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EC number: 822-547-1 | CAS number: 906673-54-9
A DEREK assessment, DPRA assay and KeratinoSensTM assay were performed:.
DEREK NEXUS version 6.0.1 did not yield any alerts for skin sensitization for PF06932437.
In the DPRA assay, the test item did not show significant binding to cysteine and/or lysine moieties.However, since precipitation of the test item was seen during the test, this negative result is uncertain and should be interpreted with caution.
In the KeratinoSens assay, PF-06932437 did not activate the anti-oxidant/electrophile responsive element (ARE) dependent pathway in keratinocytes) in a KeratinoSens
TM assay. Performance of a U-SENSTM assay was omitted, as cytotoxicity and precipitation are expected at test concentrations, which would lead to an inconclusive or positive result.
Taking all data together, the in silico, in chemico and in vitro data do not allow final
conclusion on the skin sensitizing properties of PF-06932437. It is therefore recommended to
perform an in vivo test.
The objective of this study was to evaluate whether PF-06932437 induces skin sensitization in mice after three epidermal exposures of the animals under the conditions described in this study plan. The study was carried out based on the guidelines described in: OECD, Section 4, Health Effects, No.429 (2010), EC No 640/2012, Part B: "Skin Sensitization: Local Lymph Node Assay" EPA, OPPTS 870.2600 (2003) “Skin Sensitization”. Test item concentrations selected for the main study were based on the results of a pre-screen test. At a 25% and 50% test item concentration, no to very slight erythema and no signs of toxicity were noted. Variation in ear thickness during the observation period slightly exceeded 25% from Day 1 pre-dose values for one animal at 50% on Day 6. Since the results of the ear thickness measurements were not conclusive, 50% was selected as the highest concentration to be used in the main study and ear thickness measurements were added to the main study for the 50% concentration.
In the main study, three experimental groups of five female CBA/J mice were treated with test item concentrations of 10, 25 or 50% w/w on three consecutive days, by open application on the ears. Five vehicle control animals were similarly treated, but with the vehicle alone (N,N-dimethylformamide). Three days after the last exposure, all animals were injected with 3H-methyl thymidine and after five hours the draining (auricular) lymph nodes were excised and pooled for each animal. After precipitating the DNA of the lymph node cells, radioactivity measurements were performed. The activity was expressed as the number of disintegrations per minute (DPM) and a stimulation index (SI) was subsequently calculated for each group.
The very slight erythema as noted for the animals treated at 25% and 50% between Days 2 and 6 was considered not to have a toxicologically significant effect on the activity of the nodes. White test item remnants were present on the dorsal surface of the ears of the animals treated at 25% and 50% between Days 1 and 4, which did not hamper scoring of the skin reactions. Variation in ear thickness during the observation period were less than 25% from Day 1 predose values for all animals. No mortality occurred and no clinical signs of systemic toxicity were observed in the animals of the main study. Body weights and body weight gain of experimental animals remained in the same range as controls over the study period. The majority of auricular lymph nodes were considered normal in size, except for the nodes of three animals treated at 10%, two animals treated at 25% and two animals treated at 50%, which were considered to be enlarged. No macroscopic abnormalities of the surrounding area were noted for any of the animals.
Mean DPM/animal values for the experimental groups treated with test item concentrations 10, 25 and 50% were 911, 834 and 833 DPM, respectively. The mean DPM/animal value for the vehicle control group was 557 DPM. The SI values calculated for the test item concentrations 10, 25 and 50% were 1.6, 1.5 and 1.5, respectively.
Since there was no indication that the test item elicits a SI ≥ 3 when tested up to 50%, PF06932437 was not considered to be a skin sensitizer. It was established that the EC3 value (the estimated test item concentration that will give a SI =3) (if any) exceeds 50%. The six-month reliability check with Alpha-hexylcinnamaldehyde indicates that the Local Lymph Node Assay as performed at Charles River Den Bosch is an appropriate model for testing for contact hypersensitivity. Based on these results, PF-06932437 would not be regarded as a skin sensitizer according to the recommendations made in the test guidelines. The test item does not have to be classified and has no obligatory labelling requirement for sensitization by skin contact according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all amendments) and the Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).
The objective of this study was to evaluate the ability of PF-06932437 to activate the antioxidant/electrophile responsive element (ARE)-dependent pathway in the KeratinoSens assay. The study procedures described in this report were based on the most recent OECD guideline. Batch GR12302 (groten) / BFPB31711001 (suven) of PF-06932437 was an off-white powder. A correction factor of 1.013 was used to correct for the purity (98.7%). PF-06932437 was dissolved in dimethyl sulfoxide at 200 mM. From this stock 11 spike solutions in DMSO were prepared. The stock and spike solutions were diluted 100-fold in the assay resulting in test concentrations of 0.98 - 2000 µM (2-fold dilution series). The highest test concentration was the highest dose required in the current guideline. The test item precipitated at dose levels of 250 µM and upwards. Three independent experiments were performed. All experiments passed the acceptance criteria: The luciferase activity induction obtained with the positive control, Ethylene dimethacrylate glycol, was above the threshold of 1.5-fold in at least one concentration. The EC1.5 of the positive control was between 5 and 125 µM (122 µM, 63 µM and 80 µM in experiment 1, 2 and 3, respectively). A dose response was observed in all experiments and the induction at 250 µM was higher than 2-fold in 2 out of 3 experiments (2.20-fold and 2.14-fold in experiment 1 and 3, respectively). Finally, the average coefficient of variation of the luminescence reading for the vehicle (negative) control DMSO was below 20% (5.8%, 11.9% and 3.9% in experiment 1, 2 and 3, respectively). Overall it is concluded that the test conditions were adequate and that the test system functioned properly. PF-06932437 showed toxicity in all experiments (IC30 values of 153 µM, 93 µM and 27 µM and IC50 values of 180 µM, 117 µM and 59 µM in experiment 1, 2 and 3, respectively). In the first experiment an induction of the luciferase activity was measured (EC1.5 value of 72 µM). In experiment 2 and 3 no biologically relevant induction of the luciferase activity (no EC1.5 value) was measured at any of the test concentrations. The maximum luciferase activity induction (Imax) was 1.94-fold, 0.99-fold and 1.44-fold in experiment 1, 2 and 3, respectively. PF-06932437 is classified as negative in the KeratinoSensTM assay since negative results (<1.5-fold induction) were observed in 2 out of 3 experiments at test concentrations up to 2000 µM. In conclusion, PF-06932437 is classified as negative (no activation of the antioxidant/electrophile responsive element (ARE)-dependent pathway in keratinocytes) under the experimental conditions described in this report.
The objective of this study was to determine the reactivity of PF-06932437 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 photodiode array (PDA) detection at 220 nm and 258 nm. SPCC and SPCL Percent Depletion Values were calculated and used in a prediction model which allows assigning the test item to one of four reactivity classes used to support the discrimination between sensitizers and non-sensitizers. The study procedures described in this report were based on the most recent OECD guideline. Acetonitrile (ACN) 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, i.e. calibration curve, mean concentration of Reference Control (RC) samples A and C, 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 item, were all within the acceptability criteria for the DPRA. Upon preparation as well as after incubation of the SPCC and SPCL test item samples, a precipitate/phase separation was observed.
In the cysteine reactivity assay the test item showed 1.5% SPCC depletion while in the lysine reactivity assay the test item showed 7.1% SPCL depletion. The mean of the SPCC and SPCL depletion was 4.3% 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.
In conclusion, since all acceptability criteria were met this DPRA is considered to be valid. PF-06932437 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. However, since precipitation/phase separation was observed after the incubation period for both SPCC and SPCL, one cannot be sure how much test item remained in the solution to react with the peptides. Consequently, this negative result is uncertain and should be interpreted with due care.
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