Add time:08/21/2019         Source:sciencedirect.com

In the National Toxicology Program's toxicity studies, rats were more sensitive than mice to Bis(2-chloroethoxy)methane (CEM) – induced cardiac toxicity following dermal application to male and female F344/N rats and B6C3F1 mice. Thiodiglycolic acid (TDGA) is a major metabolite of CEM in rats. It has been implicated that chemicals metabolized to TDGA cause cardiac toxicity in humans. Therefore, the toxicokinetics of CEM and TDGA were investigated in male and female F344/N rats and B6C3F1 mice following a single intravenous administration or dermal application of CEM to aid in the interpretation of the toxicity data. Absorption of CEM following dermal application was rapid in both species and genders. Bioavailability following dermal application was low but was higher in rats than in mice with females of both species showing higher bioavailability than males. CEM was rapidly distributed to the heart, thymus, and liver following both routes of administration. Plasma CEM Cmax and AUC∞ increased proportionally with dose, although at the dermal dose of 400 mg/kg in rats and 600 mg/kg in mice non-linear kinetics were apparent. Following dermal application, dose-normalized plasma CEM Cmax and AUC∞ was significantly higher in rats than in mice (p-value < 0.0001 for all comparisons except for Cmax in the highest dose groups where p-value = 0.053). In rats, dose-normalized plasma CEM Cmax and AUC∞ was higher in females than in males: however, the difference was significant only at the lowest dose (p-value = 0.009 for Cmax and 0.056 for AUC∞). Similar to rats, female mice also showed higher Cmax and AUC∞ in females than in male: the difference was significant only for Cmax at the lowest dose (p-value = 0.002). Dose-normalized heart CEM Cmax was higher in rats than in mice and in females than their male counterparts. The liver CEM Cmax was lower compared to that of heart and thymus in both rats and mice following intravenous administration and in rats following dermal application. This is likely due to the rapid metabolism of CEM in the liver as evidenced by the high concentration of TDGA measured in the liver. Dose-normalized plasma and heart TDGA Cmax values were higher in rats compared to mice. In rats, females had higher plasma and heart TDGA Cmax than males; however, there was no gender difference in plasma or heart TDGA Cmax in mice. These findings support the increased sensitivity of rats compared to mice to CEM-induced cardiac toxicity. Data also suggest that, either CEM Cmax or AUC can be used to predict the CEM-induced cardiac toxicity. Although, both plasma and heart TDGA Cmax was consistent with the observed species difference and the gender difference in rats, the gender difference in mice to cardiac toxicity could not be explained based on the TDGA data. This animal study suggests that toxicologically significant concentrations of CEM and TDGA could possibly be achieved in the systemic circulation and/or target tissues in humans as a result of dermal exposure to CEM.

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