Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
dermal absorption, other
Remarks:
GastroPlus modeling
Type of information:
calculation (if not (Q)SAR)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
accepted calculation method

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2021

Materials and methods

Principles of method if other than guideline:
The potential absorption and systemic bioavailability of monomeric MDI isomers and modified MDI substances in human via the skin was predicted with the mechanistically-based pharmacokinetic software, GastroPlus®.
GLP compliance:
no

Test material

Specific details on test material used for the study:
Number Constituents MW
1 4,4’-MDI 250
2 2,4’-MDI 250
3 2,2’-MDI 250
4 3-Ring Oligomer 381
5 4,4'-MDI Carbodiimide Dimer* 457
6 4,4'-MDI Uretdione Dimer* 501
7 4-Ring Oligomer 513
8 4,4’-MDI/PG/2,4’-MDI 577
9 2,4’-MDI/PG/2,4’-MDI 577
10 4,4’-MDI/PG/4,4’-MDI 577
11 4,4’-MDI/BD/2,4’-MDI 591
12 4,4’-MDI/BD/4,4’-MDI 591
13 4,4’-MDI/DEG/2,4’-MDI 607
14 4,4’-MDI/DEG/4,4’-MDI 607
15 4,4’-MDI/DPG/4,4’-MDI 635
16 4,4’-MDI/TPG/2,4’-MDI 693
17 4,4’-MDI/TPG/4,4’-MDI 693
18 Homopolymer - first condensation adduct 707
19 PIR - second condensation adduct 751
20 4,4’-MDI/PG/4,4-MDI/PG/2,4’-MDI 903
21 4,4’-MDI/PG/4,4’-MDI/PG/4,4’-MDI 903
22 4,4’-MDI/BD/4,4-MDI/DEG/2,4’-MDI 947
23 4,4’-MDI/BD/4,4’-MDI/DEG/4,4’-MDI 947
24 4,4’-MDI/TPG/4,4’-MDI/PG/4,4’-MDI 1,019
25 1st condens adduct /PG/4,4’-MDI 1,033
26 4,4’-MDI/TPG/4,4’-MDI/1,3-BD/4,4’-MDI 1,033
27 4,4’-MDI/PG/4,4’-MDI/PG/4,4’-MDI/DEG/2,4’-MDI 1,259
28 4,4’-MDI/PG/4,4’-MDI/PG/4,4’-MDI/DEG/4,4’-MDI 1,259
29 4,4’-MDI/DEG/4,4’-MDI/DEG/4,4’-MDI/DEG/2,4’-MDI 1,319
30 4,4’-MDI/DEG/4,4’-MDI/DEG/4,4’-MDI/DEG/4,4’-MDI 1,319
31 4,4’-MDI/1,3-BD/4,4-MDI/1,3-BD/4,4-MDI/TPG /2,4’-MDI 1,374
32 4,4’-MDI/1,3-BD/4,4’-MDI/1,3-BD/4,4’-MDI/TPG/4,4’-MDI 1,374
33 4,4’-MDI/DPG/4,4’-MDI/DPG/4,4’-MDI/DPG/4,4’-MDI 1,404
34 4,4’-MDI/TPG/4,4’-MDI/TPG/4,4’-MDI/TPG/2,4’-MDI 1,578
35 2,4’-MDI/TPG/2,4’-MDI/TPG/2,4’-MDI/TPG/2,4’-MDI 1,578
36 4,4’-MDI/TPG/4,4’-MDI/TPG/4,4’-MDI/TPG/4,4’-MDI 1,578
37 4,4’-MDI/TPG/4,4’-MDI/TPG/4,4’-MDI/TPG/4,4’-MDI /TPG/4,4’-MDI 2,020
38 1st condens adduct /TPG/4,4’-MDI/TPG/4,4’-MDI/TPG/4,4’-MDI 2,034
39 4,4’-MDI/DPG/4,4’-MDI/DPG/4,4’-MDI/DPG/4,4’-MDI /DPG/4,4’-MDI /DPG/4,4’-MDI 2,172

Test animals

Species:
other: Human, Rat

Administration / exposure

Type of coverage:
occlusive
Vehicle:
acetone
Duration of exposure:
8hr

Results and discussion

Applicant's summary and conclusion

Conclusions:
Initial GastroPlus-based modeling was conducted for dermal bioavailability of testosterone in rat and human and 4,4’-MDI in rat to evaluate the accuracy of this modeling software. In silico predictions were comparable to prior in vivo results, with predicted bioavailability of testosterone in rat and human at 48% and 16%, respectively, vs. measured values of 47% and 13%, respectively. Predicted uptake of 4,4’-MDI into rat skin was 55% vs. measured values of 26-56% (for parent compound and/or metabolites), while predicted systemic bioavailability of parent compound through the skin was 0.3% vs. empirical values of <1%. Further modeling of 4,4’-MDI dermal uptake in rat with the exposure conditions used in the subsequent human simulations (1 μL acetone vehicle volume/cm2 surface area vs. 10 μL/cm2 used in in vivo study) afforded test material dermal absorption of 100% and systemic bioavailability of 4.0%. Definitive modeling of dermal absorption into skin and bioavailability through skin of monomeric MDI isomers and modified MDI substances was then conducted utilizing either volatile acetone or non-volatile octanol solvent vehicles applied to a human arm. Assuming test material exposure in an acetone solvent, predicted absorption and bioavailability of the three MDI isomers was 84-86% and 1.4-1.5%, respectively. Lower absorption/bioavailability values were predicted for oligomeric MDI species: ‘3-ring’ at 26% and 0.4%, respectively and’ 4-ring’ at 7% and 0.1%, respectively. All 34 remaining possible/expected MDI constituents were predicted to have even lower human dermal uptake (<0.1-1.3%) and bioavailability (<0.1%) than MDI monomers. In silico modeled dermal exposures in non-volatile octanol solvent, afforded overall lower predicted absorption and bioavailability than with acetone vehicle. Dermal absorption and bioavailability of the threeMDI isomers was 4-7% and 0.1%, respectively. Lower absorption/bioavailability values were predicted for oligomeric MDI constituents: 3-ring at 0.8% and <0.1%, respectively, and 4-ring at 0.2% and <0.1%, respectively. All 34 remaining possible/expected MDI constituents were predicted to have even lower human dermal uptake (<0.1-0.3%) and bioavailability (<0.1%) than MDI isomers. The results of the GastroPlus dermal absorption modeling show that 36 non-monomeric MDI constituents would have lower absorption into the skin and bioavailability than the three MDI isomers. These results are consistent regardless of vehicle solvent, test substance concentration, exposure time, or metabolic clearance rates within the skin compartments.
Executive summary:

The results of the GastroPlus dermal absorption modeling show that 36 MDI constituents would have lower absorption into the skin and bioavailability than the three monomeric MDI isomers. MDI constituents with MW > 1000 are predicted to have the lowest bioavailability. These results are consistent regardless of vehicle solvent, test substance concentration, exposure time, or metabolic clearance rates within the skin compartments.


The results of these in silico evaluations should be useful in category-based, Read-Across Assessments for monomeric MDI isomers and modified MDI substances.

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