Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
experimental study
Adequacy of study:
key study
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:
other: Thesis
Title:
Unnamed
Year:
2002

Materials and methods

Objective of study:
metabolism
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
A series of in vitro and PBPK models were used to determine and predict the skin absorption and metabolism of a series of methacrylate monomers. Initial studies were conducted using the rat epidermal membrane model.The results of these studies, when compared to the subsequent rat whole  skin model in vitro experiments clearly indicated that the latter studies were more pertinent to the goals of the studies, particularly since the use of
epidermal membranes appeared to remove the carboxylesterase activity from the skin samples.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Wistar
Sex:
male

Administration / exposure

Route of administration:
other: in vitro and intravenous in vivo

Results and discussion

Main ADME results
Type:
metabolism
Results:
The studies confirmed that alkyl-methacrylate esters are rapidly hydrolyzed by ubiquitous carboxylesterases. 

Any other information on results incl. tables

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. The studies confirmed that alkyl methacrylate esters are rapidly hydrolyzed by ubiquitous carboxylesterases. First pass (local) hydrolysis of the parent ester has been shown to be significant for all routes of exposure. In vivo measurements of rat liver indicated this organ has the greatest esterase activity. Similar measurements for skin microsomes indicated approximately 20-fold lower activity than for liver. However, this activity was substantial and capable of almost complete firstpass metabolism of the alkylmethacrylates. For example, no parent ester penetrated whole rat skin in vitro for n-butyl methacrylate, octyl methacrylate or lauryl methacrylate tested experimentally with only methacrylic acid identified in the receiving fluid. In addition, model predictions indicate that esters of ethyl methacrylate or larger would be completely hydrolyzed before entering the circulation via skin absorption. This pattern is consistent with a lower rate of absorption for these esters such that the rate is within the metabolic capacity of the skin.Parent  ester also was hydrolyzed by S9 fractions from nasal epithelium and was predicted to be effectively hydrolyzed following inhalation exposure. These studies showed that any systemically absorbed parent ester will be effectively removed during the first pass through the liver (CL as % LBF, see table). In addition, removal of methacrylic acid from the blood also occurs rapidly (T50%; see table).  


Table: Rate constants for ester hydrolysis by rat-liver microsomes and predicted systemic fate kinetics for methacrylates following i.v. administration:

 Ester    Vmax       Km        CL    T50%    Cmax    Tmax
----------------------------------------------------------
MAA        -         -       51.6%    -       -       -
MMA       445.8     164.3    98.8%    4.4    14.7     1.7
EMA       699.2     106.2    99.5%    4.5    12.0     1.8
i-BMA     832.9     127.4    99.5%   11.6     7.4     1.6
n-BMA     875.7      77.3    99.7%    7.8     7.9     1.8
HMA       376.4      34.4    99.7%   18.5     5.9     1.2
2EHMA     393.0      17.7    99.9%   23.8     5.0     1.2
OMA       224.8      11.0    99.9%   27.2     5.0     1.2
----------------------------------------------------------

Vmax (nM/min/mg) and Km (µM) from rat-liver microsome (100 µg/mL) determinations;  
CL = clearance as % removed from liver blood flow, T50% = Body  elimination time

(min) for 50% parent ester, Cmax = maximum concentration (mg/L) of MAA in blood, 

Tmax = time (min) to peak MAA concentration in blood from model predictions.

Applicant's summary and conclusion