Registration Dossier

Administrative data

Endpoint:
dermal absorption
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Skin absorption was estimated for a number of constituents of Modified Small Vinyl Ester. Estimations were performed using the QSAR programs Dermwin v2.01 and WaterNT v1.01 (estimation of water solubilities) included in the US-EPA EpiSuite 4.10.
Justification for type of information:
QSAR prediction: migrated from IUCLID 5.6
Cross-reference
Reason / purpose:
reference to other study

Data source

Materials and methods

Principles of method if other than guideline:
QSAR estimationSkin absorption was estimated for bisGMA, monomaleic bisGMA, epoxy-monoGMA, dihydroxy-monoGMA, and the residual methacrylic acid. Skin absorption was not estimated for oligomeric reaction product. These are higher molecular weight analogues to the main constituents and are judged not to contribute significantly to the estimation of dermal absorption of Modified Small Vinyl Ester.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Any other information on results incl. tables

The result of the QSAR estimations is found in the attached document Estimation of the dermal absorption potential of Modified Small Vinyl Ester. The key parameters from the QSAR estimations are seen in Table 1.

Table 1. Key parameters from the QSAR estimation

 

 

logKow

WS

Kp

tau

t*

A

bisGMA

4.94

0.12814

0.00402

80.1

192

B

Monomaleic bisGMA

6.10

0.01884

0.00661

284

682

C

Epoxy monoGMA

4.19

0.7546

0.00386

26.3

63.2

D

Dihydroxy monoGMA

3.44

17.22

0.000965

33.2

79.8

E

Methacrylic acid

0.93

30,483

0.00214

0.324

0.777

 

Unit

-

mg l-1

cm h-1

h

h

logKow   log octanol-water partition coefficient (SRC KOWWIN v1.68)
WS
       water solubility (WATERNT v1.01)
Kp
        skin penetration constant (DERMWIN v2.01)
tau
        time to skin break-through (skin penetration)
t*
         time to steady-state (equilibrium; skin penetration)

From Table 1 it is seen that compounds A, B, C and D penetrate the skin very slowly, whereas compound E (methacrylic acid) penetrates the skin fast.

The results of calculation of systemic uptake from exposed skin areas using the parameters mentioned in section 'Any other information on materials and methods incl. tables' are shown in the following tables 2-4 for exposure times 1-hour, 8-hour and 24-hour, respectively.

Table 2. Systemic uptake at 1h skin contact (systemic dose in µg kgbw-1h-1; 70 kgbwassumed)

 

 

Dermal absorption

Hands

(840 cm2)

Hands + forearms (1980 cm2)

A

bisGMA

0.0127

0.152

0.359

B

Monomaleic bisGMA

0.00579

0.070

0.164

C

Epoxy monoGMA

0.0414

0.497

1.171

D

Dihydroxy monoGMA

0.265

3.180

7.496

E

Methacrylic acid

107

1,284.0

3,027.0

 

 

µg cm-2h-1

µg kgbw-1h-1

 

Table 3. Systemic uptake at 8h skin contact (systemic dose in µg kgbw-1(8h)-1; 70 kgbwassumed)

 

 

Dermal absorption

Hands

(840 cm2)

Hands + forearms (1980 cm2)

A

bisGMA

0.0361

0.433

1.021

B

Monomaleic bisGMA

0.0164

0.197

0.464

C

Epoxy monoGMA

0.117

1.404

3.309

D

Dihydroxy monoGMA

0.749

8.988

21.186

E

Methacrylic acid

560

6,720.0

15,840.0

 

 

µg cm-2(8h)-1

µg kgbw-1(8h)-1

 

Table 4. Systemic uptake at 24h skin contact (systemic dose in µg kgbw-1d-1;70 kgbwassumed)

 

 

Dermal absorption

Hands

(840 cm2)

Hands + forearms (1980 cm2)

A

bisGMA

0.0624

0.749

1.765

B

Monomaleic bisGMA

0.0284

0.340

0.803

C

Epoxy monoGMA

0.203

2.436

5.742

D

Dihydroxy monoGMA

1.30

16.500

36.771

E

Methacrylic acid

1,590

19,080.0

44,974.0

 

 

µg cm-2d-1

µg kgbw-1d-1

From Tables 2, 3 and 4 it is seen that the dermal absorptions of compounds A, B, C and D are very low, i.e. 0.265 µg cm‑2, 0.749 µg cm‑2, and 1.30 µg cm‑2or less, respectively for 1-hour, 8-hours,and 24-hours skin contact; compound D being the compound that has the highest dermal absorption of these four compounds. Compound E has a much higher dermal absorption, i.e. maximum 107 µg cm‑2, 560 µg cm‑2, and 1,590 µg cm‑2, respectively for 1-hour, 8-hours, and 24-hours skin contact. The latter is not surprising, because the high dermal absorption is connected to the very short skin penetration times (tau and t*), which are very short for compound E.

For compounds A, B, C and D the systemic doses for a 70 kgbw person were calculated to 3.2 µg kgbw‑1, 9.0 µg kgbw‑1, and 16.5 µg kgbw‑1or less, respectively for 1-hour, 8-hours, and 24-hours contact with both hands (840 cm2). For compound E the systemic doses were calculated to maximum 1,284 µg kgbw‑1, 6,720 µg kgbw‑1, and 19,080 µg kgbw‑1, respectively for 1-hour, 8-hours, and 24-hours contact with both hands.

For compounds A, B, C and D the systemic doses for a 70 kgbw person were calculated to approximately 7.5 µg kgbw‑1, 21 µg kgbw‑1, and 37 µg kgbw‑1or less, respectively for 1-hour, 8-hours, and 24-hours contact with both hands plus forearms (1980 cm2). For compound E the systemic doses were calculated to maximum 3,027 µg kgbw‑1, 15,480 µg kgbw‑1, and 44,974 µg kgbw‑1, respectively for, 1-hour, 8-hours and 24-hours contact with both hands plus forearms.

The dermal uptake of Modified Small Vinyl Ester for 1-hour, 8-hour and 24-hour contact with both hands and forearms (1980 cm2) is calculated from the calculated dermal absorptions for the main constituents (compounds A, B, D and E, omitting the polymeric part, in total making up approximately 90% of Modified Small Vinyl Ester) and the generic composition of Modified Small Vinyl Ester. Thus, it is calculated that the uptake of Modified Small Vinyl Ester is approximately 0.013 µg cm-2h-1(1-hour contact), 0.037 µg cm-2(8h)-1(8-hour contact) and 0.065 µg cm-2d-1(24-hour contact); for a 70 kgbwperson, corresponding to 0.37, 1.05, and 1.82 µg kgbw-1d-1, respectively.

As the residual monomer, methacrylic acid, amounts less than 0.5% of Modified Small Vinyl Ester, its contribution is set to maximum 0.5%, i.e. the dermal absorption of methacrylic acid corresponds to 0.54 µg cm-2h-1(1-hour contact), 2.8 µg cm-2(8h)-1(8-hour contact), and 8.0 µg cm-2d-1(24-hour contact), corresponding to 15, 79, and 225 µg kgbw-1d-1, respectively for 70 a kgbwperson.

The relative dermal absorption of Modified Small Vinyl Ester was calculated from the dermal absorptions under the assumption that the skin load is 0.117 g cm-2, corresponding to 0.1 ml Modified Small Vinyl Ester on 1 cm2, i.e. a thickness of 0.1 cm. The relative dermal absorptions for the five constituents are calculated for the three contact times 1 hour, 8 hours and 24 hours, using the generic composition of Modified Small Vinyl Ester.

The calculated relative dermal absorptions are seen in Table 5. The compounds C, D and E are minor constituents in Modified Small Vinyl Ester, only accounting for 0.8%, 0.6% and 0.5% of the composition, respectively. Their contribution to the overall dermal absorption is evaluated to be insignificant due their low concentrations. Thus, the overall dermal absorptions for Modified Small Vinyl Ester based on constituents A and B, and the polymeric part, accounting for approximately 98% of Modified Small Vinyl Ester are less than 3 10-5%, 8 10-5%, and 1.4 10-4% for 1-hour, 8-hour, and 24-hour dermal contact times, respectively. The polymeric part is evaluated not to be absorbed through the skin.

Table 5. Calculation of the relative dermal absorption under the assumption that the skin load is 0.117 g cm-.2.

Skin absorp (1 h)

Skin absorp (8 h)

Skin absorp (24 h)

Substance

% (w/w)

mg/cm2

ug/cm2

% absorp

ug/cm2

% absorp

ug/cm2

% absorp

A

bisGMA

70

93.6

0.0127

1.4e-5

0.0361

3.9e-5

0.0624

6.7e-5

B

Monomaleic bisGMA

18

21.1

0.00579

2.7e-5

0.0164

7.8e-5

0.0284

1.3e-4

C

Epoxy monoGMA

0.8

0.94

0.0414

4.4e-3

0.117

1.2e-2

0.203

2.2e-2

D

Dihydroxy monoGMA

0.6

0.70

0.265

3.8e-2

0.749

0.11

1.30

0.19

E

Methacrylic acid

0.5

0.59

107

18.1

560

95

1,590

100

 

Applicant's summary and conclusion

Conclusions:
The main constituents of Modified Small Vinyl Ester are all calculated to have low to negligible individual dermal absorption rates - below 0.2%. The highest value is for dihydroxy-bisGMA, being 0.19% . The residual monomer methacrylic acid (<0.5%) is rapidly absorbed through the skin. The relative dermally absorbed doses are calculated to 18, 95 and 100%, respectively at contact times of 1-hour, 8-hours and 24-hours. The calculated systemic dose at 24-hours contact to both hands and forearms (1980 cm2) is 45 mg/kg bw, which approximately 12 times lower than the lowest NOAEL found in mice in repeated exposure toxicity studies (ca. 550 mg/kg bw/d).Epoxy-monoGMA, dihydroxy-monoGMA and the residual methacrylic acid account for only a maximum 5%, 5% and 1% of the composition, respectively. Their contribution to the overall dermal absorption is evaluated to be insignificant due their low concentrations. Thus, the overall dermal absorptions for Modified Small Vinyl Ester based on constituents bisGMA, monomaleic-bisGMA, and the oligomeric part, accounting for approximately 98% of Modified Small Vinyl Ester are less than 3*10-5%, 8*10-5%, and 1.4*10-4%, for 1-hour, 8-hour, and 24-hour dermal contact times, respectively. The oligomeric part is evaluated not to be absorbed through the skin.Thus,it is evaluated that Modified Small Vinyl Ester is not systemically bioavailable by skin contact.
Executive summary:

The individual relative absorption rates for Modified Small Vinyl Ester were calculated for three exposure times (1 h, 8 h and 24 h). For the constituents bisGMA, monomaleic-bisGMA, epoxy-monoGMA and dihydroxy-monoGMA the relative dermal absorption rates for calculated on the basis of QSAR estimations to be lower than 0.2% at 24 h contact time for dihydroxy-monoGMA and even lower for bisGMA and epoxy-monoGMA, and for the shorter contact times.

Only for the residual monomer methacrylic acid the relative absorption rate is not negligible; which was calculated to 18, 95 and 100%, respectively for the three exposure times. However, it should be noted that for contact with both hands and forearms (11% of the body surface of a human weighing 70 kg bw) the dermally absorbed doses of methacrylic acid using the US-EPA model are estimated to 3, 16 and 45 mg/kg bw, respectively for the contact periods of 1-hour, 8-hours and 24-hours. The latter dose is approximately 12 times lower than the lowest NOAEL for methacrylic acid found in mice in repeated exposure toxicity studies (ca. 550 mg/kg bw/d).

Epoxy-monoGMA, dihydroxy-monoGMA and the residual methacrylic acid account for only a maximum of 5%, 5% and 1% of the composition, respectively. Their contribution to the overall dermal absorption is evaluated to be insignificant due their low concentrations. Thus, the overall dermal absorptions for Modified Small Vinyl Ester based on constituents bisGMA, monomaleic-bisGMA and the oligomeric part, which accounts for approximately 98% of the substance, are less than

3*10-5%, 8*10-5%, and 1.4*10-4%, for 1-hour, 8-hour, and 24-hour dermal contact times, respectively. The oligomeric part is evaluated not to be absorbed through the skin.

 

Thus, it is evaluated that Modified Small Vinyl Ester is not systemically bioavailable by skin contact.