Hexyl methacrylate

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

in vitro and intavenous in vivo

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

Objective of study:

metabolism

Qualifier:

no guideline available

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.
Metabolism, ester hydrolysis, ADME

GLP compliance:

no

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:

other: in vitro and intavenous in vivo

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)

Metabolites identified:

yes

Details on metabolites:

Methacrylic acid

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.

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:

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-HMA the half-life was 18.5 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-HMA the half-life was 18.5 minutes and 99.7 % was removed by first-pass metabolism in the liver.

Description of key information

Short description of key information on bioaccumulation potential result:

Methacrylate esters, including n-hexyl methacrylate, are readily absorbed by all routes and rapidly hydrolyzed by carboxylesterases to methacrylic acid (MAA) and the respective alcohol. Clearance of the parent ester from the body is in the order of minutes. For n-HMA the half-life was 18.5 minutes and 99.7 % was removed by first-pass metabolism in the liver. Reliable data on the primary metabolite methacrylic acid are available and do not reveal critical properties.

Short description of key information on absorption rate:

n-HMA readily absorbs through rat and human epidermis. Human epidermis appears to be less permeable to n-HMA than rat epidermis.

Human epidermis appears to be 10 times less permeable to structural analogue 2-EHMA than rat epidermis and 20 times less permeable to structural analogue substance n-BMA than rat epidermis.