12. Pathology

12.1 Macroscopic Examination

All scheduled animals were necropsied per protocol; necropsy records, individual macroscopic observation tables and organ-weight listings are captured in the evidence chain. No treatment-related macroscopic findings were observed in the low- and mid-dose groups; in the high-dose group a few animals showed slightly darker liver coloration and mild rounding of the margins, without necrotic foci or evident mass lesions.

Considering pre-dose general condition, terminal body weight and food-consumption trends, the macroscopic examination revealed no evidence of acute deterioration indicative of systemic toxicity. A trend toward increased liver weight was seen in the high-dose group, with rounded liver margins in occasional animals; the relationship to treatment requires confirmation against the histopathology results.

Macroscopic observations of the spleen, kidney, thymus and gastrointestinal tract showed no consistent changes. A slight reduction in gastric contents in isolated animals did not form a dose-related trend, and was therefore not carried into the conclusions as a primary toxicological finding.

12.2 Histopathology Findings

Histopathology covered the protocol-specified tissues; slides were pre-screened by the pathology reading system and confirmed by a pathologist. The incidence and severity of incidental background changes in the control group were within the laboratory historical control range.

Histopathology revealed an increased incidence of hepatocellular hypertrophy in the high-dose group, showing a dose-related trend. The change was predominantly centrilobular, mostly minimal to slight in severity, without accompanying marked cellular necrosis, increased inflammatory infiltration or cholestasis.

Taken together with toxicokinetic exposure and liver-weight changes, the hepatocellular hypertrophy is most likely an adaptive change, but must be cross-confirmed with the §13 exposure data in the final conclusions.