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EC number: 218-218-1 | CAS number: 2082-81-7
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics in vitro / ex vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2012
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
Materials and methods
Test guideline
- Qualifier:
- no guideline available
- Principles of method if other than guideline:
- Determination of in vitro hydrolysis rates of methacrylate esters; determination of half-lifes in rat liver microsomes and whole rat blood. determination of Km and Vmax values for ester hydrolysis in rat liver microsomes; these values were used for PBPK modeling to simulate in vivo blood concentrations
- GLP compliance:
- yes
Test material
- Reference substance name:
- Tetramethylene dimethacrylate
- EC Number:
- 218-218-1
- EC Name:
- Tetramethylene dimethacrylate
- Cas Number:
- 2082-81-7
- Molecular formula:
- C12H18O4
- IUPAC Name:
- butane-1,4-diyl bis(2-methylacrylate)
- Test material form:
- liquid
Constituent 1
- Specific details on test material used for the study:
- - Name of test material (as cited in study report): 1,4-Butanediol dimethacrylate
- Radiolabelling:
- no
Test animals
- Species:
- other: rat liver microsomes and rat blood
Administration / exposure
- Vehicle:
- DMSO
- Duration and frequency of treatment / exposure:
- phase I: 120 min (samples collected at 0, 2, 5, 15, 30, 60 and 120 minutes)
phase II: 5 min (samples collected at 0 and 5 minutes)
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0.25 other: mM
- Remarks:
- phase I
- Dose / conc.:
- 0.05 other: mM
- Remarks:
- phase II
- Dose / conc.:
- 0.1 other: mM
- Remarks:
- phase II
- Dose / conc.:
- 5 other: mM
- Remarks:
- phase II
- No. of animals per sex per dose / concentration:
- not applicable; in vitro test
- Control animals:
- other: not applicable; in vitro test
- Positive control reference chemical:
- Methyl methacrylate
- Details on dosing and sampling:
- METABOLITE CHARACTERISATION STUDIES
- Method type(s) for identification: liquid chromatography separation with accurate mass quadrupole/time-of-flight mass spectrometry detection (LC/QTOF-MS) to quantitate methacrylic acid concentrations
- Limits of detection and quantification: LLQ (phase I) = 0.0117 mM methacrylic acid; LLQ (phase II) = 0.00509 mM methacrylic acid
Results and discussion
Main ADME results
- Type:
- metabolism
- Results:
- the ester was rapidly converted to MAA in whole rat blood (Phase I) and rat liver microsomes (Pase II): half life 4.46 min (liver microsomes) / 4.10 min (blood). In phase II hydrolyses exp. 2 mol of MAA was produced for every mol 1,4-BDDMA
Any other information on results incl. tables
Negative controls in the rat liver microsome experiments included incubations with heat-inactivated microsomes, no microsomes and no NADPH. Removal of NADPH made little or no difference in hydrolysis rates. Heat inactivation significantly reduced hydrolysis rates, and absence of microsomes resulted in no hydrolysis.
1,4 -BDDMA was rapidly converted to MAA in whole rat blood and rat liver microsomes with hydrolysis half-lives of 4.46 min (liver microsomes) and 4.10 min (blood).
Vmax (in vitro) = 129 nmol/min/mg
Vmax (in vivo) = 160 mg/hr/g liver
Km (in vitro) = 83 µM
Km (in vivo) = 19 mg/L
PBPK modelling showed rapid hydrolysis of 1,4 -BDDMA.
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): other: The metabolism data and modelling results show that 1,4-BDDMA would be rapidly hydrolysed in the rat.
The metabolism data and modelling results show that 1,4-BDDMA would be rapidly hydrolysed in the rat. - Executive summary:
This in vitro metabolism study was conducted to investigate in vitro hydrolysis rates of 1,4 -BDDMA. Half-lifes were determined in rat liver microsomes and whole rat blood. Further experiments were conducted to determine Km and Vmax values for ester hydrolysis in rat liver microsomes. These values were used for PBPK modelling.
1,4 -BDDMA was rapidly converted to MAA in whole rat blood and rat liver microsomes with hydrolysis half-lives of 4.46 min (liver microsomes) and 4.10 min (blood).
Vmax (in vitro) = 129 nmol/min/mg
Vmax (in vivo) = 160 mg/hr/g liver
Km (in vitro) = 83 µM
Km (in vivo) = 19 mg/L
In summary, the metabolism data and modelling results show that 1,4-BDDMA would be rapidly hydrolysed in the rat.
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