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EC number: 955-147-1 | CAS number: 2755813-36-4
- 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
Skin sensitisation
Administrative data
- Endpoint:
- skin sensitisation: in chemico
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 27th October 2021 to 17th November 2021
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 021
- Report date:
- 2021
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 442C (In Chemico Skin Sensitisation Assays addressing the Adverse Outcome Pathway key event on covalent binding to proteins)
- GLP compliance:
- yes
- Type of study:
- direct peptide reactivity assay (DPRA)
- Justification for non-LLNA method:
- The objective of this study was to determine the reactivity of PF-07336591-02 towards model synthetic peptides containing either cysteine or lysine, and to categorize the test item in one of four classes of reactivity for supporting the discrimination between skin sensitizers and nonsensitizers.
Test material
- Reference substance name:
- Sodium (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate
- EC Number:
- 955-147-1
- Cas Number:
- 2755813-36-4
- Molecular formula:
- C8 H12 Na N O2
- IUPAC Name:
- Sodium (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate
- Test material form:
- solid
Constituent 1
In chemico test system
- Details of test system:
- cysteine peptide, (Ac-RFAACAA-COOH)
- lysine peptide (Ac-RFAAKAACOOH)
- Details on the study design:
- Preparation of Test Item
A correction factor of 1.148 was used to correct for purity/composition of the test item. Concentrations are expressed as active ingredient. Solubility of the test item in an appropriate solvent was assessed before performing the DPRA. An appropriate solvent dissolved the test item completely, i.e., by visual inspection the solution had to be not cloudy nor have noticeable precipitate. The following solvents were evaluated: acetonitrile (ACN), milli-Q water (MQ) and ACN:MQ (1:1, v/v).
The dissolution of the test item in the SPCC and SPCL assay buffers was also evaluated by diluting the test item stock solution in the buffer based incubation mixtures. For the SPCC assay, a 20-fold dilution was prepared by mixing one volume of the test item stock solution with fifteen volumes of phosphate buffer pH 7.5 and four volumes of ACN. For the SPCL assay, a 4-fold dilution was prepared by mixing one volume of the test item stock solution with three volumes of ammonium acetate buffer pH 10.2. The presence of cloudiness, precipitate and/or phase separation was evaluated by visual inspection to aid solvent selection for the main study.
Test item stock solutions were prepared freshly for each reactivity assay. For both the cysteine and lysine reactivity assays 31.33 mg of test item was pre-weighed into a clean amber glass vial and dissolved, just before use, in 1540 uL ACN:MQ (1:1, v/v) after vortex mixing to obtain a 100mM solution. Visual inspection of the clear solution being formed was considered sufficient to ascertain that the test item was dissolved. The test item, positive control and peptide samples were prepared less than 4 hours before starting the incubation of the cysteine (cys) or lysine (lys) reactivity assay, respectively. Any residual volumes were discarded.
Sample Incubations
After preparation, the samples (reference controls, calibration solutions, co-elution control, positive controls and test item samples) were placed in the autosampler in the dark and incubated at 25+2.5°C. The incubation time between placement of the samples in the autosampler and analysis of the first RCcysB- or RClysB-sample was 24.1 hours. The time between the first RCcysB- or RClysB-injection and the last injection of a cysteine or lysine sequence did not exceed 30 hours.
Prior to HPLC analysis the samples were visually inspected for precipitation.
HPLC Analysis
SPCC and SPCL peak areas in the samples were measured by HPLC. Sample analysis was performed using the following systems:
System 1 (used for Cysteine Reactivity Assay):
Alliance separations module 2695 (Waters, Milford, MA, USA)
Dual absorbance detector 2487 (Waters)
System 2 (used for Lysine Reactivity Assay):
Alliance separations module 2695 (Waters, Milford, MA, USA)
Dual absorbance detector 2487 (Waters) - Vehicle / solvent:
- acetonitrile
- Positive control:
- cinnamic aldehyde
Results and discussion
- Positive control results:
- The mean Percent SPCC Depletion for the positive control cinnamic aldehyde was 70.6% + 0.3%. This was within the acceptance range of 60.8% to 100% with a SD that was below the maximum (SD <14.9%).
The mean Percent SPCL Depletion for the positive control cinnamic aldehyde was 60.5% + 0.03%. This was within the acceptance range of 40.2% to 69.0% with a SD that was below the maximum (SD <11.6%).
In vitro / in chemico
Resultsopen allclose all
- Key result
- Group:
- test chemical
- Run / experiment:
- mean
- Parameter:
- mean lysine depletion
- Value:
- 0.8 %
- Positive controls validity:
- valid
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Group:
- test chemical
- Run / experiment:
- mean
- Parameter:
- mean cystein depletion
- Value:
- 8.6 %
- Positive controls validity:
- valid
- Remarks on result:
- no indication of skin sensitisation
- Other effects / acceptance of results:
- The following criteria had to be met for a run to be considered valid:
a) The standard calibration curve had to have a r?>0.99.
b) The mean Percent Peptide Depletion value of the three replicates for the positive control cinnamic aldehyde had to be between 60.8% and 100% for SPCC and between A0.2% and 69.0% for SPCL.
c) The maximum standard deviation (SD) for the positive control replicates had to be <14.9% for the Percent Cysteine Peptide Depletion and <11.6% for the Percent Lysine Peptide Depletion.
d) The mean peptide concentration of Reference Controls A had to be 0.50 + 0.05 mM.
e) The Coefficient of Variation (CV) of peptide peak areas for the nine Reference Controls B and C in ACN had to be <15.0%.
The following criteria had to be met for a test item’s results to be considered valid:
a) The maximum SD for the test item replicates had to be <14.9% for the Percent Cysteine Depletion and <11.6% for the Percent Lysine Depletion.
b) The mean peptide concentration of the three Reference Controls C in the appropriate solvent had to be 0.50 + 0.05 mM.
Applicant's summary and conclusion
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- In conclusion, this DPRA test is valid. PF-07336591-02 was negative in the DPRA and was classified in the “no or minimal reactivity class” when using the Cysteine 1:10 / Lysine 1:50 prediction model.
- Executive summary:
The objective of this study was to determine the reactivity of PF-07336591-02 towards model synthetic peptides containing either cysteine (SPCC) or lysine (SPCL). After incubation of the test item with either SPCC or SPCL, the relative peptide concentration was determined by High-Performance Liquid Chromatography (HPLC) with gradient elution and spectrophotometric detection at 220 nm and 258 nm. SPCC and SPCL Percent Depletion Values were calculated and used in a prediction model which assigns the test item to one of four reactivity classes used to support the discrimination between sensitizers and nonsensitizers.
The study procedures described in this report were based on the most recent OECD 442C guideline.
Acetonitrile (ACN):milli-Q water (MQ) (1:1, v/v) was found to be an appropriate solvent to dissolve the test item and was therefore used in this Direct Peptide Reactivity Assay (DPRA) study.The validation parameters, 1.e., calibration curve, mean concentration of Reference Control (RC) samples A, C and Cacn:moa, the CV for RC samples B and C, the mean percent peptide depletion values for the positive control with its standard deviation value and the standard deviation value of the peptide depletion for the test 1tem, were all within the acceptability criteria for the DPRA as stated in the OECD 442C guideline.
Upon preparation as well as after incubation of the SPCC and SPCL test item samples, no precipitate or phase separation was observed in any of the samples.
An overview of the individual results of the cysteine and lysine reactivity assays as well as the mean of the SPCC and SPCL depletion are presented in the table below. In the cysteine reactivity assay the test item showed 8.6% SPCC depletion while in the lysine reactivity assay the test item showed 0.8% SPCL depletion. The mean of the SPCC and SPCL depletion was 4.7% and as a result the test item was considered to be negative in the DPRA and classified in the “no or minimal reactivity class” when using the Cysteine 1:10 / Lysine 1:50 prediction model.Test Item SPCC depletion SPCL depletion Mean of SPCC and SPCL depletion DPRA prediction and reactivity classification Mean +/- SD Mean +/- SD Cysteine 1:10 / Lysine 1:50 prediction model PF-07336591-02 8.6% +/- 1.3% 0.8% +/- 0.7% 4.7% Negative: No or minimal reactivity In conclusion, as all acceptability criteria were met this DPRA is considered to be valid.
PF-07336591-02 was negative in the DPRA and was classified in the “no or minimal reactivity class” when using the Cysteine 1:10 / Lysine 1:50 prediction model.
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