REGULATION & COMPLIANCE strategies are already being applied , supporting the industry in making regulatory compliance decisions , either as single technologies or in combination with other approaches .
OECD test methods for in vitro testing for skin irritation , skin sensitisation and genotoxicity are methods of first choice , well established and well accepted . Predictive in silico tools and toxicokinetic and toxicodynamic ( TK-TD ) modelling are applied to datapoor substances to build up readacross and category approaches , or to get a better understanding of underlying modes of action ( MoA ).
The most used NAM under REACH is the read-across approach , where relevant information from analogous ( structurally related ) substances is used to predict the properties of target substances . Finally , the threshold of toxicological concern approach can be used to justify waiving of the generation of new animal data .
Other non-standard approaches are gaining more and more attention . For example , the incorporation of highthroughput multi ‘ omics ’ approaches enables a wide-ranging screening of potentially modified biological pathways , understanding
the molecular and cellular mechanisms of chemical toxicity , and supporting the identification of MoAs . This information needs to be interpreted on the basis of adverse outcome pathway know-how .
REACH contains upfront testing requirements on vertebrate animals as a last resort . However , incorporating NAMs into compliance and regulatory decisions , with the long-term replacement of animal testing in hazard assessment and risk characterisation of chemicals under REACH and CLP , is highly challenging for industry and regulators . It requires a high level of scientific knowledge and expertise , robust , valid and standardised methodologies and performance , and reliable data interpretation and extrapolation .
In addition , the legislative and regulatory framework needs to be in place for acceptance of NAMgenerated data . This should make it possible to identify hazards with conclusions on whether a substance does or does not have hazardous properties . In case a toxic property has been identified , these methods should be able to characterize hazard types and determine hazard levels based on changes at the molecular or cellular level .
Low tonnage bands
To protect consumers , vulnerable groups and workers from the most harmful chemicals , the EC intends to extend the generic risk management approach by banning these chemicals from the EEA market .
Currently , this categorisation covers chemicals known to cause cancer , gene mutations , reproductive or endocrine system damage , or are persistent and bioaccumulative . In the future , the definition of most harmful chemicals will expand to affecting the immune , neurological or respiratory systems , or which are toxic to a specific organ .
The standard data requirements for chemicals registration in each tonnage band are listed in Annexes VII to X . It is questionable , however , whether the requirements in the lower tonnage bands provide sufficient data to identify the most harmful substances .
Hence , increased data requirements for low and medium tonnages have been presented in March 2023 . The planned changes implement NAMs in the standard data requirements but also pave the way for highertier studies to become mandatory for lower tonnages , depending on substance-specific triggers .
The expected changes in human health data requirements include the replacement of in vivo acute oral toxicity study by in silico model CATMoSin and in vitro cytotoxicity testing ( Neutral Red Uptake Assay ). Furthermore , a TK in vitro package will be added , which addresses the following properties :
• In chemico protein binding ( fraction unbound in human plasma )
• In vitro human hepatic clearance ( isolated human hepatocytes )
• In vitro intracellular bioaccumulation ( Caco-2 cells )
• In vitro intestinal absorption ( Caco-2 permeability )
• In vitro mechanistic information on endocrine disruptors ( ED ), which is relevant to human health and the environment , will be addressed through the following assays :
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