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The current approach for the risk assessment of chemicals does not account for the complex human real-life exposure scenarios. Exposure to chemical mixtures in everyday life has raised scientific, regulatory, and societal concerns in recent years. Several studies aiming to identify the safety limits of chemical mixtures determined hazardous levels lower than those of separate chemicals. Following these observations, this study built on the standards set by the real-life risk simulation (RLRS) scenario and investigated the effect of long-term exposure (18 months) to a mixture of 13 chemicals (methomyl, triadimefon, dimethoate, glyphosate, carbaryl, methyl parathion, aspartame, sodium benzoate, EDTA, ethylparaben, butylparaben, bisphenol A and acacia gum) in adult rats. Animals were divided into four dosing groups [0xNOAEL (control), 0.0025xNOAEL (low dose—LD), 0.01xNOAEL (medium dose—MD) and 0.05xNOAEL (high dose-HD) (mg/kg BW/day)]. After 18 months of exposure, all animals were sacrificed, and their organs were harvested, weighed, and pathologically examined. While organ weight tended to be higher in males than in females, when sex and dose were taken into account, lungs and hearts from female rats had significantly greater weight than that of males. This discrepancy was more obvious in the LD group. Histopathology showed that long-term exposure to the chemical mixture selected for this study caused dose-dependent changes in all examined organs. The main organs that contribute to chemical biotransformation and clearance (liver, kidneys, and lungs) consistently presented histopathological changes following exposure to the chemical mixture. In conclusion, exposure to very low doses (below the NOAEL) of the tested mixture for 18 months induced histopathological lesions and cytotoxic effects in a dose and tissue-dependent manner. [ABSTRACT FROM AUTHOR]