Joint poster with DSM: Case study on process-related impurities in polymeric materials

In vitro assessment of skin sensitizing potential of process-related impurities in polymeric materials during product development.

Presented at 2022 ESTIV

 

Abstract

Andy Forreryd1, Stefan Kaiser2, Roman Goy2, Florian Glaus2, Ulrika Mattson1, Robin Gradin1, Henrik Johansson1

1 SenzaGen AB, 22381 Lund, Sweden

2 DSM Nutritional Products Ltd, 4303 Kaiseraugst, Switzerland

Skin sensitization testing represents a key toxicological endpoint during safety evaluation of ingredients intended for consumer products with topical exposure, both in a regulatory context and during product development, to early understand the toxicological profile of the end-product and potential impurities.

The inclusion of New Approach Methods (NAMs) for skin sensitization testing into OECD TGs have resulted in a broader acceptance of such methods as replacements to animal models. However, these methods are not universally applicable, and compounds with certain properties, such as lipophilicity, or of complex composition, are frequently considered outside the applicability domain.

GARDskin is a genomic-based next-generation in vitro assay for assessment of skin sensitizers progressing towards regulatory acceptance. The assay is highly sensitive, is compatible with a variety of solvents and has a demonstrated applicability for testing of lipophilic materials.

The aim of this study was to evaluate the skin sensitization potential of a lipophilic polymeric material (Mw > 2000g/mol) containing approximately 2% impurities, during product development. The polymeric material was initially flagged as a skin sensitizer. A preparative procedure was applied to purify the polymer from impurities, while generating enriched by-product fractions (oligomeric fraction, Mw: 500-1000 g/mol and small molecule fraction, Mw: <500 g/mol). The fractions were evaluated in GARDskin, using acetone or DMSO as solvents, and classified as skin sensitizers (by-products) and non-sensitizers (purified polymers, n=2), respectively, indicating that the impurities were responsible for the positive classification of the initial non-purified polymeric material.

In conclusion, the GARDskin protocol enabled for testing of the lipophilic materials, using a selection of solvents to increase solubility. Results from this study informed that actions to reduce concentration of impurities may be a useful strategy to prevent skin sensitization properties of the final end-product, highlighting the importance of skin sensitization testing during the production development.

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The GARDskin assay: Investigation of the applicability domain for metals

Joint publication with Johnson Matthey

ALTEX – Alternatives to animal experimentation, published Nov 03, 2022, accepted manuscript

DOI: https://doi.org/10.14573/altex.2203021

Forreryd, A., Gradin, R., Larne, O., Rajapakse, N., Deag, E. and Johansson, H.


Abstract

New approach methods (NAMs) for hazard identification of skin sensitizing chemicals have been adopted as test guidelines by the OECD during the last decade as alternatives to animal models. These models align to individual key events (KE) in the adverse outcome pathway (AOP) for skin sensitization for which the molecular initiating event (MIE) is covalent binding to proteins. As it currently stands, the AOP does not include mechanistic events of sensitization by metals, and limited information is available on whether NAMs accurately the predict sensitization potential of such molecules, which have been proposed to act via alternative mechanisms to organic chemicals.

Methods for assessing the sensitization potential of metals would comprise valuable tools to support risk management within e.g., occupational settings during production of new metal salts or within the medical device industry to evaluate leachables from metal alloys.

This paper describes a systematic evaluation of the applicability domain of the GARD™skin assay for assessment of metals. Hazard classifications were supplemented with an extended analysis of gene expression profiles induced by metal sensitizers to compare the induction of toxicity pathways between metals and organic sensitizers. Based on the results of this study, the accuracy, sensitivity, and specificity of GARD™skin for prediction of skin sensitizing hazard were 92% (12/13), 100% (7/7) and 83% (5/6), respectively.

Thus, the performance of GARD™skin for assessment of metals was found to be similar to what is observed on conventional organic substances, providing support for inclusion of metals within the applicability domain of the test method.

Keywords

skin sensitization, metals, regulatory testing, medical devices

Full article on line with open access