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Administrative data

Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
experimental study
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

Data source

Reference
Reference Type:
other: thesis
Title:
Using physiologically based pharmacokinetic modelling to predict the pharmacokinetics and toxicity of methacrylate esters
Author:
Jones O
Year:
2002
Bibliographic source:
A Thesis submitted to Univ. of Manchester for the degree of Doctor of Philosophy

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. Several kinetic parameters were determined experimentally - including dermal absorption.
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Methacrylic acid
EC Number:
201-204-4
EC Name:
Methacrylic acid
Cas Number:
79-41-4
Molecular formula:
C4H6O2
IUPAC Name:
methacrylic acid
Test material form:
liquid

Test animals

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 Fisher 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

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Duration of exposure:
up to 48 h
Doses:
100 µL/cm2
No. of animals per group:
3 (human: 2)

Results and discussion

Percutaneous absorptionopen allclose all
Key result
Time point:
8 h
Dose:
100 µl/cm2
Parameter:
percentage
Absorption:
ca. 36.5 %
Remarks on result:
other: whole rat skin; peak absorption period 5-8 h
Key result
Time point:
4 h
Dose:
100 µl/cm2
Parameter:
percentage
Absorption:
81 %
Remarks on result:
other: rat epidermis; peak absorption period 0.5-4h;
Time point:
24 h
Dose:
100 µL/cm2
Parameter:
percentage
Absorption:
ca. 93 %
Remarks on result:
other:
Remarks:
rat epidermis; peak absorption rate 0.5-4 h
Dose:
100 µL/cm2
Parameter:
percentage
Absorption:
>= 70 %
Remarks on result:
other: 24 h
Remarks:
rat whole skin, peak absorption rate 5-8 h
Conversion factor human vs. animal skin:
Based on the experimentally supported model, the peak rate of absorption in for human vs. rat epidermis is predicted to 3.1 % while the peak rate for whole human vs whole rat skin is predicted to 7.1 %.

Any other information on results incl. tables

Rat epidermis


The fastest rate of absorption of MAA through rat epidermal membrane was recorded as being 23825μg*cm-2*hr-1 and this occurred between 0.5 and 4 hrs following application of the chemical. After 24 h, 93 % of the applied dose appeared in the receptor chamber indicating a practically complete absorption through rat epidermis within 24 h.


 


Human epidermis


Experimental data are only available for methyl-, n-butyl- and 2-ethylhexyl methacrylate. With the model developed with these experimental data the peak rate of absorption of methacrylic acid through human skin was estimated being 812 μg*cm-2*hr-1. The rates of absorption through human epidermis are considerably slower than those measured for MAA through rat epidermis.


 


Whole rat skin


Of the methacrylates whose rate of absorption through whole rat skin was investigated, methacrylic acid is the most rapidly absorbed chemical - faster than all esters, triggered by the small molecular volume. The peak rate of appearance of MAA occurred between 5 and 8 hrs and was calculated as 4584 μg cm-2 hr-1. While the esters are partly or completely hydrolysed by carboxylesterases present in the viable tissue, MAA passes the tissue almost quantitatively. Of the original dose applied to the whole skin, 70% appeared in the receptor chamber within 24 hrs.

Applicant's summary and conclusion

Conclusions:
Epidermal studies
The fastest rate of absorption of MAA through rat epidermal membrane was recorded as being 23825 μg*cm-2*hr-1 and this occurred between 0.5 and 4 hrs following application of the chemical. Methacrylic acid absorption through human skin was estimated being 812 μg*cm-2*hr-1, based on a model developed with experimental data on rat and human skin with MMA, n-BMA and 2-EHMA.. The rates of absorption through human epidermis are considerably slower than those measured through rat epidermis.

Whole rat skin
Of the methacrylates whose rate of absorption through whole rat skin was investigated, methacrylic acid is the most rapidly absorbed chemical - faster than all esters. While the esters are partly or completely hydrolysed by carboxylesterases present in the viable tissue, MAA passes the tissue almost quantitatively. The peak rate of appearance of MAA, which occurred between 5-8 hrs was calculated to be 4584 μg*cm-2*hr-1. Of the original dose applied to the whole skin, 70% appeared in the receptor chamber within 24 hrs.
Executive summary:

The in vivo and in vitro investigations as well as the PBPK models developed from the data showed that methacrylic acid and the lower alkyl-methacrylate esters are rapidly absorbed and the esters 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).

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