1-methyltrimethylene dimethacrylate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2017

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:

2017

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, i.e. 1,3-BDDMA & 1,4-BDDMA; determination of half-lifes, elimination rates and intrinsic clearance in rat liver microsomes and whole rat blood.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

1-methyltrimethylene dimethacrylate

EC Number:

214-711-0

EC Name:

1-methyltrimethylene dimethacrylate

Cas Number:

1189-08-8

Molecular formula:

C12H18O4

IUPAC Name:

4-[(2-methylprop-2-enoyl)oxy]butan-2-yl 2-methylprop-2-enoate

Test material form:

liquid

Radiolabelling:

no

Test animals

Species:

other: rat liver microsomes and rat blood

Strain:

Fischer 344

Administration / exposure

Vehicle:

DMSO

Duration and frequency of treatment / exposure:

120 min (samples collected at 0, 2, 5, 15, 30, 60 and 120 minutes)

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0.25 other: mM

Remarks:

Whole blood

Doses / concentrations 2

Dose / conc.:

0.229 other: mM

Remarks:

Liver Microsomes

No. of animals per sex per dose / concentration:

not applicable; in vitro test

Control animals:

other: not applicable; in vitro test

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/ESI/QTOF-MS) to quantitate methacrylic acid concentrations

Statistics:

Descriptive statistics were used, i.e., mean ± standard deviation. All calculations in the database were conducted using Microsoft Excel (Microsoft Corporation, Redmond, Washington) spreadsheets and database was set to full precision mode (15 digits of accuracy).

Results and discussion

Main ADME results

Type:

metabolism

Results:

The ester was rapidly converted to MAA in whole rat blood (12.4 min) and rat liver microsomes (3.55 min).

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Methacrylic acid

Any other information on results incl. tables

1,3 -BDDMA was rapidly converted to MAA in whole rat blood and rat liver microsomes with hydrolysis half-lives of 3.55 min (liver microsomes) and 12.4 min (blood).

Based on the half-live values, the intrinsic clearance rate Cl_intand elimination rate k_evalues for 1,3-BDDMA in rat liver microsomal incubation conditions, were calculated as 116 µl/min/mg and 0.195 min^-1, respectively.

Based on the half-live values, the intrinsic clearance rate Cl_intand elimination rate k_evalues for 1,3-BDDMA in rat whole blood incubation conditions, were calculated as 112 µl/min/mg and 0.0559 min^-1, respectively.

Applicant's summary and conclusion

Conclusions:

The metabolism data and modelling results show that 1,3-BDDMA would be rapidly hydrolysed in the rat.

Executive summary:

Overall, the current study results show that both 1,3-BDDMA and1,4-BDDMA were quickly hydrolyzed in both rat blood and rat liver microsomes. In blood, the hydrolysis half-life of 1,3-BDDMA was about two times longer (slower hydrolysis) than 1,4-BDDMA; however, in rat liver microsomes, 1,3-BDDMA and 1,4-BDDMA have a similarly short half-life (~ 3.5 min). Based on these study results, it is expected that both 1,3-BDDMA and 1,4-BDDMA will be rapidly hydrolyzed to MAA in vivo and therefore, both compounds would be expected to have similar toxicity potential.