<![CDATA[Castanopsis costata (cep-cepan ) leaves are traditionally used in North Sumatra and have demonstrated antidiabetic, analgesic, anti-inflammatory, and antioxidant activities. However, their safety following repeated administration remains inadequately characterized, and comparative toxicological data within the Castanopsis genus and the broader Fagaceae family remain limited. This study aimed to evaluate the 28-day subchronic oral toxicity of C. costata leaf ethanol extract based on liver and kidney histopathological findings in female mice. An experimental post-test-only control group design was employed. Twenty female mice (n = 5 per group; four groups; total N = 20) were randomly allocated to a control group receiving 0.5% Na-CMC and three treatment groups receiving C. costata leaf ethanol extract at doses of 250, 500, and 1000 mg/kg body weight (BW) orally once daily for 28 days, following an adapted OECD Test Guideline 407. On day 29, the animals were euthanized; liver and kidney tissues were collected, processed using hematoxylin-eosin staining, and evaluated using a semiquantitative histopathological scoring system. Data were analyzed using the Shapiro-Wilk and Kruskal-Wallis tests. Phytochemical screening identified alkaloids, flavonoids, tannins, steroids/triterpenoids, and anthraquinone glycosides, whereas saponins were not detected. The extract yield was 11.39%. Kidney histopathology scores did not differ significantly among groups (H = 7.028; p = 0.071), and glomerular and tubular architecture remained preserved across all dose levels. In contrast, liver histopathology scores differed significantly among groups (H = 46.793; p < 0.001). Mild, non-diffuse hepatocellular degeneration and isolated apoptosis or necrosis lesions affecting less than 5% of the hepatic parenchyma increased with dose and were most pronounced at 1000 mg/kg BW, whereas steatosis and fibrosis were absent at all grouops. These field-level statistical findings should be considered preliminary pending reanalysis using the individual animal, rather than the microscopic field, as the unit of analysis. Under the conditions of this study, repeated administration of C. costata leaf ethanol extract for 28 days did not induce structural renal alterations but was associated with mild, dose-dependent hepatic histopathological changes that became evident at 500 mg/kg BW and were most pronounced at 1000 mg/kg BW. Doses up to 250 mg/kg BW showed no discernible histopathological changes in either organ, supporting the extract’s relative safety at this dose for the parameters evaluated, whereas the 1000 mg/kg BW dose warrants caution pending biochemical confirmation. Further studies incorporating serum biochemical analyses, corrected animal-level statistical re-analysis, and longer-term toxicity assessments are recommended before prolonged use can be considered. Keywords: Castanopsis costata, subacute toxicity, subchronic toxicity, hepatic histopathology, liver, kidney]]>
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