tert-butyl methacrylate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

A series of in vitro and in vivo studies were used to develop PBPK models

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2002

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:

absorption

metabolism

Principles of method if other than guideline:

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.
A physiologically based pharmacokinetic model has been formulated to predict the pharmacokinetics and systemic disposition of alkylmethacrylate esters in rats and humans. Physiological (species specific) model parameters were obtained from the literature, while chemical specific model parameters were derived mainly from in vitro experiments. These in vitro experiments, which utilised rat and human tissues, included methods for estimating (1) the in vivo clearance from the liver, blood and skin, (2) the rates of absorption through skin and (3) the biological partition coefficients of the alkyl-methacrylate esters. A limited number of in vivo studies in the rat served to validate the PBPK model.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Butyl methacrylate

EC Number:

202-615-1

EC Name:

Butyl methacrylate

Cas Number:

97-88-1

Molecular formula:

C8H14O2

IUPAC Name:

butyl methacrylate

Test material form:

other: liquid

Specific details on test material used for the study:

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:

other: in vitro and intavenous in vivo

Results and discussion

Main ADME results

Main ADME results 1

Type:

clearance

Results:

Systemically absorbed parent ester will be effectively removed during the first pass through the liver (%LBF) resulting in their relatively rapid elimination from the body (T50%).

Main ADME results 2

Type:

absorption

Results:

Alkyl-methacrylate esters are rapidly absorbed

Main ADME results 3

Type:

metabolism

Results:

Alkyl-methacrylate esters are hydrolyzed at exceptionally high rates to methacrylic acid. These studies showed that any systemically absorbed parent ester will be effectively removed during the first pass through the liver.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

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 first-pass metabolism of the alkyl-methacrylates. 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. In addition, removal of methacrylic acid from the blood also occurs rapidly.

Any other information on results incl. tables

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.

 

 

Table 2: Rate constants for ester hydrolysis by human-liver microsome samples

 Ester    Vmax (nM/min*mg) Km (mM) CL (µL/min*mg)    
-----------------------------------------------
MMA       1721      4103     419   
EMA        936      1601     584  
i-BMA       80       441     181
n-BMA      211       158    1332
HMA        229 66 3465
2EHMA       53        48    1109
OMA        243 38 6403

----------------------------------------------------------

CL is calculated from the mean Vmax and Km

Applicant's summary and conclusion

Conclusions:

Using a reliable experimental method, the in vivo and in vitro investigations as well as the PBPK models developed from the data showed that alkyl-methacrylate esters are rapidly absorbed and are hydrolyzed at exceptionally high rates to methacrylic acid by high capacity, ubiquitous carboxylesterases. Further, the removal of the hydrolysis product, methacrylic acid, also is very rapid (minutes). For n-BMA the half-life was 7.8 minutes and 99.7 % was removed by first-pass metabolism in the liver.

Executive summary:

Using a reliable experimental method, the in vivo and in vitro investigations as well as the PBPK models developed from the data showed that alkyl-methacrylate esters are rapidly absorbed and are hydrolyzed at exceptionally high rates to methacrylic acid by high capacity, ubiquitous carboxylesterases. Further, the removal of the hydrolysis product, methacrylic acid, also is very rapid (minutes). For n-BMA the half-life was 7.8 minutes and 99.7 % was removed by first-pass metabolism in the liver.