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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
other: Thesis
Title:
Unnamed
Year:
2002

Materials and methods

Objective of study:
metabolism
Principles of method if other than guideline:
Determination of half-life in blood after i.v. application
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Methacrylic acid from Ineos Acrylics (Lot 98/42; purity > 99%), methyl methacrylate from Ineos Acrylics (Lot 98/15; purity > 99%), ethyl methacrylat from Atofina (Lot 011666; purity: > 99%), i-butyl methacrylate from Ineos Acrylics (Lot 98/15; purity 99%), n-butyl methacrylate from Ineos Acrylics (Lot 98/15; purity 99%), hexyl methacrylate from Röhm GmbH (Lot 78070243; purity > 98%), 2-ethylhexyl methacrylate from Röhm GmbH (Lot 78080370; purity > 98%), octyl methacrylate from Röhm GmbH (Lot 22-902-13914-28; purity > 98%)
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male

Administration / exposure

Route of administration:
intravenous
Vehicle:
physiological saline
Details on exposure:
Single i.v. injections of 10 or 20 mg/kg at a dosing volume of 2 ml/kg in physiological saline
No. of animals per sex per dose:
2 at 10 mg/kg
3 at 20 mg/kg
Control animals:
no
Details on study design:
A series of in vitro and in vivo studies with a series of methacrylates were used to develop PBPK models that accurately predict the metabolism and fate of these monomers. This study segment was performed in order to validate the model.
Details on dosing and sampling:
Blood samples were taken at defined intervals post-dosing. Not more than 10 % of the total average blood volume were taken.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parametersopen allclose all
Toxicokinetic parameters:
half-life 1st: 1.7 min
Toxicokinetic parameters:
other: Vmax = 19.8 mg/ hr * SRW
Remarks:
SRW = standard rat weight (250 g)
Toxicokinetic parameters:
other: km = 20.3 mg/L

Any other information on results incl. tables

Non-compartmental analysis of the blood concentration data for MAA at the two doses, gives volumes of distribution of 23 ml (10 mg kg-1) and 35 ml (20 mg kg-1). The clearance of MAA was calculated to be 0.324 L hr-1 SRW-1 at the 10 mg kg-1 dose and 0.25 L hr-1 SRW-1 at the 20 mg kg-1 dose. The change in clearance from the lower dose to the higher dose indicates non-linear saturable metabolism in the rat.

Based on that information, the following kinetic parameters were determined from a simultaneous fit of the in vivo data to a one-compartment model with non-linear elimination (Vss = 0.039 L/SRW; Vmax = 19.8 mg/hrxSRW; Km = 20.3 mg/L; SRW: standard rat weight = 250 g) the half-life of MAA in blood was calculated to 1.7 min.

Applicant's summary and conclusion

Conclusions:
In conclusion, from a simultaneous fit of the in vivo data to a one-compartment model with non-linear elimination the half-life of MAA in blood was calculated to 1.7 min.
Executive summary:

The PBPK model data were validated by i.v. administration of MAA in rats and subsequent analysis of blood from the tail vein.

In conclusion, from a simultaneous fit of the in vivo data to a one-compartment model with non-linear elimination, the half-life of MAA in blood was calculated to 1.7 min.

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