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Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Public literature, no detailed study report available
Objective of study:
other: distribution and excretion
Principles of method if other than guideline:
The uptake, distribution and excretion of radio labeled BisGMA applied via gastric and intravenous administration were examined in vivo in guinea pigs.
GLP compliance:
not specified
Radiolabelling:
yes
Remarks:
14-C
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male
Details on test animals and environmental conditions:
Adult male guinea pigs (400 g). Each animal was put into a separate metabolic cage 3 days before the start of the study, and food was removed 12 hours before the start of the treatment. No details were provided on the environmental conditions.
Route of administration:
other: gavage and intravenous
Vehicle:
DMSO
Duration and frequency of treatment / exposure:
Single exposure.
Details on study design:
In situ experiment:Guinea pigs were randomized and allotted to 3 groups of 4 animals each. The ductus cysticus was ligated, and a cannula was placed in the bile duct. A 1 ml/kg quantity of BisGMA, dissolved in DMSO (final concentration DMSO 1%) was injected via the jugular vein (0.02 µmol/kg bw, labeled with a tracer dose of [14C]BisGMA (0.3 kBq/g bw). Control animals received either 0.9% NaCl solution or DMSO (final concentration 1% DMSO in 0.9% NaCl). In vivo ExperimentsTwelve guinea pigs were allotted to 3 groups of 4 animals each. Each animal received BisGMA (0.02 µmol/kg bw, dissolved in 1% DMSO), labeled with a tracer dose of [14CBisGMA (0.3 kBq/g bw), via gavage. Control animals received either 0.9% NaCl solution or DMSO (final concentration 1% DMSO in 0.9% NaCl). The volume for the application through the gastric tube was 4 ml/kg. A second set of 12 guinea pigs was treated as described above, with the addition, that each animal was kept in a closed chamber with controlled air flow.
Details on dosing and sampling:
In situ experiment:Blood was withdrawn form the carotid artery. Samples of the bile (0.4 ml) and blood (0.2 ml) were taken every 10 minutes. The experimental period was 60 minutes. The organs and their contents were immediately removed and their [14C]-radioactivity measured. In vivo experiment:Feces and urine were collected at 1, 2, 4, 6, 8, 12, and 24 hours after [14C]BisGMA administration, and the [14C]-radioactivity was measured. Twenty four hours after the beginning of the experiment, the animals were killed in ether. The organs and their contents were immediately removed and their [14C]-radioactivity measured. From the animals kept in the closed chamber, the exhaled air was captured during the 24-hour experimental period, in addition to the collection of urine and feces for 24 hours and analysis of organs. Guinea pig organs:For all experiments the following organs were taken: liver, kidney, blood, skin, brain, heart, spleen, lung, muscle, testes, eyes, bone, nerve tissue, spinal cord, wall of stomach, content of stomach, wall and content of ileum and jejunum, wall and content of colon, wall and content of caecum, wall of gall bladder and fat tissue. Organs were immediately washed with 2 x 10 ml distilled H2O, the wash-water was saved, and then the tissues were weighed and homogenized. Determination of Radioactivity:Tissues were dissolved in TEAH (20%) in aqueous solution with Omni-Szintisol. Radioactivity was determined with a liquid scintillation counter.
Statistics:
Data were presented as means +/- SEM. Statisticall significance of the differences between the experimental groups was determined by the Bonferroni-Holm t test.

During the first hour after [14C]BisGMA intravenous injection, about 12% of the radio label was excreted via the bile, and about 50% reamined in the tissues at 1 hour, the time the guinea pigs were killed. Radio label was rapidly removed from the blood. No significant change in bile flux was observed during the 60 minutes in guinea pigs that had received radio labeled BisGMA, when compared to controls. One hour after intravenous injection, radio activity found in the l ungs was about 8% and in the brain 1% of the administered radio label (per gram organ). Radio activity in other organs was lower than 0.4% (per gram organ).

In the total blood, radio activity was foudn to be about 4% of the dose, 10 minutes after intravenous administration. From these data a plasma half-life period for BisGMA can be calculated that must be lower than 10 minutes.

In vivo experiments:

Duirng the first 24 hours after radio labelled BisGMA oral gavage, guinea pigs exhaled 14CO2 equivalent to about 65% fo the radio label administered. About 7% of the radiolabel was excreted via urine, 5% was excreted via feces, and about 6% remained in the tissues at 24 hours, the time the animals were killed. The total recovery was about 85% of the radio label administered. During the 24 hours, the amount of feces and urine excreted was not changed when compared to control animals. Radio label in organs ans walls and/or contents of organs in guinea pigs at 24 hours, was found in lungs about 0.035% and in the brain about 0.002% of the administered radio label.

Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Public literature, no detailed study report available
Justification for type of information:
Study published in a peer-reviewed journal.
Objective of study:
excretion
metabolism
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Principle of test: Investigate the urinary metaboilite profile following oral exposure of BisGMA in guinea pigs.- Short description of test conditions: BisGMA was dissolved in DMSO (1%) and NaCl (0.9%) before administration via oral gavage to guinea pigs. Urine was collected 24 hours post-dosing and metabolites were identified using LC-MS.- Parameters analysed / observed: Levels of metabolites formed.
GLP compliance:
not specified
Radiolabelling:
no
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS- Weight at study initiation: 400-700g - Housing: metabolic cage - Diet (e.g. ad libitum): ad lib - Water (e.g. ad libitum): ad lib - Acclimation period: 1 day
Route of administration:
oral: gavage
Vehicle:
other: 0.9% NaCl and 1% DMSO
Duration and frequency of treatment / exposure:
Single dose.
Dose / conc.:
0.02 other: mmol/kg bw
No. of animals per sex per dose:
Test - 2 animals/doseControl - 2 animals/dose
Control animals:
yes, concurrent vehicle
Positive control:
None.
Type:
excretion
Results:
Unchanged parent substance: 11.4% Methacrylate: 2.2% Bisphenol-A-bis(2,3-dihydroxypropyl)ether: 60.1%
Details on excretion:
Unchanged parent substance: 11.4% ± 2.7%Methacrylate: 2.2% ± 0.6%Bisphenol-A-bis(2,3-dihydroxypropyl)ether: 60.1% ± 5.2%
Metabolites identified:
yes
Details on metabolites:
Unchanged parent substance: 11.4% ± 2.7%Methacrylate: 2.2% ± 0.6%Bisphenol-A-bis(2,3-dihydroxypropyl)ether: 60.1% ± 5.2%
Conclusions:
The urinary metabolites detected in guinea pigs following administration of BisGMA by oral gavage are unchanged BisGMA, methacrylate and bisphenol-A-bis(2,3-dihydroxypropyl)ether.
Executive summary:

The urinary excretion of metabolites of BisGMA was investigated in guinea pigs following a single treatment by oral gavage. The metabolites were detected using LC-MS 24 -hours post-dosing. The metabolites detected in urine were unchanged parent substance at 11.4% ± 2.7%, methacrylate: 2.2% ± 0.6% and bisphenol-A-bis(2,3-dihydroxypropyl)ether: 60.1% ± 5.2%. No other metabolites were detected in this study.

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
Reason / purpose:
reference to other study
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

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

 

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.

Description of key information

The substance is a UVCB which contains a number of constituents including bisGMA, monomaleic adduct of bisGMA, oligomeric reaction products (higher molecular weight analogues), epoxy-monoGMA, dihydroxy-monoGMA and methacrylic acid. Exposure to the UVCB substance will result in exposure to all the constituents. There is no data on the absorption, distribution, metabolism and excretion of the substance itself. Due to negligible vapour pressures and very low skin absorption rates the systemic bioavailability of the substance into the body is negligible by the inhalation and dermal exposure routes and thus would not be systemically bioavailable via these exposure routes. Moreover, QSAR estimations predicts that dermal and inhalation absorption rates are not expected to be a major exposure pathway for the substance based on estimates for the constituents of the substance. An oral absorption rate of 80% was calculated for the substance using QSAR estimates for the constituents of the UVCB. Published data for bisGMA (the principal component of the substance) demonstrates that it is rapidly biotransformed in the body and excreted as carbon dioxide (65%) within 24 hours and a minor part is excreted via the bile (7%). Guinea pigs exposed orally to bisGMA demonstrated the urinary excretion (at 24 hours post-dosing) of the major metabolite bisphenol-A-bis(2,3-dihydroxypropyl)ether at 60.1% together with the unchanged parent compound at 11.4% and methacrylic acid at 2.2%.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
80

Additional information

MultiCase (MC4PC v2.1.0.18) was employed to provide QSAR estimatesof relative oral absorption for bisGMA, monomaleic adduct of bisGMA, epoxy-monoGMA and dihydroxy-monoGMA. The following relative oral absorption rates were indicated:

bisGMA                         82%
monomaleic bisGMA     82%
epoxy-monoGMA          91%
dihydroxy-monoGMA    64%

Methacrylic acid is expected to be absorbed almost completely absorbed following oral exposure.The absorption of BisGMA was confirmed in guinea pigs using the radiotracer technique (Reichl et al, 2008, 2008a).These constituents contribute to the total relative oral absorption proportionally to their relative amount in the substance. Using this information an oral absorption rate of 80% was calculated for the whole UVCB substance.

Dermwin v2.01 of US-EPA EPISuite v4.1 was used to calculate relative dermal absorption rates for bisGMA, monomaleic bisGMA, epoxy-monoGMA, dihydroxy-monoGMA and methacrylic acid for three exposure times (1 h, 8 h and 24 h). Based on the relative dermal absorption rates and the composition of the substance, the overall relative dermal absorption rate for the substance was calculated to be lower than 0.00014% at 24 h contact time. Thus, dermal absorption is negligible and the substance is not expected to be systemically bioavailable. The relative absorption rate for methacrylic acid was calculated to be 18, 95 and 100%, respectively for 1-hour, 8-hours and 24-hours skin contact. This is significant absorption, however the calculated systemic dose at 24-hours skin contact (1980 cm2) is 45 mg/kg bw, which is approximately 12 times lower than the lowest NOAEL found in mice in repeated exposure toxicity studies.

Vapour pressures were calculated using US-EPA EPIsuite v4.0, cf. IUCLID section 13 (assessment reports.001). Vapour pressures were estimated for bisGMA, monomaleic bisGMA, epoxy-monoGMA, dihydroxy-monoGMA and methacrylic acid. The following vapour pressures were found:

bisGMA                         2.0e-13 Pa
monomaleic bisGMA     4.9e-17 Pa
epoxy-monoGMA          1.7e-10 Pa
dihydroxy-monoGMA    7.7e-14 Pa
methacrylic acid              132 Pa

The vapour pressures of bisGMA, monomaleic bisGMA, epoxy-monoGMA, dihydroxy-monoGMA, and also oligomeric reaction products (judged) are negligible and will not give to inhalation exposure of vapours.

The vapour pressure of the methacrylic acid is expected to be significant thus may give rise to inhalation exposure. However, methacrylic acid amounts to less than 1% of the substance and is not expected to leave the substance matrix.

The substance is placed on the market in approximately 50% dilutions in a reactive diluent for industrial use only, i.e., consumers will have no contact with this product. Due to the pungent smell and taste of the reactive diluent, oral intake of the substance is highly unlikely. Thus, systemic exposure is very unlikely via this exposure route. The substance is not released to the environment and consequently does not enter the aqueous environment. Thus, the general population is not likely to be exposed to the substance through the environment, e.g. the general population would not be exposed via drinking-water.