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Toxicological information

Basic toxicokinetics

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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.

Data source

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

Constituent 1
Chemical structure
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 parametersopen allclose all
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

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.