The European Partnership for Alternative Approaches to Animal Testing (EPAA) held the "New Approach Methodologies (NAMs) User Forum Kick-Off Workshop", at the European Chemicals Agency (ECHA), Helsinki, Finland on 7-8 December 2023. The aim of the User Forum was to gain insight into the regulatory use of NAMs, with a particular reference to Next Generation Risk Assessment (NGRA), for chemical safety assessment. To achieve this, presentations summarised the learnings and experiences of previous EPAA Skin Sensitisation User Forums as well as that of the European Commission's Scientific Committee on Consumer Safety (SCCS). The findings of five case studies were summarised that illustrated the use of NAMs. The presentations and subsequent discussions allowed for learnings and insights to be compiled from all stakeholders with regard to the use of NAMs. Recommendations for the regulatory use of NAMs in NGRA were made, namely for exposure assessment; hazard identification; using tiered and targeted testing strategies; performing risk assessment using NAM data; the practical implementation of NAMs; the use of -omics technologies; and the needs for capacity building and training. The EPAA User Forum provided an open platform for safety assessors to share learnings and experiences. Recommendations for the format and topics of future EPAA User Forums were also made.

Environmental Safety Assessments (ESA) are mandatory for several regulatory purposes and are an important component of stewardship/sustainability initiatives. Fish testing is used for assessing chemical toxicity and bioaccumulation potential; amphibians are included in some jurisdictions and their use is increasing to assess endocrine disruption. Alternative methods are becoming more available, covering the principles of the 3Rs (i.e., replacing, reducing and refining animal tests), but their regulatory incorporation is still limited. A cross-sector review by the European Partnership for Alternative Approaches to Animal Testing (EPAA), discussed the status and priorities for accelerating the adoption of non-animal approaches in ESA. The lack of an internationally agreed definition for "animal testing" was recognized as a challenge. For example, testing with vertebrate embryos up to specific developmental stages is a suitable refinement alternative only in some jurisdictions. Invertebrate testing offers refinement alternatives to develop tiered approaches using vertebrate testing as a last resort. Aquatic ESA was identified as a common need by all sectors and regulatory areas, while terrestrial ESA is particularly relevant for agrochemicals. The standardization and validation of some alternative methods as OECD test guidelines (TGs) for fish acute toxicity and fish bioaccumulation have not yet triggered the expected replacement in regulatory settings. Priority actions in these areas are needed to generate confidence in the regulatory use of the available OECD TGs designed as alternatives, including the identification of applicability domains and guidance/decision-trees for integrating different lines of evidence. Case studies under the OECD Integrated Approaches to Testing and Assessment (IATA) program could facilitate further global regulatory uptake. Replacement of fish chronic toxicity testing is more complex and less advanced. A dual approach was suggested, in the short-term, exploring lines of evidence that, alone or in combination, could identify when further fish testing is not needed. The second phase should focus on the application of the 3Rs in those cases where chronic information is needed. Another area of increasing interest is endocrine disruption. It represents a challenge but also an opportunity for implementing mechanistic non-animal methods, in addition to integrate human and ESA. This requires a step-by-step approach with continuous dialogue to ensure that technical developments will address regulatory needs. The review also agreed that the long-term aspiration is a new ESA paradigm, mapping the protection goals and providing connectivity between the chemical legislation and environmental protection policies.

Mechanistically based non-animal methods for assessing skin sensitization hazard have been developed, but are not considered sufficient, individually, to conclusively define the skin sensitization potential or potency of a chemical. This resulted in the development of defined approaches (DAs), as documented in OECD TG 497, for combining information sources in a prescriptive manner to provide a determination of risk or potency. However, there are currently no DAs within OECD TG 497 that can derive a point of departure (POD) for risk assessment. The Skin Allergy Risk Assessment - Integrated Chemical Environment (SARA-ICE) DA for skin sensitization is a Bayesian statistical model that estimates a human-relevant metric of sensitizer potency, the ED01, an estimate of the human predictive patch test dermal dose at which there is 1% chance of inducing sensitization, which can be used in a risk assessment paradigm. The model accounts for variability of input data and explicitly quantifies uncertainty. SARA-ICE derives the ED01 from a variety of in vitro and in vivo test method data and is built upon historical human, murine, and in vitro test data for 434 chemicals. In addition to the ED01 POD SARA-ICE DA also provides a Globally Harmonized System of Classification and Labelling of Chemicals (GHS) classification probability for GHS subcategories 1A, 1B and not classified (NC). Here we describe the SARA-ICE model and its evaluation, including performance versus benchmark PODs. In addition, via a case study with isothiazolinones (ITs), we demonstrate the utility of SARA-ICE for integrating different data inputs and compare the ED01 for six ITs to existing historical data.

Some fragrance ingredients may have the potential to induce skin sensitization in humans but can still be safely formulated into consumer products. Quantitative Risk Assessment (QRA) for dermal sensitization is required to determine safe levels at which potential skin sensitizers can be incorporated into consumer products. The no expected sensitization induction level or NESIL is the point of departure for the dermal QRA. Sensitization assessment factors are applied to the NESIL to determine acceptable exposure levels at which no skin sensitization induction would be expected in the general population. This paper details the key steps involved in deriving a weight of evidence (WoE) NESIL for a given fragrance ingredient using all existing data, including in vivo, in vitro, and in silico. Read-across can be used to derive a NESIL for a group of structurally similar materials when data are insufficient. When sufficient target and read-across data are lacking, exposure waiving threshold (the DST) may be used. We outline the process as it currently stands at the Research Institute for Fragrance Materials Inc. (RIFM) and provide examples, but it is dynamic and is bound to change with evolving science as new approach methodologies (NAMs) are actively incorporated.