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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: 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:
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
Test material form:
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%)

Test animals

Species:
rat
Strain:
Wistar
Sex:
male

Administration / exposure

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

Results and discussion

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 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 (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

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 2-EHMA the half-life was 23.8 minutes and 99.9 % 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 2-EHMA the half-life was 23.8 minutes and 99.9 % was removed by first-pass metabolism in the liver.