro Sciences, Inc. (IIVS).
Evaluation of Test Results
A test article was predicted to have sensitization potential if:1) The EC1.5
value fell below 1000 μM or 200 μg/ml in at least 2 of 3 repetitions; 2) At the lowest concentration
with a gene induction above 1.5, cellular viability was greater than 70%; and 3) There was apparent
overall dose response which was similar between repetitions. - Positive control results:
- The positive control cinnamic aldehyde had an EC 1.5 of <4 μM and IC50 of >64μM.
- Key result
- Run / experiment:
- other: Mean of 3 definitive runs
- Parameter:
- other: EC 1.5 Value (uM)
- Value:
- 2 000
- Vehicle controls validity:
- valid
- Negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Remarks on result:
- other: Gene fold induction above the solvent control There was no induction above 1.5 and cytotoxicity was greater than 70%
- Other effects / acceptance of results:
- Criteria for Determination of a Valid Definitive Assay
The KeratinoSens assay was accepted when the positive control (cinnamic aldehyde) caused an
EC1.5 value that fell within two standard deviations of the historical mean. Additionally, the results
of the three definitive trials for each plate are assessed using similar criteria outlined in the validation
ring trial . Those acceptance criteria included: 1) variability in DMSO solvent control wells for each
definitive assay was <20%; and 2) the positive control produced a statistically significant induction
above 1.5 fold below 64 μM in each definitive assay. - Interpretation of results:
- GHS criteria not met
- Remarks:
- DPRA and H-CLAT still in progress
- Conclusions:
- Based on the data from The Induction of Antioxidant-Response-Element Dependent Gene Activity and Cytotoxicity (Using MTT) in the Keratinocyte ARE- Reporter Cell Line KeratinoSens assay, the test article Di-sec-butyl peroxydicarbonate was predicted to be a skin non-sensitizer.
- Executive summary:
The Induction of Antioxidant-Response-Element Dependent Gene Activity and Cytotoxicity (Using MTT) in the Keratinocyte ARE- Reporter Cell Line KeratinoSens was used to assess the skin sensitization
potential of the test article, Di-sec-butyl peroxydicarbonate (Lot# 17121B3105). The skin sensitization potential of the test article was evaluated using the protocol that is consistent with the OECD Test Guideline 442D “In VitroSkin Sensitisation: ARE-Nrf2 Luciferase Test Method”[1]. Based upon the results of this study, the test article, Di-sec-butly peroxydicarbonate (Lot# 17121B3105) was classified as a skin non sensitizer.
[1] OECD Test Guideline 442D “In VitroSkin Sensitisation: ARE-Nrf2 Luciferase Test Method)”, Adopted 4 February 2015.
- Endpoint:
- skin sensitisation, other
- Remarks:
- QSAR Prediction of Skin Sensitisation potential
- 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, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
- Justification for type of information:
- 1. SOFTWARE
2. MODEL
DEREK Nexus v.6.0.1; 2018
Biovia Discovery Studio (TOPKAT); 2018
VEGA-QSAR v.1.1.4; 2017
OECD QSAR Toolbox v.4.2; 2018
Danish QSAR database (which includes Leadscope, CASE Ultra and SciQSAR models); 2016
ACD / ToxSuit v2.95
With respect to the prediction of Skin Sensitisation, TOPKAT, DEREK, VEGA and the OECD Toolbox were used.
3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
CCC(C)OC(=O)OOC(=O)OC(C)CC
4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
5. APPLICABILITY DOMAIN
6. ADEQUACY OF THE RESULT
QMRF and QPRF are included in the attached QSAR report. - Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- - Software tool(s) used including version:
DEREK Nexus v.6.0.1; 2018
Biovia Discovery Studio (TOPKAT); 2018
VEGA-QSAR v.1.1.4; 2017
OECD QSAR Toolbox v.4.2; 2018
- Model description: see field 'Justification for non-standard information', 'Attached justification'
- Justification of QSAR prediction: see field 'Justification for type of information', 'Attached justification' - Parameter:
- other: No quantitative result was obtained. Refer to "Any other information on results", below
- Remarks on result:
- not measured/tested
- Interpretation of results:
- study cannot be used for classification
Referenceopen allclose all
The test article, Di-sec-butyl peroxydicarbonate was tested in three definitive assays. Each definitive
assay included a
set of 4 plates (3 for gene induction, 1 for cytotoxicity assessment). The test article, was
tested at 12 concentrations ranging from 0.977 to 2000 μM. The positive control, Cinnamic Aldehyde,
was tested at 5 concentrations ranging from 4 to 64 μM. A summary of the EC1.5 (concentration
for a statistically significant induction of 50% above solvent controls) and IC(concentration leading to
50% viability as compared to solvent controls) results of the definitive assays are presented in Table
1. Additional luciferase induction information (which was not used for the current prediction model) that
includes the Imax(the maximal fold induction) and the CImax(the concentration at which the maximal
fold induction occurs), is also presented . A summary graph representing the luciferase fold induction
and the cell viability for each tested concentration of the test article is included .
A test article was predicted to have sensitization potential if: 1) The EC1.5 value fell below 1000 in at
least 2 of 3 repetitions; 2) At the lowest concentration with a gene induction above 1.5, cellular viability
was greater than 70%; and 3) There was an apparent overall dose response which was similar between
the three definitive assays.
According to the current prediction model, the test article, Di-sec-butyl peroxydicarbonate was predicted
to be a non sensitizer.
Individual model predictions were as follows:
TOPKAT: Strong sensitiser (with zero instance of "features unknown or out of range")
DEREK: Plausible (Alert: 406, Acyl Peroxide); same results under "Certain" category
VEGA: Non-sensitiser (low reliability)
OECD QSAR Toolbox: Substance profiling did not indicate a mechanistic basis for skin sensitising potential; however, the Automated Workflow for Skin Sensitiser feature predicted it to be positive for sensitisation based on data on the category member, CAS#16111 -62 -9, which is a Cat 1B skin sensitiser.
The skin sensitising potential of di-sec-butyl peroxydicarbonate (the test substance) was predicted to be positive by TOPKAT, DEREK and the OECD QSAR Toolbox (Automated Workflow approach). The VEGA QSAR model predicted the substance to be a non-sensitiser to the skin, but with a low reliability. By weight of evidence, it was concluded that the substance is a skin sensitiser. However, it cannot be ruled out that the effects noted might also be linked to reaction by-products between the test substance and molecules present in the skin.
Justification for classification or non-classification
A weight-of-evidence assessment of four QSAR models used to assess the sensitisation potential of di-sec-butyl peroxydicarbonate concluded that the substance is likely to be a sensitiser. An available OECD422D study (Keratinosens) concluded that the substance did not show any indication of sensitising activity. Additional in-vitro sensitisation studies (specifically a DPRA study and an h-CLAT study) are currently underway, however the results are not currently available.
It is considered that the available data do not permit a conclusive assessment of the sensitising potential of di-sec-butyl peroxydicarbonate. Although the QSAR data indicates possible sensitising potential, when considered alongside thw negative Keratinosens assay it is the registrant's conclusion that this is not sufficient to apply a classification for sensitisation. This conclusion will be revisited after the results of furhter testing become available.
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