reaction products of diglycidyl ether bisphenol F (DGEBF) and oligomeric phenol diglycidyl ethers with acrylic acid

Endpoint summary

Description of key information

Experimental toxicokinetic studies for Epoxy half acrylate are not available.
The physicochemical properties (log Kow in the range of 2.90 – 3.06, water solubility 10.13 - 25.99 mg/L) the molecular weight of 312.36 - 384.42 g/mol are suggestive of oral absorption from gastro-intestinal tract, by dermal route or from the lungs.
Thus, 100% absorption by all routes is assumed as worst case default for chemical safety assessment.
Based on physicochemical properties, no potential for bioaccumulation is to be expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

Experimental toxicokinetic studies are not available for Epoxy half acrylate. Thus, the assessment of toxicokinetics is based on the physicochemical properties:

molecular weight: 312.36 - 384.42 g/mol

water solubility: 10.13 - 25.99 mg/L

log Kow = 2.90 - 3.06

 

Oral absorption

The physicochemical properties of Epoxy half acrylate (log Kow in the range of 2.90 – 3.06) and the molecular weight of 312.36 - 384.42 g/mol are in a range suggestive of absorption from the gastro-intestinal tract subsequent to oral ingestion.

Supporting data are available for the structurally related substance Bisphenol-A-diglycidylether (DGEBPA):

When 14C-DGEBPA was dosed orally to mice (at 55 mg/kg bw), radioactivity was eliminated mostly in the faeces (ca. 80%) and to a lesser extent in the urine (ca. 11%) over the first three days of the experiment. Excretion was very rapid, being over 88% of the administered dose within two days. The tissue radioactivity rapidly depleted from all the tissues studied during the course of the eight day experiment. The mean total recovery of radioactivity, including cage washings, was 93%.

The results from the oral dosing experiment show that 14C-DGEBPA is rapidly eliminated from the body. After eight days only approximately 0.1%, of the administered dose remained in the animals.

The urinary and faecal metabolic profiles from the dermal and oral studies are similar, despite the very different elimination data in the two experiments, and therefore were not dependent on the route of administration of the compound.

 

For chemical safety assessment an oral absorption rate of 100% is assumed as a worst case default value in the absence of other data. 

 

Dermal absorption

Log Kow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high.

The substance is a skin irritant; damage to the skin surface may enhance penetration. As the substance has been identified as a skin sensitizer, some uptake must have occurred although it may only have been a small fraction of the applied dose.

 

Supporting data are available for the structurally related substance Bisphenol-A-diglycidylether (DGEBPA):

When 14C-DGEBPA was applied to the shaved dorsal area of mice (at 56 mg/kg bw), daily elimination of radioactivity in the urine rose to a maximum of only 1.3% of the administered dose two days after treatment. During the remaining six days of the experiment the daily excretion of radioactivity slowly fell to 0.3%, of the administered dose. A similar pattern of elimination was observed for faeces. Daily excretion of radioactivity rose to a broad maximum of approximately 8%, two and three days after the dermal application, falling to 2.35 of the dose after eight days.

A relatively large proportion of the administered dose could be extracted from the skins of the mice one, three and eight days after treatment. Additionally, 26% of the administered dose could be recovered by washing the foil, covering the application area, with methanol. The radioactivity recovered in this manner, remained approximately constant throughout the experiment.

Percutaneous absorption of DGEBPA is slow; 90% of the applied radiochemical can be recovered from the skin and foil covering the application area 24 h after application. This figure falls to about 40% after eight days.

The amount of radiochemical bound to the skin after eight days of continuous contact was 1.8% of the applied dose. There was some evidence to suggest that the rate of chemical binding was higher during the first half of the experiment than during the second half. This effect is probably a result of ‘saturation’ of the reactive sites in the skin (e.g. thiol and amino groups) by interaction with the DGEBPA. Consequently, there are fewer reactive sites available in the skin during that latter half of the experiment. No signs of irritation were observed during the experimental period.

The 14C-DGEBPA was applied to the skin in acetone (50 µL), and although percutaneous absorption of the chemical was slow, the solvent could have facilitated the initial absorption of the compound. A limited study in which two mice were exposed to 14C-DGEBPA in the absence of solvent, to test this hypothesis, indicated that the initial absorption was indeed facilitated by the solvent, but the daily excretion of 14C from day four onwards was approximately the same.

 

In the absence of detailed dermal penetration data it has to be assumed that dermal penetration may occur. For chemical safety assessment a dermal absorption rate of 100% is assumed as a worst case default value based on the physicochemical properties and toxicological data.

 

Inhalative absorption

For chemical safety assessment an inhalative absorption rate of 100% is assumed as a worst case default value in the absence of other data.

 

Distribution

As a small molecule a wide distribution can be expected. No information on potential target organs are available.

 

Supporting data are available for the structurally related substance Bisphenol-A-diglycidylether (DGEBPA):

Neither after dermal nor oral application to mice target organ specificity was observed. Less than 1% of the applied radioactivity was detected in organs, blood or cadaver (Climie et al., 1981).

 

Metabolism

It is very difficult to predict the metabolic changes a substance may undergo on the basis of physico-chemical information alone.

Based on the structurehydrolytic opening of theepoxide ringas well as hydrolysis of the acrylate ester are expected to occur.

Acrylic acid is expected to undergo subsequent rapid metabolism to produce exhaled CO2 or urinary metabolites (mercapturic acid derivatives) (OECD SIDS report, 2005).

 

Supporting data are available for the structurally related substance Bisphenol-A-diglycidylether (DGEBPA):

The major metabolic pathway is hydrolytic opening of the two epoxide groups to form the bis-diol of DGEBPA. This metabolite is eliminated to a small extent in both free and conjugated forms; however, the majority undergoes further metabolic transformations to carboxylic acids. The metabolite profile was similar after oral and dermal application of the substance.

The major metabolic pathway after oral and dermal application of 14C-DGEBPA to mice is hydrolytic opening of the two epoxide groups to form the bis-diol of DGEBPA. This metabolite is eliminated to a small extent in both free and conjugated forms; however, the majority undergoes further metabolic transformations to carboxylic acids (Climie et al., 1981).

Bisphenol-A-diglycidylether was sequenlially hydrolysed to the bis diol via the diol epoxide.

Bisphenol-A-diglycidylether was an excellent substrate for mouse liver cytosolic and microsomal epoxide hydrolases, the specific activity with both enzymes being very similar (Bentley, 1989).

DGEBPA is a substrate for microsomal and cytosolic epoxide hydrolase of skin and liver.Hydrolysis of the epoxide groups leads to metabolic inactivation. Efficient metabolic deactivation is also expected in humans, as epoxide hydrolase activities in liver and skin are higher in humans than in mouse and rat (MAK, 1997).

 

Elimination

The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces.

This is supported by data on the structurally related substance Bisphenol-A-diglycidylether (DGEBPA):

14C-DGEBPA dermally applied to mice was only slowly eliminated in the faeces (20% of the applied dose) and urine (3%), as a mixture of metabolites, over three days. Most of the applied radioactivity (66%) was extracted from the application area and its covering foil.

When 14C-DGEBPA was given orally to mice it was rapidly excreted; 80% of the administered radioactivity was eliminated in the faeces and 11% in the urine 0-3 days after a single oral dose.

 

Bioaccumulation

Based on the log Kow of 2.90 – 3.06 the substance is unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace.

 

References:

Bentley P et al., 1989, Hydrolysis of hisphenol A diglycidylether by epoxide hydrolases in cytosolic und microsomal fractions of mouse liver and skin: inhihition by bis epoxycyclopentylether and the effects upon the covalent binding to mouse skin DNA, Carcinogenesis, vol. 10, no. 2, pp. 321-327, 1989

 

Climie et al., 1981a, Metabolism of the epoxy resin component 2,Z-bis[4-(2,3-epoxypropoxy)phenyl]propane, the diglycidyl ether of bisphenol A (DGEBPA) in the mouse. Part I. A comparison of the fate of a single dermal application and of a single oral dose of 14C-DGEBPA; Xenobiotica, 1981, vol.11, no. 6, 391-399

 

Climie et al., 1981b, Metabolism of the epoxy resin component 2,2-bis[4-(2,3-epoxypropoxy)phenyl]propane, the diglycidyl ether of bisphenol A (DGEBPA) in the mouse. Part II. Identification of metabolites in urine and faeces following a single oral dose of 14C-DGEBPA, Xenobiotica, 1981, vol 11, no. 6, 401-424

MAK, 2012:Bisphenol-A-diglycidylether [MAK Value Documentation in German language, 1997].The MAK Collection for Occupational Health and Safety. 1–30

 

OECD SIDS report, 2005: HYDROXYPROPYL ACRYLATE CAS N°: 25584-83-2, SIDS Initial Assessment Report For SIAM 20

 

JUSTIFICATION FOR READ-ACROSS

Hypothesis for the analogue approach

 

This read-across is based on the hypothesis that source and target substances have similar toxicokinetic properties because they share structural similarities with common functional groups:

-      diphenylmethane derivatives / bisphenols

-      hydroxyphenyl groups

-      glycidyl-ether

 

1. Substance Identity

The target substance Epoxy half acrylate is a UVCB substance containing the reaction products of diglycidyl ether of bisphenol F (DGEBF) and oligomeric phenol diglycidyl ethers with acrylic acid. The main components are shown in Fig. 1.

 

The source substance Bisphenol-A-diglycidylether (BADGE or DGEBPA) has essentially the same structural elements as the main component of the target substance (Bisphenol-F-diglycidyl ether) but contains two additional Methyl groups at the center carbon-atom.

 

Figure 1: Structures of target substance Epoxy half acrylate, main components - see attachment

Figure 2: Structure of thesource substance Bisphenol-A-diglycidylether - see attachment

 

Table 1: Substance identities

	Target substance Epoxy half acrylate	Source substance DGEBPA, Bisphenol-A-diglycidylether
CAS number	n.a.	1675–54–3
EC number	700-487-6	216 -823 -5
Molecular weight	312.36 -384.42	340.42 g/mol
log Kow	2.90 – 3.06	approx. 3.8
Water solubility	10.13 - 25.99 mg/L	No data

 

 2. Analogue approach justification

The read-across hypothesis is based on structural similarity and common functional groups of target and source substance.

 

2.1 Structural similarity

a. Structural similarity and functional groups

The target substance Epoxy half acrylate is a derivative of Bisphenol F where the two hydroxyphenyl groups are modified with glycidol. The glycidol group is partly modified with acrylic acid.

 

The source substance Bisphenol-A-diglycidylether (BADGE or DGEBPA) is a derivative of Bisphenol A where the two hydroxyphenyl groups are modified with glycidol. It has essentially the same structural elements as the main component of the target substance (Bisphenol-F-diglycidyl ether) but contains two additional Methyl groups at the center carbon-atom.

The structures of the target and source substance are depicted in figure 1, see attachment.

 

b. Common breakdown products:

From the structural similarity and identical functional groups it can be expected that the main metabolic pathways – especially the hydrolytic opening of the epoxide groups to form the respective diol – will be essentially the same.

 

c. Differences

The source substance Bisphenol-A-diglycidylether contains two additional Methyl groups at the center carbon-atom, which may explain the higher log Kow of approx. 3.8 compared to the log Kow of 2.90 – 3.06 for the target substance.

The target substance additionally contains half or fully acrylated components (approx. 13.2%).

 

Quality of the experimental data of the analogues

Experimental toxicokinetic data for the target substance are not available.

The available data for the source substance Bisphenol-A-diglycidylether are reliable (RL = 2), well documented publications which meet basic scientific principles or from competent authorities reviewed data.The available data from the source substance are sufficiently reliable to justify the read-across approach.

 

Conclusion for read-across

The structural and physicochemical similarities between the source and the target substances and the similarities in their breakdown products presented above support the read-across hypothesis.