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

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated 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: Well documented publication which meets basic scientific principles

Data source

Reference

Reference 1

Reference Type:

publication

Title:

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

Author:

CLIMIE IJG et al.

Year:

1981

Bibliographic source:

Xenobiotica, 1981, vol.11, no. 6, 391-399

Reference 2

Reference Type:

publication

Title:

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

Author:

CLIMIE IJG et al.

Year:

1981

Bibliographic source:

Xenobiotica, 1981, vol 11, no. 6, 401-424

Materials and methods

Objective of study:

excretion

metabolism

other: dermal absorption

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Metabolism and extrection after single oral or dermal administration of 2,2-Bis-[4-(2,3-epoxypropoxy)phenyl][2-14C]propane (DGEBPA) was studied in mice.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

1675-54-3 (2,2-Bis-[4-(2,3-epoxypropoxy)phenyl][2-14C]propane, DGEBPA)

IUPAC Name:

1675-54-3 (2,2-Bis-[4-(2,3-epoxypropoxy)phenyl][2-14C]propane, DGEBPA)

Details on test material:

- Name of test material (as cited in study report): 2,2-Bis-[4-(2,3-epoxypropoxy)phenyl][2-14C]propane, 14C-DGEBPA
- Radiochemical purity (if radiolabelling): >99%
- Specific activity (if radiolabelling): 6.33 µCi/mg

Radiolabelling:

yes

Test animals

Species:

mouse

Strain:

CF-1

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 28 g
- Housing: individually in metabolism cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

Administration / exposure

Route of administration:

other: oral, dermal

Vehicle:

other: oral: DMSO:water 3:1; dermal: acetone

Duration and frequency of treatment / exposure:

single oral or dermal application

Doses / concentrations

Remarks:

Doses / Concentrations:
oral: 55 mg/kg bw
dermal: 56 mg/kg bw

No. of animals per sex per dose / concentration:

6 (killed in groups of 2 at day 1, 3 and 8 after treatment)

Control animals:

no

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, blood, skin, liver, kidney, intestine, fat, remaining carcass
- Time and frequency of sampling: urine + faeces daily; other samples day 1, 3, 8

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, blood, skin, liver, kidney, intestine, fat, remaining carcass
- Time and frequency of sampling: urine + faeces daily; other samples day 1, 3, 8
- Method type(s) for identification: TLC, MS, NMR

Results and discussion

Main ADME results

Main ADME results 1

Type:

other: dermal absorption

Results:

Percutaneous absorption was slow: 90% of the applied radiochemical was recovered from skin and foil covering the application area 24 h after application, 40% after 8 days.

Main ADME results 2

Type:

metabolism

Results:

The major metabolic transformation of orally ingested or dermally applied 14C-DGEBPA is by hydrolytic ring-opening of the epoxide rings to form diols.

Main ADME results 3

Type:

metabolism

Results:

similar metabolic profiles after oral and dermal application

Main ADME results 4

Type:

excretion

Results:

rapid excretion after oral administration

Toxicokinetic / pharmacokinetic studies

Details on excretion:

14C-DGEBPA dermally applied to mice was slowly eliminated in the faeces (ca. 2.3-3.4% of the applied dose after 24 h, ca. 12-18% after 3 d, ca. 40.9% aftre 8 d) and urine (ca. 0.43-0.9% of the applied dose after 24 h, ca. 3-3.8% after 3 d, ca. 4.3-5.6% after 8 d) as a mixture of metabolites.
Most of the applied radioactivity (90% after 24 h, 40% after 8 d) 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.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

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.

Any other information on results incl. tables

Dermal application

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.Alimited 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.

 

Oral application

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.

 

Metabolism

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.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
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.
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.