## 5 Toxicological Data
### Subchronic and Chronic Toxicological Data  
Several studies have been conducted on the chronic behavior of date seed extracts. Date seed extracts were administered at different dose levels. An overview of the available animal and human studies is given in Table 6.  
An in vivo rat study was performed to compare the physiological effects of _C. arabica_ coffee, date seed coffee, _Cassia occidentalis_ seed coffee, and barley coffee consumption [79]. All test samples were prepared identically. A group of 25 male adult rats were divided into five sub-groups. The control group received water only and the test groups received a basal diet of 15-20 mL per day of each coffee-like beverage over 8 weeks. There were no significant differences in body weight gain or organ weight among all groups. The group that consumed date seed coffee showed a normal histological brain structure and mucosal lining of the stomach. The serum lipid profile revealed the highest total lipid value in the date seed coffee group (773 \(\pm\) 37 mg/dL) compared to the control group (617 \(\pm\) 30 mg/dL). Total cholesterol, LDL, and HDL levels were slightly increased in the date seed coffee group, but were significantly lower than those in the _C. arabica_ coffee sample group. Triglyceride levels were measured at 139 \(\pm\) 26 mg/dL compared to 95 \(\pm\) 6 mg/dL in the control group. \begin{table}
\begin{tabular}{c c c c c c} \hline \hline
**Effect Assessed** & **Species** & **Dose Rate** & **Duration (d)** & **Outcome** & **Reference** \\ \hline \multirow{4}{*}{ \begin{tabular}{c} Effects of DS extract on liver \\ function, lipid profile, and heart \\ function \\ \end{tabular}  } & \multirow{4}{*}{rat} & \multirow{4}{*}{ \begin{tabular}{c} Basal diet, supplemented by \\ 15-20 mL/d DS extract \\ \end{tabular}  } & \multirow{4}{*}{56} & \multirow{4}{*}{ \begin{tabular}{c} Increase in serum lipids; \\ decrease in CK-NAC, CK-MB, \\ LDH-P, high ALP; normal \\ histological brain structure and \\ mucosal lining of the stomach \\ \end{tabular}  } & \multirow{4}{*}{[79]} \\  & & & & \\ \hline \multirow{4}{*}{ \begin{tabular}{c} Effects of DS extract on liver \\ function and lipid profile \\ \end{tabular}  } & \multirow{4}{*}{rat} & \multirow{4}{*}{ \begin{tabular}{c} (1) Feed: 1\%, 5\%, or 10\% \\ DS fiber \\ \end{tabular}  } & \multirow{4}{*}{24} & \multirow{4}{*}{ \begin{tabular}{c} Increase in serum lipids and \\ cholesterol; overall weight gain \\ \end{tabular}  } & \multirow{4}{*}{[29]} \\  & & & & \\ \hline \multirow{4}{*}{\ \begin{tabular}{c} Effects of DS extract on the NO \\ concentration, MDA level, total \\ cholesterol, triglycerides (TGs), \\ AST, ALT, amyloid A, and \\ C-reactive protein (CRP) \\ \end{tabular}  } & \multirow{4}{*}{[51]} \\  & & & & \\ \hline \multirow{4}{*}{ \begin{tabular}{c} Effects of DS extract in a \\ high-fat diet on body and liver \\ weight, glucose and insulin, \\ total cholesterol, TGs \\ \end{tabular}  } & \multirow{4}{*}{rat} & DS extracts of QT, BR, or RT \\  & & & & \\ \cline{1-1}  & & &Consumption of date seed coffee resulted in a decrease in creatine kinase activity (CK-NAC and CK-MB), while LDH-P activity showed a slight increase. The group that consumed date seed coffee showed a significantly higher ALP value (111.9 \(\upmu\)/mL) compared to the control group (71.5 \(\upmu\)/mL) and a lower AST value, which was half of the control group's value. An increase in the ALP value may indicate adverse effects on liver cells and could be related to cholestasis, but the elevated reading should still be within the reference range. The study linked the increase to the degradation of fatty acids. However, the study did not provide any further description of possible harmful impacts or a histological examination of liver tissue [79]. A feeding study was conducted to investigate the effects of date seed fiber on male Sprague-Dawley rats [29]. The test groups received either 1%, 5%, or 10% date seed fiber (adolescent rats) over 24 days.