Reaction products of methacrylic acid and 2,2'-[(1-methylethylidene)bis(4,1-phenyleneoxymethylene)]bisoxirane

Dermal absorption

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: see 'Remark'

Remarks:

Skin absorption was estimated for three major constituents in Small Vinyl Ester plus methacrylic acid. Estimations were performed the QSAR programs Dermwin v2.01, and WaterNT v1.01 (estimation of water solubilities) included in the US-EPA EpiSuite v4.1.

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Materials and methods

Principles of method if other than guideline:

QSAR estimation

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-hydroxy-3-{4-[2-(4-{2-hydroxy-3-[(2-methylprop-2-enoyl)oxy]propoxy}phenyl)propan-2-yl]phenoxy}propyl 2-methylprop-2-enoate

EC Number:

701-308-4

Cas Number:

36425-15-7

Molecular formula:

n/a

IUPAC Name:

2-hydroxy-3-{4-[2-(4-{2-hydroxy-3-[(2-methylprop-2-enoyl)oxy]propoxy}phenyl)propan-2-yl]phenoxy}propyl 2-methylprop-2-enoate

Details on test material:

Skin absorption was estimated for three constituents and the residual monomer methacrylic acid (<1%).
Skin absorption was not estimated for polymeric reaction product (13% of Small Vinyl Ester). This is higher molecular weight analogues to the main constituent, bisGMA, and is judged not to contribute significantly to the estimation of dermal absorption of Small Vinyl Ester.

Results and discussion

Percutaneous absorption

Remarks on result:

other:

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 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	Epoxy monoGMA	4.19	0.7546	0.00386	26.3	63.2
C	Dihydroxy monoGMA	3.44	17.22	0.000965	33.2	79.8
D	Methacrylic acid	0.93	30,483	0.00214	0.324	0.777
	Unit	-	mg l^-1	cm h^-1	h	h

logK_ow   log octanol-water partition coefficient (SRC KOWWIN v1.68)
WS       water solubility (WATERNT v1.01)
Kp        skin penetration constant (DERMWIN v1.43)
tau        time to skin break-through (skin penetration)
t^*         time to steady-state (equilibrium; skin penetration)

The results of calculation of systemic uptake from exposed skin areas using the paramaters 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 1 h skin contact (systemic dose in µg kg_bw^-1h^-1, 70 kg_bw assumed)

		Dermal absorption	Hands (840 cm^2)	Hands + forearms (1980 cm^2)
A	bisGMA	0.0127	0.152	0.359
B	Epoxy monoGMA	0.0414	0.497	1.171
C	Dihydroxy monoGMA	0.265	3.180	7.496
D	Methacrylic acid	107	1,284	3,027
		µg cm^-2h^-1	µg kgbw^-1h^-1

Table 3. Systemic uptake at 1h skin contact (systemic dose in µg kg_bw^-1 (8h)^-1, 70 kg_bw assumed)

		Dermal absorption	Hands (840 cm^2)	Hands + forearms (1980 cm^2)
A	bisGMA	0.0361	0.433	1.021
B	Epoxy monoGMA	0.117	1.404	3.309
C	Dihydroxy monoGMA	0.749	8.988	21.186
D	Methacrylic acid	560	6,720	15,840
		µg cm^-2(8h)^-1	µg kgbw^-1(8h)^-1

Table 4. Systemic uptake at 24h skin contact (systemic dose in µg kg_bw^-1d^-1,70 kg_bw assumed)

		Dermal absorption	Hands (840 cm^2)	Hands + forearms (1980 cm^2)
A	bisGMA	0.0624	0.749	1.765
B	Epoxy monoGMA	0.203	2.436	5.742
C	Dihydroxy monoGMA	1.30	16.500	36.771
D	Methacrylic acid	1,590	19,080	44,974
		µg cm^-2d^-1	µg kgbw^-1d^-1

From Tables 2, 3 and 4 it is seen that the dermal absorptions of constituents A, B and C 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; constituent C being the constituent

that has the highest dermal absorption of these three constituents. Constituent D 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 constituent D.

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

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

The dermal uptake of 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 three constituents and the generic composition of Small Vinyl Ester, cf. Section 1.2. Thus, it is calculated that the uptake of Small Vinyl Ester is approximately 0.017 µg cm^-2h^-1(1-hour contact), 0.047 µg cm^-2(8h)^-1(8-hour contact) and 0.082 µg cm^-2d^-1(24-hour contact); for a 70 kg_bw person, corresponding to 0.47, 1.34, and 2.32 µg kg_bw^-1d^-1, respectively.

As the residual monomer, methacrylic acid, amounts less than 1% of Small Vinyl Ester, its contribution is set to 1%, i.e. the dermal absorption of methacrylic acid corresponds to 1.07 µgcm^-2h^-1(1-hour contact), 5.6 µg cm^-2(8h)^-1(8-hour contact), and 15.9 µg cm^-2d^-1(24-hour contact), corresponding to 30, 158, and 450 µg kg_bw^-1d^-1, respectively for a 70 kg_bw person.

The following assumptions are used for the calculation of the relative dermal absorption:

a) density of Small Vinyl Ester is 1.17 g/ml, cf. Section 4.4

b) 1 drop (0.1 ml) of Small Vinyl Ester weighs 0.117 g

c) the drop is in contact with 1 cm2 skin, giving a skin load of 117 mg/cm2

d) the generic composition of Small Vinyl Ester is as seen in Section 1.2.

e) the polymeric reaction product part of Small Vinyl Ester amount 13%. It is a higher molecular weight analogue to bisGMA, and thus judged to have lower skin absorption rates than bisGMA, which is found to be very low.

From these parameters and the estimated penetration rates, cf. the attached document Estimation of the dermal absorption potential of Small Vinyl Ester, the relative dermal absorption (in %) is calculated for the three contact times, 1 hour, 8 hours and 24 hours as seen in the Table 5 below.

Table 5				Skin absorp (1 h)		Skin absorp (8 h)		Skin absorp (24 h)
Substance		% (w/w)	mg/cm^2	ug/cm^2	% absorp	ug/cm^2	% absorp	ug/cm^2	% absorp
A	bisGMA	80	93.60	0.0127	1.4e-5	0.0361	3.9e-5	0.0624	6.7e-5
B	Epoxy monoGMA	3	3.51	0.0414	1.2e-3	0.117	3.3e-3	0.203	5.8e-3
C	Dihydroxy monoGMA	2	2.34	0.265	1.1e-2	0.749	3.2e-2	1.30	5.6e-2
D	Methacrylic acid	<1	1.17	107	9.1	560	47.9	1,590	100

The relative skin absorptions were calculated to be lower than 0.056% at 24-hours contact time constituent C (dihydroxy-monoGMA) and even lower for constituents A and B, and for the shorter contact times. Thus, it may be concluded that the relative dermal absorption for Small Vinyl Ester is approximately 0.056%, omitting constituent D (residual monomer methacrylic acid). For constituent D the relative dermal absorption was calculated to 9.1, 47.9 and 100%, respectively for the three exposure times.

The substances B, C and D are constituents in Small Vinyl Ester, accounting for 3%, 2% and <1% of the composition, respectively. Substance D (methacrylic acid) is omitted from the calculation of the relative dermal absorption due to its low amount in Small Vinyl Ester. The overall dermal absorptions for Small Vinyl Ester based on the main constituents A, B and C are calculated to approximately than 0.013%, 0.035%, and 0.061%, for 1-hour, 8-hour, and 24-hour dermal contact times, respectively. The polymeric part is evaluated not to be absorbed through the skin.

Applicant's summary and conclusion

Conclusions:

The main constituents all are estimated to have negligible dermal absorption rates - below 0.056%.
The residual monomer methacrylic acid (<1%) is rapidly absorbed through the skin. The relative dermally absorbed doses are calculated to 9.1, 47.9 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 24 times lower than the lowest LD50 found in rats.

Executive summary:

The relative absorption rates for were calculated for three exposure times (1 h, 8 h and 24 h). For three constituents the relative dermal absorption rates for calculated on the basis of QSAR estimations to be lower 0.056% at 24 h contact time for dihydroxy-monoGMA and even lower for bisGMA and epoxy-monoGMA and for shorter contact times. Only for the residual monomer methacrylic acid the relative absorption rate is not negligible; which was calculated to 9.1, 47.9 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 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 24 times lower than the lowest NOAEL for methacrylic acid found in rats.