Alternative approaches for acute inhalation toxicity testing to address global regulatory and non-regulatory data requirements: an international workshop report

Inhalation toxicity testing, which provides the basis for hazard labeling and risk management of chemicals with potential exposure to the respiratory tract, has traditionally been conducted using animals. Significant research efforts have been directed at the development of mechanistically based, non-animal testing approaches that hold promise to provide human-relevant data and an enhanced understanding of toxicity mechanisms. A September 2016 workshop, “Alternative Approaches for Acute Inhalation Toxicity Testing to Address Global Regulatory and Non-Regulatory Data Requirements”, explored current testing requirements and ongoing efforts to achieve global regulatory acceptance for non-animal testing approaches. The importance of using integrated approaches that combine existing data with in vitro and/or computational approaches to generate new data was discussed. Approaches were also proposed to develop a strategy for identifying and overcoming obstacles to replacing animal tests. Attendees noted the importance of dosimetry considerations and of understanding mechanisms of acute toxicity, which could be facilitated by the development of adverse outcome pathways. Recommendations were made to (1) develop a database of existing acute inhalation toxicity data; (2) prepare a state-of-the-science review of dosimetry determinants, mechanisms of toxicity, and existing approaches to assess acute inhalation toxicity; (3) identify and optimize in silico models; and (4) develop a decision tree/testing strategy, considering physicochemical properties and dosimetry, and conduct proof-of-concept testing. Working groups have been established to implement these recommendations

PvT Measurements of trans-1,3,3,3-Tetrafluoroprop-1-ene + Methane and trans-1,3,3,3-Tetrafluoroprop-1-ene + Nitrogen Binary Pairs

Presented in this work are 102 vapor phase PvT measurements for blends of trans-1,3,3,3-tetrafluoroprop-1-ene (R1234ze(E)) + methane and 85 vapor phase PvT measurements for blends of R1234ze(E) + nitrogen. The R1234ze(E) + methane data consist of eight data sets measured along five isochores (0.12, 0.09, 0.06, 0.04, and 0.03) m(3 center dot)kg(-1) for (267 < T < 413) K. The blends consisted of four methane mole fractions (0.25, 0.31, 0.50, and 0.75) mol.mol(-1). The R1234ze(E) + nitrogen data consist of six data sets measured along three isochores (0.07, 0.11, and 0.14) m(3 center dot)kg(-1) for (263 < T < 413) K. The blends consisted of three nitrogen mole fractions (0.25, 0.50, and 0.75) mol.mol(-1)

Applying non-animal strategies for assessing skin sensitisation report from an EPAA/cefic-LRI/IFRA Europe cross sector workshop, ECHA helsinki, February 7th and 8th 2019

Four years on since the last cross sector workshop, experience of the practical application and interpretation of several non-animal assays that contribute to the predictive identification of skin sensitisers has begun to accumulate. Non-animal methods used for hazard assessments increasingly are contributing to the potency sub-categorisation for regulatory purposes. However, workshop participants generally supported the view that there remained a pressing need to build confidence in how information from multiple methods can be combined for classification, sub-categorisation and potency assessment. Furthermore, the practical experience gained over the last few years, highlighted the overall high potential value of using the newly validated methods and testing strategies, but also that limitations for certain substance/product classes may become evident with further use as had been the case with other new regulatory methods. As the available information increases, review of the data and collated experience could further determine strengths and limitations leading to more confidence in their use. Finally, the need for a substantial and universally accepted dataset of non-sensitisers and substances of different sensitising potencies, based on combined human and in vivo animal data for validation of methods and test strategies was re-emphasised.JRC.F.3-Chemicals Safety and Alternative Method

Chemical carcinogen safety testing: OECD expert group international consensus on the development of an integrated approach for the testing and assessment of chemical non-genotoxic carcinogens

While regulatory requirements for carcinogenicity testing of chemicals vary according to product sector and regulatory jurisdiction, the standard approach starts with a battery of genotoxicity tests (which include mutagenicity assays). If any of the in vivo genotoxicity tests are positive, a lifetime rodent cancer bioassay may be requested, but under most chemical regulations (except plant protection, biocides, pharmaceuticals) this is rare. The decision to conduct further testing based on genotoxicity test outcomes creates a regulatory gap for the identification of non-genotoxic carcinogens (NGTxC). In 2016 the Organisation of Economic Cooperation and Development (OECD) established an expert group to address the development of an integrated approach to the testing and assessment (IATA) of NGTxC, with the objective of addressing this gap. Through that work, a definition of NGTxC in a regulatory context was agreed. Using the adverse outcome pathway (AOP) concept, various cancer models were developed, and overarching mechanisms and modes of action were identified. After further refining and structuring with respect to the common hallmarks of cancer and knowing that NGTxC act through a large variety of specific mechanisms, with cell proliferation commonly being a unifying element, it became evident that a panel of tests covering multiple biological traits will be needed to populate the IATA. Consequently, in addition to literature and database investigation, the OECD opened a call for relevant assays in 2018 to receive suggestions. Here we report on the definition, on the development of the overarching NGTxC IATA, and on the development of ranking parameters to evaluate the assays. Ultimately, the intent is to select best scoring assays for each IATA module for further validation, for OECD test guideline development, and for their integration in a NGTxC IATA to better identify carcinogens and reduce public health hazards.JRC.F.3-Chemicals Safety and Alternative Method

Chemical carcinogen safety testing: OECD expert group international consensus on the development of an integrated approach for the testing and assessment of chemical non-genotoxic carcinogens

International audienceWhile regulatory requirements for carcinogenicity testing of chemicals vary according to product sector and regulatory jurisdiction, the standard approach starts with a battery of genotoxicity tests (which include mutagenicity assays). If any of the in vivo genotoxicity tests are positive, a lifetime rodent cancer bioassay may be requested, but under most chemical regulations (except plant protection, biocides, pharmaceuticals), this is rare. The decision to conduct further testing based on genotoxicity test outcomes creates a regulatory gap for the identification of non-genotoxic carcinogens (NGTxC). With the objective of addressing this gap, in 2016, the Organization of Economic Cooperation and Development (OECD) established an expert group to develop an integrated approach to the testing and assessment (IATA) of NGTxC. Through that work, a definition of NGTxC in a regulatory context was agreed. Using the adverse outcome pathway (AOP) concept, various cancer models were developed, and overarching mechanisms and modes of action were identified. After further refining and structuring with respect to the common hallmarks of cancer and knowing that NGTxC act through a large variety of specific mechanisms, with cell proliferation commonly being a unifying element, it became evident that a panel of tests covering multiple biological traits will be needed to populate the IATA. Consequently, in addition to literature and database investigation, the OECD opened a call for relevant assays in 2018 to receive suggestions. Here, we report on the definition of NGTxC, on the development of the overarching NGTxC IATA, and on the development of ranking parameters to evaluate the assays. Ultimately the intent is to select the best scoring assays for integration in an NGTxC IATA to better identify carcinogens and reduce public health hazards