Intrathecal (IT) and intracerebroventricular (ICV) administration enable direct access to the central nervous system but introduce route-specific complexities in nonclinical study design, execution, and interpretation. This webinar translates those complexities into practical principles for toxicologists aiming to deliver sound risk assessment and regulatory-ready packages. The speakers will examine how administration parameters, surgical technique, catheter/device considerations, dosing paradigms, and species selection (rodent vs. nonrodent) shape data quality and translational relevance. Direct IT delivery can produce procedure-related microscopic findings from localized injury or irritation of CNS tissues; however, microscopic changes of similar character and/or severity may also arise from the test article (TA), complicating interpretation. Approaches that can be used to help differentiate procedure-related from TA-related microscopic changes will also be discussed.