Registration Dossier

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:
other: 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

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Methacrylic acid from Ineos Acrylics (Lot 98/42; purity > 99%)

Test animals

Species:
other: rat and human
Strain:
other: Wistar/Fischer F344/ not applicable
Sex:
male
Details on test animals 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
Dose:
100 µL/cm2
Parameter:
percentage
Absorption:
ca. 93 %
Remarks on result:
other: 24 h
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.

---

The results of the whole-skin penetration studies and the model predictions for other methacrylates are presented in the table.



Summary of the peak rates of absorption of MAA & alkyl-methacrylate esters through whole rat and human skin

Substance

Molecular volume

Rat whole rat

Human whole skin

Peak rate of appearance (µg*cm-2*h-1)+- SEM

Period of

peak

absorption

rate (hours)

% age of

applied

dose

absorbed

over x hours

Rate of

absorption of

ester/MAA

(μg*cm-2 *hr-1)

Ester

MAA

MAA

78.96

 

4584+-344

5-8

70%/24

327

MMA

93.1978

360+-20.9

108+-4.59

2.5-24

11.3%/24

33.4**

EMA

107.436

 

190**

 

 

13.6**

iBMA

135.646

 

56**

 

 

4**

nBMA

135.856

 

40+-9.4

2-10

0.4%/10

2.9**

6HMA

164.277

 

20**

 

 

1.4**

2EHMA

191.66

 

9**

 

 

0.6**

OMA

192.696

 

10.3+-0.65

8-24

0.24%/24

0.7**

12LMA

249.536

 

11.8+-2.11

8-24

0.26%/24

0.8**

The values in normal type were obtained experimentally, whilst those in italics are predicted values.

** Values are predicted rates of appearance of total chemical including parent ester and metabolite


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).