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Toxicological information

Basic toxicokinetics

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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:
2013

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

Constituent 1
Chemical structure
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
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.