Tetrahydrofuran

Endpoint summary

Additional information

The metabolism, disposition and toxicokientics of tetrahydrofuran have been well characterized. Tetrahydrofuran was administered to rats and mice in oral gavage metabolism and disposition studies. It has also been measured in the blood of various test animal species after inhalation exposures. The in vitro metabolism of tetrahydrofuran was determined using liver microsomes from rats, mice and humans. Also, dermal absorption rates were determined following administration of tetrahydrofuran to human cadaver skin samples. In a non-guideline study that was well-conducted and documented and was GLP-compliant, male and female Fischer 344 rats and B6C3F1 mice were dosed by single gavage dose with ¹⁴C-tetrahydrofuran at dose levels of 50 and 500 mg/kg. Total radioactivity was quantitated in expired air, plasma, urine and feces at various time points up to 168 hours post-dosing. In rats, tetrahydrofuran was rapidly absorbed and metabolized with the majority of radioactivity eliminated as CO₂ in both sexes of rat (20.3% of dose, 500 mg/kg bwt; 47.6% of dose, 50 mg/kg bwt). Based on plasma samples for low dose male and female rats, a T_max of approximately 4 hours was obtained for both sexes. The T_max value for male rats in the high dose group was 8 hours, about twice that of the low dose. Female rats at the high dose level had an average T_max value of 3.2 hours but individual female rat values varied widely. The average C_max values for high dose male and female rats were within one standard deviation of each other. The C_max values for the 50 mg/kg bwt dose level rats were approximately 4-fold lower than for the high dose group. The half-life for total radioactivity in the 500 mg/kg bwt dose rats was 53.5 +/-6.6 hours, comparable to the half-life value for the low dose rats of 51.3 +/- 2.8 hours. Rats were sacrificed at 168 hours and tissue samples collected, oxidized and analyzed for radioactivity by liquid scintillation counting. At both dose levels and in both male and female rats, the average of all tissues combined represented an average of 6.8% of the dose. The carcasses contained the most radioactivity, followed by muscle, liver and skin.

As in the case of rats, tetrahydrofuran was rapidly absorbed and metabolized with the majority of radioactivity eliminated as CO₂ in both sexes of mice following oral gavage administration (43.6% of dose, 500 mg/kg bwt; 71.6% of dose, 50 mg/kg bwt). Pharmacokinetic parameters were calculated based on radioactivity analysis of plasma samples from mice. The 500 mg/kg bwt male and female mouse plasma samples each had similar T_max values (males, 0.8 +/- 0.3 hours; females, 1.0 +/- 0.0 hours). These values were approximately twice that of the 50 mg/kg bwt mice (males, 0.5 +/- 0.0 hours; females, 0.4 +/- 0.1 hours). The half-life for the 500 mg/kg bwt male mice was within one standard deviation of the 50 mg/kg bwt value for male and female mice (54.1 +/- 12.2 hours). The female high dose mice had a wide variation in half-life values (98.5 +/- 41.0 hours). Mice were sacrificed serially from 15 minutes to 168 hours and tissue samples collected, oxidized and analyzed for radioactivity for the high and low dose male mice. Most tissue concentrations were at a maximum at the 2-hour sacrifice for the high dose, and 30 minutes for the low dose. For all time points, radioactivity was highest in the carcass, liver, kidney, muscle, and gastrointestinal tract.

Liver microsomes from rats, mice and humans were incubated with 70 micromolar tetrahydrofuran for up to 55 minutes. There were no significant differences in the in vitro half-life values between male and female rats or mice. The order of decreasing half-lives (min) were 40.1 (rat), 28.6 (human) and 9.0 (mouse), respectively. There was no difference observed in calculated CL_int values between males and females in either rats or mice. The CL_int was greatest for mice and decreased for the other species as follows: mouse > rat > human. These values were calculated by two different methods that gave comparable results (160.5, 30.6 and 27.31 mL/min/kg, respectively, versus 205.4, 30.6, and 28.6 mL/min/kg). Comparison of hepatic blood flow relative to CL_int values indicates that it is likely the mouse liver can metabolize all tetrahydrofuran present in the blood during first pass. The similarity in value of hepatic blood flow and CL_int in humans suggests that tetrahydrofuran will also be extensively metabolized during first pass. A single metabolite was identified in all species as gamma hydroxybutyric acid, which, can be metabolized through the tricarboxylic acid (TCA) cycle to yield carbon dioxide.

A physiologically-based, pharmacokinetic (PBPK) model has been developed to predict levels of human exposure under various exposure scenarios. Model agreement was found to be satisfactory when compared with field data (worker exposures) from 3 of 4 reported studies. The PBPK model was applied to predict biological levels of exposure to tetrahydrofuran following repeated occupational exposures. It was proposed that the PBPK model results were reliable in predicting biological levels of tetrahydrofuran occupational exposure and that the model might serve as the basis for establishment of a biological exposure index (BEI).

In a well-conducted and documented guideline study, the in vitro absorption of tetrahydrofuran through human cadaver skin was measured in static diffusion cells after application of either neat (100%) tetrahydrofuran or as 10% or 30% aqueous solutions. In separate experiments, dermal absorption was measured for either 10- or 60-minute periods or for a 14-hour period. The 10%- and 30%-tetrahydrofuran aqueous solutions did not significantly alter the barrier function of the skin, as assessed by the percutaneous absorption of ³H₂0. However, neat (100%) tetrahydrofuran exposure to the skin did alter the skin’s barrier function, suggesting damage to the stratum corneum. Therefore, the results from the 10%- and 30%-tetrahydrofuran solutions may better represent human skin permeability in un-damaged skin from short-term exposures. Two permeability coefficients (Kp) were calculated to be 0.015 ± 0.003 cm/hr, for the absorption period of t = 1-6 hrs, and 0.011 ± 0.002 cm/hr, for the absorption period of t = 4-14 hrs, based on the mean rate of penetration derived from the time spans indicated as observed during the 14 hour dose duration study. The first of these may represent the upper limit of initial or early steady state like penetration whereas the second may represent a more conservative value for tetrahydrofuran absorption over longer periods of time. Based on the results obtained in these studies, tetrahydrofuran may be considered a fast penetrant of human skin.