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EC number: 700-261-7 | CAS number: 4427-96-7
Toxicological information
Endpoint summary
Administrative data
Link to relevant study record(s)
- 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:
ADME Profiles Predicted results Probability Interpretation Absorption Human Intestinal Absorption + 0.9939 HIA+ Human oral bioavailability + 0.6143 HOB+ Caco-2 - 0.5306 Caco2- P-glycoprotein inhibitior - 0.9852 Non-inhibitor P-glycoprotein substrate - 0.9763 Non-substrate Distribution Blood Brain Barrier + 0.7750 BBB+ Plasma protein binding 26.4% - Plasma protein binding 26.4% Subcellular localzation Mitochondria 0.7600 Mitochondria Metabolism CYP1A2 inhibition - 0.7519 Non-inhibitor CYP2C19 inhibition - 0.7920 Non-inhibitor CYP2C9 inhibition - 0.9309 Non-inhibitor CYP2C9 substrate - 0.6172 Non-substrate CYP2D6 inhibition - 0.8800 Non-inhibitor CYP2D6 substrate - 0.7507 Non-substrate CYP3A4 inhibition - 0.9452 Non-inhibitor CYP3A4 substrate - 0.6672 Non-substrate CYP inhibitory promiscuity - 0.8768 Low 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:
ADME Profiles Predicted results Unit Interpretation Absorption Pgp-inh 0.0 - Non-inhibitor Pgp-sub 0.001 - Non-substrate HIA 0.004 - 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 -4.543 log cm/s The predicted Caco-2 permeability is excellent (> -5.15 log cm/s). MDCK 0.00018 cm/s The predicted MDCK permeability is excellent (> 2E-05 cm/s). Distribution BBB 0.998 - The predicted of BBB penetration is more than 0.1 cm/s (BBB+). PPB 28.06% - The predicted Plasma protein binding is excellent (<= 90%). VD 0.659 L/kg The predicted Volume Distribution is excellent (0.04-20 L/kg). Fu 73.60% - The predicted Fraction unbound in plasms is > 20% (High Fu). Metabolism CYP1A2-inh 0.089 - Non-inhibitor CYP1A2-sub 0.298 - Non-substrate CYP2C19-inh 0.057 - Non-inhibitor CYP2C19-sub 0.645 - Non-substrate CYP2C9-inh 0.011 - Non-inhibitor CYP2C9-sub 0.152 - Non-substrate CYP2D6-inh 0.008 - Non-inhibitor CYP2D6-sub 0.611 - Non-substrate CYP3A4-inh 0.132 - Non-inhibitor CYP3A4-sub 0.314 - Non-substrate Excretion CL 8.31 ml/min/kg The clearance of target chemical is moderate clearance (5-15 ml/min/kg). T1/2 0.848 - The predicted T1/2 > 3h
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