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Toxicological information

Dermal absorption

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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.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Methyl methacrylate from Ineos Acrylics (Lot 98/15; 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. 55 %
Remarks on result:
other: 16 h
Remarks:
rat epidermis; linear absorption for 8 h
Dose:
100 µL/m2
Parameter:
percentage
Absorption:
ca. 10 %
Remarks on result:
other: 4-24 h
Remarks:
human epidermis; linear absorption for >= 24 h

Any other information on results incl. tables

Rat epidermis

The fastest rate of absorption of MMA through rat epidermal membrane was recorded as being 5688 μg*cm-2*hr-1 and this occurred between 2 and 8 hrs following application of the chemical. The rate slowed considerably after 8 hours, falling to virtually zero by 16 hours. Nearly half (45.5%) of the donor reservoir had been depleted by 8 hours with 55% of the chemical appearing in the receptor chamber by 16 hours. The rate plateaus after eight hours, which is indicative of the donor reservoir being depleted.

 

Human epidermis

Methyl methacrylate absorbed at a peak rate of 453 μg*cm-2*hr-1, between 4 and 24 hrs, with 10.2% of the applied dose having been absorbed during this time. There appears to be a lag time with the rate of absorption between 0-4 hrs calculated to be 259 μg cm-2 hr-1. The rates of absorption through human epidermis are considerably slower than those measured for MMA through rat epidermis.

 

Whole rat skin

Of the alkyl-methacrylate esters whose rate of absorption through whole rat skin was investigated, methyl methacrylate is the most rapidly absorbed chemical. Carboxylesterases present in the viable tissue mediate the hydrolysis of these esters, producing the acid metabolite, together with the structurally corresponding alcohol. In contrast to the larger esters, MMA is not completely hydrolysed during the absorption process; this is substantiated by the appearance of both the parent ester and the metabolite MAA in the receptor fluid. Appearance of both chemicals in the receptor fluid can be explained by MMA possessing a rate of absorption that is higher than the rate with which it is hydrolysed.

The peak rate of appearance of MMA, which occurred between 2.5-24 hrs was calculated to be 360 μg*cm-2*hr-1. This compares to a peak rate of appearance for the metabolite MAA, which occurred between 4-24 hrs and was calculated as 108 μg cm-2 hr-1. Of the original dose applied to the whole skin, 8.7% appeared as MMA in the receptor chamber, while 2.6% appeared as MAA. Therefore in total, 11.3% of the ester was depleted from the donor reservoir.

---

The results of the whole-skin penetration studies and the model predictions for 

other methacrylate esters 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:
The fastest rate of absorption of MMA through rat epidermal membrane was recorded as being 5688 μg /cm²/hr and this occurred between 2 and 8 hrs following application of the chemical. Absorption through human epidermal membrane was slower with a peak rate of 453 μg/cm²/hr, between 4 and 24 hrs, with 10.2% of the applied dose having been absorbed during this time. There appears to be a lag time with the rate of absorption between 0-4 hrs calculated to be 259 μg /cm²/hr.

Penetration of alkyl methacrylate through whole rat skin was slower than through separated epidermal membrane. MMA was the most rapidly absorbed chemical of the alkyl methacrylates studied. Carboxylesterases present in the viable tissue mediate the hydrolysis of these esters, producing the acid metabolite, together with the structurally corresponding alcohol. In contrast to the larger esters, MMA is not completely hydrolysed during the absorption process; this is substantiated by the appearance of both the parent ester and the metabolite MAA in the receptor fluid. Appearance of both chemicals in the receptor fluid can be explained by MMA possessing a rate of absorption that is higher than the rate with which it is hydrolysed.
The peak rate of appearance of MMA, which occurred between 2.5-24 hrs was calculated to be 360 μg /cm²/hr. This compares to a peak rate of appearance for the metabolite MAA, which occurred between 4-24 hrs and was calculated as 108 μg /cm²/hr. Of the original dose applied to the whole skin, 8.7% appeared as MMA in the receptor chamber, while 2.6% appeared as MAA. Therefore in total, 11.3% of the ester was depleted from the donor reservoir.
Executive summary:

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).