Phenoxymethylpenicillin potassium

Endpoint summary

Description of key information

The test substance is considered to be a skin sensitizer. From an occupational point of view sensitization and possible hypersensitivity reactions can occur at inhalation and dermal exposure. Furthermore it is generally accepted that especially relatively high peak concentrations can induce sensitization, and that prevention of such concentrations will prevent workers from developing respiratory allergy.
A history of a previous hypersensitivity reaction to any of the penicillins is a contraindication for the use of Penicillin V.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation, other

Remarks:

QSAR Toolbox prediction

Type of information:

calculation (if not (Q)SAR)

Adequacy of study:

supporting study

Study period:

2021

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

accepted calculation method

Justification for type of information:

results derived from the standardized workflow [see attachment]

Qualifier:

according to guideline

Guideline:

other: REACH Guidance on QSARs R.6

Version / remarks:

Software tool(s) used including version: OECD QSAR Toolbox version 4.1
- Model(s) used: automated workflow for the prediction of skin sensitisation (read-across model)
- Model description: see field 'Attached justification'
- Justification of QSAR prediction: see field 'Attached justification'

Specific details on test material used for the study:

SMILES: CC1(C)S[C@@H]2[C@@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C([OH])=O

Key result

Run / experiment:

other: other: other: other: other: Human Health Hazards -> Sensitisation -> Skin -> in Vivo -> GPMT LLNA -> EC3 Skin sensitisation

Parameter:

other: Skin sensitisation II (ECETOC)

Remarks:

Positive

Remarks on result:

positive indication of skin sensitisation

Interpretation of results:

Category 1 (skin sensitising) based on GHS criteria

Conclusions:

The automated workflow for Skin sensitization resulted in a positive indication in skin sensitisation.

Reference 2

Endpoint:

skin sensitisation: in chemico

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2 July 2019 - 17 September 2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 442C (In Chemico Skin Sensitisation: Direct Peptide Reactivity Assay (DPRA))

GLP compliance:

yes (incl. QA statement)

Type of study:

direct peptide reactivity assay (DPRA)

Specific details on test material used for the study:

Test item: Pen V Potassium
CAS No.:132-98-9
Lot No.: B519322
Appearance:White solid powder
Expiry date:30 April 2024
Purity:99.0 %
Storage: Room temperature, protected from light
Molecular mass:388.48 g/mol

Details on the study design:

The test item was formulated in a non-GLP trial forming as follows: the solubility of the test item was evaluated at the concentration of 100 mM. Acetonitrile did not dissolve the test item, it sank to the bottom of the test tube even after vortexing. Therefore, the test item was tried to be dissolved in ultrapure water and a homogenous, clear and transparent solution was formed after about 3 minutes of vortexing at 100 mM. The formulation with ultrapure water was tried to be mixed with the buffers of the test system (phosphate and acetate buffer) in a ratio corresponding to the reaction sample assembly in order to observe the compatibility of the formulation with the buffers of the test system. No precipitate was observed in any cases, homogenous solutions were gained. Since ultrapure water is the preferred vehicle after acetonitrile according to the guideline and the formulation complied with all obligations of the test guideline, it was chosen as the appropriate vehicle for the study and solubility in other vehicles was not evaluated. The pre-experiments on solubility of the test item was not performed in compliance with the GLP-Regulations and is excluded from the Statement of Compliance in the final report, but the raw data of these tests will be archived under the study code of present study.

The reactivity of a test chemical and synthetic Cysteine or Lysine containing peptides is evaluated by combining the test chemical with a solution of the peptide and monitoring the remaining concentration of the peptide following 24 hours of interaction time at room temperature. The peptide is a custom material containing phenylalanine to aid the detection and either Cysteine (“C”) or Lysine (“K”) as the reactive center. Relative concentrations of the peptides following the 24 hour incubation are determined by high performance liquid chromatography with gradient elution and UV detection at 220 nm. Reaction samples, reference controls A, B and C, co-elution controls and positive controls are prepared and analysed in triplicates in batches of up to 26 chemicals (including controls).
Steps of the DPRA Method done in chronological order
-Solubility assessment of the test chemical – ultrapure water was used as a solvent
-Preparation of buffer solutions -Pre-weighting of test chemicals and positive control
-Pre-weighting of cysteine or lysine peptide for the stock solution
-Test chemical and positive control solution preparation
-Peptide stock solution preparation -Serial dilution of standards
-Assembling of standards, reaction samples, positive controls, reference controls (A, B and C) and co-elution controls. For each set of control/sample replicates, the triplicate vials are prepared individually but from the same solutions.
-Preparation of HPLC system (column equilibration)
-HPLC analysis
-Data evaluation

HPLC system:SHIMADZU LC2030 (Prominence-i LC-2030C)
Serial number:L21445402951AE
Detector:220 nm – D2 lamp
Column: Zorbax SB-C18 (2.1 x 100 mm, 3.5 μm)
Serial number:USRY003976
Column temperature: 30°C
Sample temperature: 25°C
Injection volume: 7μL
System equilibration: 50% phase A and 50% phase B for 2 hours at 30°C and running the gradient twice before injecting the first sample
Run time:20 min
Flow conditions: gradient flow
Mobile phases for HPLC:
Mobile Phase A – 0.1 % (v/v) trifluoroacetic acid in ultra-pure water
Mobile Phase B – 0.085 % (v/v) trifluoroacetic acid in acetonitrile

Positive control results:

The mean peptide depletion value for the positive control was 61.53 %

Key result

Run / experiment:

mean

Parameter:

other: cysteine depletion (migrated information)

Value:

4.94 %

Vehicle controls validity:

valid

Negative controls validity:

not specified

Positive controls validity:

valid

Key result

Run / experiment:

mean

Parameter:

other: lysine depletion (migrated information)

Value:

15.11 %

Vehicle controls validity:

valid

Positive controls validity:

valid

Interpretation of results:

Category 1 (skin sensitising) based on GHS criteria

Conclusions:

Based on these results and thecysteine 1:10 / lysine 1:50 prediction model, the test item “Pen V Potassium” was concluded to be positive and to show low reactivity towards the synthetic peptides thus is a potential skin sensitizer under the experimental conditions of the in chemico Direct Peptide Reactivity Assay (DPRA) method.

Executive summary:

In the course of this study the skin sensitization potential of the test item “Pen V Potassium” was studied using the Direct Peptide Reactivity Assay (DPRA). For the test chemical and positive control substance, in order to derive a prediction two independent tests were conducted, one with cysteine and lysine peptides each. The results of the two valid runs were used for the classification of the test item.Peptide depletion resulted from the positive control cinnamaldehyde was 70.67 % ± 0.09 % with cysteine peptide and 52.39 % ± 0.15 % with the lysine peptide. The mean back-calculated peptide concentrations of the reference control replicates were within the expected molarity concentration range for the cysteine (0.48 – 0.51 mM) and lysine peptides (0.49 mM – 0.50 mM) and the CV % for the for the nine reference controls B and C in acetonitrile were 2.7 % and 0.4 % percentages for the cysteine and lysine peptides. For each peptide, all validity criteria were met, confirming the validity of the assay.The percent cysteine peptide depletion value of the test item was 4.94 % ± 3.83 % while the percent lysine peptide depletion was 15.11 % ± 0.48 %. The mean depletion value of the peptides was used to categorize the test chemical in one of the four classes of reactivity. No co-elution was observed with either cysteine or lysine peptides; therefore the cysteine 1:10 / lysine 1:50 prediction model was used for the discrimination between sensitizers and non-sensitizers. The mean peptide depletion of the test item was 10.03 %, which exceeded the 6.38 % threshold of the applicable prediction model and fell into the low reactivity class.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Respiratory sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

respiratory sensitisation: in vivo

Type of information:

other: Case reports from workers.

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Case reports, having only the abstracts.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Reporting of cases.

GLP compliance:

not specified

Interpretation of results:

Category 1 (respiratory sensitising) based on GHS criteria

Executive summary:

From an occupational point of view sensitization and possible hypersensitivity reactions can occur at inhalation and dermal exposure.

Reference 2

Endpoint:

respiratory sensitisation, other

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Study period:

2021

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

see attached justification

Qualifier:

according to guideline

Guideline:

other: ECHA Guidance on information requirements and chemical safety assessment - Chapter R.06: QSARs and grouping of chemicals

Species:

other: human (in vitro)

Results:

The substance is estimated to be a respiratory sensitiser

	Exp	Battery	CASE Ultra	Leadscope	SciQSAR
Respiratory Sensitisation in Humans		POS_IN	POS_IN	POS_IN	POS_IN

Conclusions:

According to the result of the Battery algorithm, applied on CASE Ultra, Leadscope Predictive Data Miner and SciQSAR models, the systematic sub‐structural analysis related to the respiratory sensitisation property of Penicillin V potassium estimated a positive activity.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Justification for classification or non-classification

Conclusive for classification as skin sensitizer and respiratory sensitizer.