Methyl methacrylate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: experimental result and PBPK model

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Cross-reference

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

basic toxicokinetics

Type of information:

other: experimental result and PBPK model

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

Reason / purpose for cross-reference:

reference to same study

Objective of study:

absorption

metabolism

Qualifier:

no guideline available

Principles of method if other than guideline:

A physiologically based pharmacokinetic model has been formulated to predict the pharmacokinetics and systemic disposition of alkylmethacrylate esters in rats and humans.

GLP compliance:

not specified

Species:

other: rat and human

Strain:

other: Wistar/Fischer F344/ not applicable

Sex:

male

Details on test animals or test system and environmental conditions:

Epidermal membrane absorption studies
Skin was used from male rats of the Wistar-derived strain (supplied by Charles River UK Ltd, Margate, Kent, UK.) aged 28 days ± 2 days

Whole skin absorption studies
Skin was taken from male Fischer F344 (supplied by Harlan Olac) rats weighing between 200 and 250 g.

Human epidermal membrane absorption studies
Extraneous tissue was removed from human abdominal whole skin samples obtained post mortem in accordance with local ethical guidelines.

Route of administration:

intravenous

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. 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.

Type:

metabolism

Results:

Half-life of MMA after i.V. injection: 4.4 min (PBPK estimate)

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 4.4 min

Remarks:

i.v./ rat liver microsomes

Test no.:

#1

Toxicokinetic parameters:

other: 98.8% removed from liver blood flow i.e. by first pass liver clearance

Remarks:

clearance/ i.v./ rat liver microsomes

Test no.:

#1

Toxicokinetic parameters:

Cmax: 14.7  (mg/L) of MAA in blood

Remarks:

i.v./ rat liver microsomes

Test no.:

#1

Toxicokinetic parameters:

Tmax: 1.7 min to peak MAA concentration in blood from model predictions

Remarks:

i.v./rat liver microsomes

Metabolites identified:

yes

Details on metabolites:

Methacrylic acid

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 1:
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

Conclusions:

The in vivo and in vitro investigations as well as the PBPK models developed from the data showed that MMA, like other alkyl-methacrylate esters, is rapidly absorbed and 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 (within minutes). The half-time after i.v. application in rat liver is 4.4 min for MMA.

Executive summary:

The in vivo and in vitro investigations as well as the PBPK models developed from the data showed that MMA, like other alkyl-methacrylate esters, is rapidly absorbed and 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 (within minutes). The half-time after i.v. application in rat liver is 4.4 min for MMA.

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

A physiologically based pharmacokinetic model has been formulated to predict the pharmacokinetics and systemic disposition of alkylmethacrylate esters in rats and humans.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Methyl methacrylate

EC Number:

201-297-1

EC Name:

Methyl methacrylate

Cas Number:

80-62-6

Molecular formula:

C5H8O2

IUPAC Name:

methyl 2-methylprop-2-enoate

Test material form:

liquid

Results and discussion

Main ADME results

Type:

metabolism

Results:

Half-life of MMA after i.V. injection: 4.4 min (PBPK estimate)

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parameters

Toxicokinetic parameters 1

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 4.4 min

Remarks:

i.v./ rat liver microsomes

Toxicokinetic parameters 2

Test no.:

#1

Toxicokinetic parameters:

other: 98.8% removed from liver blood flow i.e. by first pass liver clearance

Remarks:

clearance/ i.v./ rat liver microsomes

Toxicokinetic parameters 3

Test no.:

#1

Toxicokinetic parameters:

Cmax: 14.7  (mg/L) of MAA in blood

Remarks:

i.v./ rat liver microsomes

Toxicokinetic parameters 4

Test no.:

#1

Toxicokinetic parameters:

Tmax: 1.7 min to peak MAA concentration in blood from model predictions

Remarks:

i.v./rat liver microsomes

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Methacrylic acid

Any other information on results incl. tables

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 1:
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:

The in vivo and in vitro investigations as well as the PBPK models developed from the data showed that MMA, like other alkyl-methacrylate esters, is rapidly absorbed and 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 (within minutes). The half-time after i.v. application in rat liver is 4.4 min for MMA.

Executive summary:

The in vivo and in vitro investigations as well as the PBPK models developed from the data showed that MMA, like other alkyl-methacrylate esters, is rapidly absorbed and 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 (within minutes). The half-time after i.v. application in rat liver is 4.4 min for MMA.