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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:
supporting 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
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
In vitro and in vivo studies with other methacrylate esters have demonstrated that the first step in metabolism is ester cleavage and that this occurs rapidly at both locally, at the site of contact, and systemically to methacrylic acid (MAA) and the free alcohol the metabolism of which is well understood.
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%)

Test animals

Species:
rat
Strain:
not specified
Sex:
not specified

Results and discussion

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

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
----------------------------------------------------------
EMA       699.2     106.2    99.5%    4.5    12.0     1.8
----------------------------------------------------------
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:
In conclusion, 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).
Executive summary:

In a valid sientific study, 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).