Ranking of substances included in epoxy resin systems according to their sensitizing potency

Status:

completed 12/2012

Aims:

Epoxy resin systems contain sensitizing substances within the resin, the reactive diluents and/or in curing agents. This represents a relevant health problem in occupational use of these systems. Aims of this project: Development of an assessment method in order to discriminate the sensitizing potency of the single substances and selection of such epoxy resin systems which are associated with the lowest health impairment. Ranking of a number of currently 52 sensitizing substances, which may occur in epoxy resin systems, enabled by the assessment method, based on an integrative "weight of evidence" approach. Assessment of the relevance of the respective health impairments due to occupational exposure to sensitizing substances contained in epoxy resin systems also by observational human data.

Activities/Methods:

1. Evaluation of in vivo-, in vitro- and in silico-methods related to sensitization and sensitizing potency for their applicability to assess the substances in question. 2. Aggregation of single results by a weight of evidence approach to an overall assessment. 3. Rating of the assessment of the sensitizing properties to other health effects of the respective substances and including in the ranking outcome. 4. The feasibility should be validated and demonstrated by realistic examples. 5. Literature data, human testing results, as well as retrospective and prospective questionnaires of exposed or sensitized persons (up to 150 interviews) for supporting the analysis of causal relationships and demonstrating the relevance of the issue.

Results:

For potency classification of substances contained in epoxy resin systems we used existing results from in vivo-experiments (Guinea pig maximisation test (GPMT), Buehler-test, Local Lymph node assay (LLNA), Mouse ear swelling test (MEST), Human Repeat Insult Patch Test (HRIPT), Human maximization test (HMT)) as well as results from in vitro-testing (to cover all stages of the sensitization process, i.e. bioavailability, skin penetration, haptenisation, reaction by keratinocytes (specifically: KeratinoSensTM), maturation (specifically: h-CLAT) and migration of dendritic cells, T-cell activation and proliferation of allergen specific T-cells) and including results from in silico-analysis. The suitability of tests was confirmed and conditions of the test results were considered. Data of human experience (from literature research and from an extended data base by the dermatological association IVDK) were also analysed and used for assessment. The practical relevance of substances was included by evaluation of safety data sheets and by reference to a questionnaire to the members of a steering committee assigned to this project. For the data gaps detected a targeted test program was proposed and performed in parts for a subset of reactive diluents (in vitro-tests: h-CLAT and KeratnoSensTM) in order to check the suitability of the testing proposal. From the testing a few first substances with formerly unknown properties could be assigned to potency classes. For the remaining substances with currently no adequate data a specific testing program was proposed but not yet performed. From initially 51 substances contained in epoxy resin systems there finally resulted 46 classifications. More than half of the substances were assigned to a default category because of the lack of appropriate data (category "U", 21 substances, or 45.7 percent, respectively). For the time being they should be regarded as if they were of high potency (category: "HS"). 16 substances were directly assigned to this category ("HS"). Further 9 substances were allocated to the group of substances with low or moderate sensitizing potency (category: "GMS"), corresponding to 34.8 ("HS") and 19.6 percent ("GMS"), respectively. The following substances were associated with a high sensitizing potency ("HS"): - Epoxy resins: Bisphenol A-resin (CAS-Nr.: 25068-38-6 & 25085-99-8), Bisphenol-A-Epichlorohydrin MW 340 (1675-54-3), Bisphenol F-resin (9003-36- 5 & 28064-14-4), - Hardeners: Ethylenediamine (107-15-3), Diethylenetriamine (111-40-0), Trimethylhexamethylenediamine (25620-58-0), Triethylenetetramine (112-24-3), Isophorone diamine (2855-13-2), m-Xylidenediamine (1477-55-0), Phthalic anhydride (85-44-9), Tetrahydrophthalic anhydride (85-43-8), Hexahydrophthalic anhydride (85-42-7), - Reactive diluents: 1,4-Butanediol diglycidyl ether (2425-79-8), 1,6-Hexandiol diglycidyl ether (16096-31-4), Phenyl glycidyl ether (122-60-1), Cresyl glycidyl ether (26447-14-3 & 2210-79-9). For these substances substitutes should be considered if possible (substances with lower sensitizing potency or non-sensitising chemicals). It is, however, acknowledged that some of the substances may not be substituted because of technical reasons. The results of this project provide a qualified platform to characterize the sensitising properties of many substances contained in epoxy resin systems. Furthermore, the project provides a suitable input to perform rankings for the sensitising potency of these substances.

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