(5R,6S)-allyl 6-((R)-1-(tert-butyldimethylsilyloxy)ethyl)-7-oxo-3-(propylthio)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Skin sensitisation

Administrative data

Endpoint:

skin sensitisation, other

Remarks:

Qsar in silico prediction

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Study period:

2018

Reliability:

1 (reliable without restriction)

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:

1. SOFTWARE:
DEREK NEXUS

2. MODEL (INCL. VERSION NUMBER)
DEREK NEXUS Lhasa edition

3. SMILES OR OTHER INDENTIFIERS USED AS INPUT FOR THE MODEL
CAS NUMBER: (5R, 6S)-allyl-6-((R)-1-(tert-butyldimethylsilyloxy)ethyl)-7-oxo-3-(propylthio)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

4.SCIENTIFIC VALIDITY OF THE QSAR MODEL
This above mentioned tool was selected according to the OECD Guidance Documents on the VAlidation of (Q)SAR models:
-Document on the Validation of (Quantitative) Structure Acitivity Relationship models. OECD Series on testing and Assessment Nà69 ENV/JM/MONO (2007)2.
- Enoch SJ, Madden J.C, Cronin M.T.(2008),Identification of mechanism of toxic action for skin sensitisation using a SMARTS pattern based approach, SAR QSAR Envir Res., 19(5-6):555-78

5.APPLICABILITY DOMAIN
-DEREK NEXUS: the prediction is generated by applying expert knowledge rules in toxicology

6. ADEQUACY OF THE RESULT
Derek Nexus: Skin sensitisastion is plausible

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: OECD Series on testing and assessment n.69

Version / remarks:

ENV/JM/MONO(2007)2

Deviations:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

(5R,6S)-allyl 6-((R)-1-(tert-butyldimethylsilyloxy)ethyl)-7-oxo-3-(propylthio)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

EC Number:

820-260-6

Cas Number:

93603-76-0

Molecular formula:

C20H33NO4S2Si

IUPAC Name:

(5R,6S)-allyl 6-((R)-1-(tert-butyldimethylsilyloxy)ethyl)-7-oxo-3-(propylthio)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Results and discussion

In vitro / in chemico

Results

Parameter:

other: QSAR prediction is not an in vitro study

Remarks on result:

other: QSAR prediction skin sensitiser

In vivo (non-LLNA)

Results

Reading:

other: QSAR it is not an in vivo study

Remarks on result:

other: QSAR prediction skin sensitiser

In vivo (LLNA)

Results

Parameter:

other: QSAR it is not an in vivo study

Remarks on result:

other: QSAR prediction Skin sensitiser

Any other information on results incl. tables

This study was designated to generate estimated "in silico" data to be used for the hazard assessment of the substance.

the table below shows the result obtained:

ENDPOINT	DEREK NEXUS PREDICTION
SKIN SENSITISATION	PLAUSIBLE

Skin sensitisation: murine local lymph node assay (LLNA), guinea pig maximisation test (GPMT), human maximisation patch test Potential mechanism: Hapten acting as an electrophilic acylating agent [Aptula and Roberts] Fused beta-lactam molecules based on the penicillin (II) and cephalosporin (III) scaffold have demonstrated sensitisation in the LLNA, GPMT and human maximisation patch test. The most studied compound is penicillin G (benzylpenicillin) which has displayed activity in the LLNA [Ashby et al], GPMT [Kristofferson et al] and human maximisation patch test [Kligman].

Two additional penicillins [Kristofferson et al] and seven cephalosporin-based antibiotics [Hattori et al] have also shown activity in the GPMT, examples include cephalothin and flomoxef. In support of toxicophore (I) unfused beta-propiolactone is classified as a strong sensitiser in the LLNA [Ashby et al]. In exposed human populations, sensitisation to penicillin was reported in 21 out of 333 nurses [Rudzki et al 1989a] and 8 out of 107 pharmaceutical workers [Rudzki et al 1989b] with occupational dermatitis. In their role as antibiotics, beta-lactams are electrophilic acylating agents that undergo ring-opening [Page and Laws] and are expected to promote skin sensitisation through the formation of adducts with skin proteins through a similar mechanism. Whilst fused beta-lactam systems (II, III) are inherently reactive due to distorted amide bond geometries, unfused monolactams possess comparable hydrolysis rates to acyclic amides [Washkuhn and Robinson]. Conversely, beta-lactones (I) are highly reactive acylating agents [Perez-Prior et al]. The scope of this alert has been defined to include fused lactam and unfused lactone molecules with positive LLNA, GPMT or human patch test results. beta-Lactam containing pharmaceuticals conforming to toxicophores II and III have been designed to be efficient acylating agents. Features that promote reactivity include an electron withdrawing substituent positioned at C3 [Boyd et al] or a leaving group at 3' in cephalosporins [Boyd, Perez-Inestrosa et al]. Sulphoxides, sulphones or ethers attached to C4 also promote reactivity [Mulchande et al] with tazobactam reported to produce a moderate sensitising response in the LLNA [ECHA 2008]. Additionally clavulanic acid was responsible for a case of occupational contact dermatitis in one subject [Kim et al] but did not produce a positive response in the LLNA up to 50%, despite exhibiting dose-related responses [ECHA 2013]. Thioxocephalosporin [Tsang et al] demonstrated similar reactivity to cephalosporin Derek Nexus Prediction Report and therefore thio-analogues of penicillins and cephalosporins are included in the alert. Unfused beta-lactams are excluded from this alert based on their lack of reactivity, but unfused betalactones (I) [Perez-Prior et al] and beta-thioxolactones are inherently reactive and therefore are included with the scope of this alert.

Applicant's summary and conclusion

Interpretation of results:

Category 1 (skin sensitising) based on GHS criteria

Conclusions:

skin sensitisation:

Prediction : plausible

Executive summary:

The skin sensitisation of the target compound was predicted employing an in silico approach: the decision rule system provided by Derek Nexus.

The predictor was employed in order to apply a weight of evidence approach. In the case of the target PF-598 Derek Nexus predicted the skin sensistisation as plausible.