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Endpoint:
basic toxicokinetics, other
Type of information:
(Q)SAR
Adequacy of study:
supporting study
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 limited documentation / justification
Justification for type of information:
1. SOFTWARE
admetSAR 2.0

2. MODEL (incl. version number)

Absorption:
Human intestinal absorption (HIA)
Human oral bioavailability (HOB)
Caco-2 permeability
Plasma protein binding (PPB)
P-glycoprotein substrate, inhibitor

Distribution:
Blood-brain barrier penetration (BBB)
Blood-placenta barrier (BPB)
Subcellular localzation

Metabolism:
Cytochrome P450 (CYP450) substrate, inhibitor
Substrate: CYP2C9, 2D6, 3A4
Inhibitor: CYP1A2, 2D6, 2C9, 2C19, 3A4

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
SMILES: C=CC1COC(=O)O1

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
[[Explain how the model fulfils the OECD principles for (Q)SAR model validation. Consider attaching the QMRF and/or QPRF or providing a link]
- Defined endpoint:

Absorption:
Human intestinal absorption (HIA)
Human oral bioavailability (HOB)
Caco-2 permeability
Plasma protein binding (PPB)
P-glycoprotein substrate, inhibitor

Distribution:
Blood-brain barrier penetration (BBB)
Blood-placenta barrier (BPB)
Subcellular localzation

Metabolism:
Cytochrome P450 (CYP450) substrate, inhibitor
Substrate: CYP2C9, 2D6, 3A4
Inhibitor: CYP1A2, 2D6, 2C9, 2C19, 3A4

- Unambiguous algorithm:
Please see the link: http://lmmd.ecust.edu.cn/admetsar2/about/models

- Defined domain of applicability:
Please see the attachment "admetSAR 2.0_supplementary_data.docx"

- Appropriate measures of goodness-of-fit and robustness and predictivity:
Please see the attachment "admetSAR 2.0_supplementary_data.docx"

- Mechanistic interpretation:
Please see the attachment "admetSAR 2.0_supplementary_data.docx"

5. APPLICABILITY DOMAIN
[Explain how the substance falls within the applicability domain of the model]
- Descriptor domain:
In admetSAR (version2), five physicochemical or topological properties are used to defined the applicability domain, which are molecular weight, AlogP, H-bond Acceptors, H-bond Donors and Rotatable Bonds. The molecular weight, AlogP, H-bond Acceptors, H-bond Donors and Rotatable Bonds of target chemical are 114.10, 0.70, 3, 0, 1, respectively.They are all fall within the applicability domain.

- Structural domain: N/A
- Mechanistic domain: N/A
- Similarity with analogues in the training set: N/A
- Other considerations (as appropriate): N/A

6. ADEQUACY OF THE RESULT
[Explain how the prediction fits the purpose of classification and labelling and/or risk assessment]

Executive summary:

































































































































ADMEProfilesPredicted resultsProbabilityInterpretation
AbsorptionHuman Intestinal Absorption+0.9939HIA+
 Human oral bioavailability+0.6143HOB+
 Caco-2-0.5306Caco2-
 P-glycoprotein inhibitior-0.9852Non-inhibitor
 P-glycoprotein substrate-0.9763Non-substrate
DistributionBlood Brain Barrier+0.7750BBB+
 Plasma protein binding26.4%-Plasma protein binding 26.4%
 Subcellular localzationMitochondria0.7600Mitochondria
MetabolismCYP1A2 inhibition-0.7519Non-inhibitor
 CYP2C19 inhibition-0.7920Non-inhibitor
 CYP2C9 inhibition-0.9309Non-inhibitor
 CYP2C9 substrate-0.6172Non-substrate
 CYP2D6 inhibition-0.8800Non-inhibitor
 CYP2D6 substrate-0.7507Non-substrate
 CYP3A4 inhibition-0.9452Non-inhibitor
 CYP3A4 substrate-0.6672Non-substrate
 CYP inhibitory promiscuity-0.8768Low CYP Inhibitory Promiscuity
Endpoint:
basic toxicokinetics, other
Type of information:
(Q)SAR
Adequacy of study:
key study
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 limited documentation / justification
Justification for type of information:
1. SOFTWARE
ADMETlab 2.0

2. MODEL (incl. version number)
ADMETlab 2.0

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
SMILES: O1C(=O)OC(C1)C=C

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
[[Explain how the model fulfils the OECD principles for (Q)SAR model validation. Consider attaching the QMRF and/or QPRF or providing a link]
- Defined endpoint:
1) Absorption:
Caco-2 Permeability, MDCK Permeability, Pgp-inhibitor, Pgp-substrate, HIA, F20%, F30%
2) Distribution:
PPB, VD, BBB Penetration, Fu
3) Metabolism:
CYP 1A2 / 2C19 / 2C9 / 2D6 / 3A4 inhibitor, CYP 1A2 / 2C19 /2C9 / 2D6 / 3A4 substrate
4) Excretion
CL, T1/2

- Unambiguous algorithm:
Multi-task graph attention (MGA) framework

- Defined domain of applicability:

- Appropriate measures of goodness-of-fit and robustness and predictivity:
Please see the attachment "ADMETlab 2.0_an integrated online platform for accurate and comprehensive predictions of ADMET properties" Table 1 and Table 2.

- Mechanistic interpretation:
Please see the attachment "ADMETlab 2.0_an integrated online platform for accurate and comprehensive predictions of ADMET properties"

5. APPLICABILITY DOMAIN
[Explain how the substance falls within the applicability domain of the model]
- Descriptor domain:
- Structural domain:
- Mechanistic domain:
- Similarity with analogues in the training set:
- Other considerations (as appropriate):

6. ADEQUACY OF THE RESULT
[Explain how the prediction fits the purpose of classification and labelling and/or risk assessment]
Specific details on test material used for the study:
SMILES: O1C(=O)OC(C1)C=C
Executive summary:

 













































































































































































ADMEProfilesPredicted resultsUnitInterpretation
AbsorptionPgp-inh0.0-Non-inhibitor
 Pgp-sub0.001-Non-substrate
 HIA0.004-The predicted human intestinal absorption is more than 30%.
 F(20%)0.038-The predicted human oral bioavailability is more than 20%.
 F(30%)0.949-The predicted human oral bioavailability is less than 30%.
 Caco-2-4.543log cm/sThe predicted Caco-2 permeability is excellent (> -5.15 log cm/s).
 MDCK0.00018cm/sThe predicted MDCK permeability is excellent (> 2E-05 cm/s).
DistributionBBB0.998-The predicted of BBB penetration is more than 0.1 cm/s (BBB+).
 PPB28.06%-The predicted Plasma protein binding is excellent (<= 90%).
 VD0.659L/kgThe predicted Volume Distribution is excellent (0.04-20 L/kg).
 Fu73.60%-The predicted Fraction unbound in plasms is > 20% (High Fu).
MetabolismCYP1A2-inh0.089-Non-inhibitor
 CYP1A2-sub0.298-Non-substrate
 CYP2C19-inh0.057-Non-inhibitor
 CYP2C19-sub0.645-Non-substrate
 CYP2C9-inh0.011-Non-inhibitor
 CYP2C9-sub0.152-Non-substrate
 CYP2D6-inh0.008-Non-inhibitor
 CYP2D6-sub0.611-Non-substrate
 CYP3A4-inh0.132-Non-inhibitor
 CYP3A4-sub0.314-Non-substrate
ExcretionCL8.31ml/min/kgThe clearance of target chemical is moderate clearance (5-15 ml/min/kg).
 T1/20.848-The predicted T1/2 > 3h

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