Establishing best practice for N-nitrosamine read-across and surrogate selection

Area of Science:

• * Toxicology and risk assessment
• * Pharmaceutical impurity analysis
• * Computational chemistry and cheminformatics

Background:

• * Read-across is a key method for assessing compound activity using analogue data.
• * Regulatory guidance recommends read-across for N-nitrosamine acceptable intakes, equal in weight to other toxicological methods.
• * Manual read-across is complex, leading to backlogs and driving the development of new approaches like the Carcinogenic Potency Categorization Approach (CPCA).

Purpose of the Study:

• * To propose essential factors for conducting robust manual read-across assessments.
• * To outline considerations for next-generation semi-automated in silico read-across tools.
• * To ensure confident and well-documented conclusions in read-across evaluations for N-nitrosamine compounds.

Main Methods:

• * Review and proposal of factors for manual read-across assessment.
• * Identification of key considerations for semi-automated in silico tools.
• * Presentation of case studies involving N-nitrosamine degradation products (NDSRIs).

Main Results:

• * The study outlines critical factors for both manual and in silico read-across approaches.
• * Case studies demonstrate the practical application and validity of the proposed read-across methodology for NDSRIs.
• * The approach aims to streamline the assessment process and ensure reliable safety evaluations.

Conclusions:

• * A structured approach to read-across, considering specific factors, enhances assessment robustness.
• * Semi-automated in silico tools, guided by these factors, can improve efficiency and confidence.
• * This methodology supports confident decision-making for N-nitrosamine acceptable intakes, addressing safety concerns effectively.