Registration Dossier
Registration Dossier
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EC number: 939-719-8 | CAS number: 5502-75-0
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics
- Type of information:
- (Q)SAR
- Adequacy of study:
- supporting study
- Study period:
- 2013
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Accepted calculation method
- Justification for type of information:
- QSAR prediction: migrated from IUCLID 5.6
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
Materials and methods
- Objective of study:
- metabolism
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- In vitro model: The metabolism training set contains experimentally observed (documented) in vitro metabolic pathways for 261 parent chemicals of a wide structural diversity, and 1070 observed metabolites compiled into a searchable electronic database. Published data on the metabolism of these chemicals in rodent (mostly rat) liver microsomes and S9 fraction, collected mainly from research publications in scientific journals and, also, from some websites were extracted and introduced into an electronic database. In vivo model: The metabolism training set contains experimentally observed (documented) in vivo metabolic pathways for 647 structurally different parent chemicals, and 4382 observed metabolites compiled into a searchable electronic database. Published data on the in vivo metabolism of these chemicals in rodents (mostly rats) collected mainly from research publications in scientific journals and from some websites were extracted and introduced into an electronic database.
- GLP compliance:
- no
Test material
- Reference substance name:
- [(1r,4r)-4-(propan-2-yl)cyclohexyl]methanol; [(1s,4s)-4-(propan-2-yl)cyclohexyl]methanol
- EC Number:
- 939-719-8
- Cas Number:
- 5502-75-0
- Molecular formula:
- C10H20O
- IUPAC Name:
- [(1r,4r)-4-(propan-2-yl)cyclohexyl]methanol; [(1s,4s)-4-(propan-2-yl)cyclohexyl]methanol
- Test material form:
- not specified
- Details on test material:
- - Name of test material (as cited in study report): Mayol
Constituent 1
- Radiolabelling:
- no
Test animals
- Species:
- rat
- Strain:
- not specified
- Sex:
- not specified
Administration / exposure
- Route of administration:
- other: In Silico rodent metabolic simulator
- Vehicle:
- unchanged (no vehicle)
- Duration and frequency of treatment / exposure:
- Not applicable: In Silico rodent metabolic simulator
Doses / concentrations
- Remarks:
- Doses / Concentrations:
Not applicable: In Silico rodent metabolic simulator
- No. of animals per sex per dose / concentration:
- Not applicable: In Silico rodent metabolic simulator
- Control animals:
- no
Results and discussion
- Preliminary studies:
- Not applicable: In Silico rodent metabolic simulator
Toxicokinetic / pharmacokinetic studies
- Details on absorption:
- Not applicable: In Silico rodent metabolic simulator
- Details on distribution in tissues:
- Not applicable: In Silico rodent metabolic simulator
- Details on excretion:
- Not applicable: In Silico rodent metabolic simulator
Metabolite characterisation studies
- Metabolites identified:
- yes
- Details on metabolites:
- TIMES in vitro Rat Liver S9 v.06 simulator: Three Phase I metabolites and four Phase II metabolites are generated.
TIMES in vivo Rat Liver S9 v. 03 simulator: Three Phase I metabolites and six Phase II metabolites are generated.
Bioaccessibility (or Bioavailability)
- Bioaccessibility (or Bioavailability) testing results:
- Not applicable: In Silico rodent metabolic simulator
Any other information on results incl. tables
Table 1. Metabolites generated by In vitro Rat Liver S9 v.06
Generated metabolite (the substance): SMILES |
Type of reactions |
C(C)(C)(O)C1CCC(CO)CC1 |
Aliphatic C-oxidation |
C(C)(C)C1CCC(C=O)CC1 |
Aliphatic C-oxidation |
C(=O)(O)C1CCC(C(C)C)CC1 |
Aliphatic C-oxidation |
C(=O)(O)C1C(O)C(O)C(O)C(OCC2CCC(C(C)C)CC2)O1 |
O-Glucoronidation |
C(=O)(O)C1C(O)C(O)C(O)C(OC(=O)C2CCC(C(C)C)CC2)O1 |
O-Glucoronidation |
C(C)(C)(O)C1CCC(COC2C(O)C(O)C(O)C(C(=O)O)O2)CC1 |
O-Glucoronidation |
C(C)(C)(C1CCC(CO)CC1)OC1C(O)C(O)C(O)C(C(=O)O)O1 |
O-Glucoronidation |
Table 2. Metabolites generated by In vivo Rat Liver v.03
Generated metabolite (the substance): SMILES |
Type of reactions |
C(C)(C)(O)C1CCC(CO)CC1 |
Aliphatic C-oxidation |
C(C)(C)C1CCC(C=O)CC1 |
Aliphatic C-oxidation |
C(=O)(O)C1CCC(C(C)C)CC1 |
Aliphatic C-oxidation |
C(=O)(O)C1C(O)C(O)C(O)C(OCC2CCC(C(C)C)CC2)O1 |
O-Glucoronidation |
C(=O)(O)C1C(O)C(O)C(O)C(OC(=O)C2CCC(C(C)C)CC2)O1 |
O-Glucoronidation |
C(C)(C)(O)C1CCC(COC2C(O)C(O)C(O)C(C(=O)O)O2)CC1 |
O-Glucoronidation |
C(C)(C)(C1CCC(CO)CC1)OC1C(O)C(O)C(O)C(C(=O)O)O1 |
O-Glucoronidation |
C(=O)(C1CCC(C(C)C)CC1)NCC(=O)O |
Amino Acid conjugation |
C(C)(C)C1CCC(COS(=O)(=O)O)CC1 |
Sulfation |
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): no data
TIMES in vitro Rat Liver S9 v.06 simulator: Three Phase I metabolites and four Phase II metabolites are generated.
TIMES in vivo Rat Liver S9 v. 03 simulator: Three Phase I metabolites and six Phase II metabolites are generated. - Executive summary:
The metabolism of the substance was predicted using the Tissue Metabolism Simulator (TIMES) tool (Laboratory of Mathematical Chemistry). The results indicate rapid oxidative metabolism for the substance, as follows:
TIMES in vitro Rat Liver S9 v.06 simulator: Three Phase I metabolites and four Phase II metabolites are generated.
TIMES in vivo Rat Liver S9 v. 03 simulator: Three Phase I metabolites and six Phase II metabolites are generated.
The three Phase I metabolites are predicted both in vitro and in vivo to be the results of aliphatic C-oxidation:
C(C)(C)(O)C1CCC(CO)CC1
C(C)(C)C1CCC(C=O)CC1
C(=O)(O)C1CCC(C(C)C)CC1
Phase II metabolites include O-glucuronidation metabolites.
Expert analysis confirmed that all generated metabolites are credible. Also most of the generated Phase I and O-Glucuronidation metabolites are in coherence with the observed metabolites of the analogue structure of L-menthol (Yamaguchi, et al., 1994; Miyazawa, et al., 2011). The in vivo Sulfation and Amino acid Conjugation Phase II metabolites although not documented are believed to occur by expert judgment.
References
Miyazawa, M. et al., 2011. Metabolism of (+) and (-) Menthols by CYP2A6 in Human Liver Microsomes. J OLEO SCI, 60(3), pp. 127-132.
Yamaguchi, T., Caldwell, J. & Farmer, P., 1994. Metabolic Fate of [3H]-l-Menthol in the Rat. DRUG METAB DISPOS, 22(4), pp. 616-624.
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