Benzothiazole-2-thiol

Endpoint summary

Additional information

Several toxicokinetic studies were conducted to evaluated absorption, metabolism, distribution and elimination of MBT.

Percutaneous absorption and distribution of MBT was evaluated in male and female Fischer rats and female Harley guinea pigs (CMA 1987). Groups of four rats of each sex and four female guinea pigs were dosed topically with 14C-labeled MBT as a single dose (0.0361 mg/animal).

In rats there were no sex specific differences in the disposition of 14C-MBT. Compared to rats, which showed a percutaneous absorption rate of 16.1% to 17.5 %, guinea pigs absorbed a greater percentage of the dose (38.4 %). 96 hours after test substance application, the ratio of radioactivity in whole blood to that in plasma was 12.7, 12.9 and 7.3 for male rats, female rats and guinea pigs, respectively. By washing the skin, more of the radioactivity could be removed from guinea pigs (38.2 %) than from the skin of rats (6.07 %to 9.01 %).

Male rats, female rats and female guinea pigs dosed topically with 14C MBT excreted 11.9 %, 13.4% and 33% of the dose, respectively in the urine and 0.98, 0.641 and 0.388% of the dose in the faeces.

For 14C-MBT urine was the primary route for excretion of absorbed radioactivity. Of the absorbed dose of 14C-MBT, the amounts excreted in urine were 74% by male rats, 77% by female rats, and 87% by guinea pigs, whereas less than 7% of MBT was excreted in faeces.

The oral absorption and distribution of MBT was evaluated in male and female Fischer 344 rats (CMA 1987). Male and female rats were dosed orally for 14 days with unlabeled MBT prior to dosing with 14C-labeled MBT. The average dose of the unlabeled compound was 0.510 mg/kg/day; the dose of the labeled compound was 0.503 mg/kg (0.0586 mCi/kg). Groups of four rats of each sex were dosed with 14C-MBT and sacrificed at each selected time point (8, 24, 48, 72 and 96 h). Whole blood, plasma various tissues, urine, and faeces were collected and analyzed for radioactivity. Male rats orally dosed with the 14C-MBT excreted 90.7% and the females 101% in urine 96 hours after application. Similarly, 9.99% and 5.22% of the dose, respectively, is excreted in the faeces in 96 hours. A small portion of the administered radioactivity (1.20 to 1.53 % of the dose) remains associated with the erythrocytes at 96 hours after dosing. Most of this radioactivity was bound to the erythrocyte membranes. Half-lives of elimination from the plasma have been calculated to be 4.7 to 8.56 h and 5780 to 6000 h for the alpha and beta phases, respectively. At 96 hours after dosing, only trace amounts of radioactivity remain in other tissues. Of these tissues, thyroid contained the highest concentration. No intact MBT was seen in the urine. Only two metabolites were detected in the urine 8 hours after sample administration. The major one was a glucuronide derivate of MBT. The other metabolite was not subject to hydrolysis by acid, beta-glucuronidase, or sulfatase, and thus the author concluded that this metabolite was not a conjugate.

In another toxicokinetic study, male and female Fischer 344 rats were dosed once orally with a low or high dose (0.592 or 55.5 mg/kg) of 14C-labeled MBT (CMA 1986). Groups of four rats of each sex were dosed and sacrificed at each selected time point (8, 24, 48, 72, and 96 hours). Whole blood, plasma, urine and faeces were collected and analyzed for radioactivity, and a profile of urinary metabolites was obtained.

Rats dosed with 14C-labeled MBT excreted 72.1 % to 106 % of the radioactivity administered in the urine in 96 hours; whereas in faeces 4.03% to 10.3% of the radioactivity was excreted in this time. A small portion of the administered radioactivity (0.423 to 2.04% of the dose) remains associated with the erythrocytes at 96 hours after dosing; and for rats given low doses of MBT, there were greater values for percent of the dose in whole blood and plasma, relative to the high dose, indicating that a saturable process is operative at the high dose.

Although tissues, except blood, were not examined in this study, the recovery data did not indicate that appreciable amounts of radioactivity from 14C-labled MBT were retained in tissues other than blood. In a preliminary analysis of the urine a total of seven metabolites of MBT were detected.

The authors concluded that MBT was readily absorbed and excreted, primarily in the urine and only small amounts in the faeces.

In addition, male and female Fischer 344 rats were dosed intravenously with 14C-labeled MBT. The animals were treated with 0.602 mg/kg 14C-MBT (CMA 1986). Groups of four rats of each sex were dosed and sacrificed at each selected time point (5min, 15 min, 1 h, 2 h, 24 h and 72 h). Whole blood, plasma, urine, and faeces were collected and analyzed for radioactivity; and a profile of urinary metabolites was obtained.

The treated rats excreted 90.9 to 101% of the radioactivity administered in the urine in 72 hours; 3.79 % to 15.1% of the radioactivity was excreted in the faeces in this time. A small amount of the administered radioactivity (1.52 to 1.96 % of the dose) remains associated with the erythrocytes at 72 hours after dosing. Although tissues, except blood and tail, were not examined in this study, the recovery data did not indicate that appreciable amounts of radioactivity from 14C-labeled MBT were retained in tissues other than blood.

A total of four metabolites of 14C-MBT were detected in urine two were major metabolites and two minor metabolites.

In an early study with guinea pigs (Nagamatsu 1979) two metabolites glucuronide and sulphate of MBT, were identified in urine by thin layer chromatography; 7.62% of MBT and 90% of conjugates were determined in the sampled urine six hours after treatment. Metabolism studies revealed that metabolic transformation of MBT takes place exclusively at SH-group of the molecule. A glucuronide, a glutathione conjugate and the mercapturic acid formed from this as well as a sulphate and dibenzothiazyl disulfide have been detected as metabolites (Fukuoka 1987, 1995).

Summary and discussion on toxicokinetics

The toxicokinetic of MBT was evaluated in several studies in rats and guinea pigs (CMA 1986, CMA 1987, Nagamatsu 1979). The dermal absorption of MBT is low. In topically treated rats percutenous absorption rates of 16.1 % to 17% were measured, in guinea pigs 38.4%. Orally administered MBT was readily absorbed and excreted, whereas excretion was primarily in the urine, and small amounts in faeces (CMA 1986, 1987). Recovery data, after oral or intravenously administered of MBT, did not indicate that appreciable amounts of radioactivity from 14C-labeled MBT were retained in tissues other than blood. Metabolism studies revealed a glucuronide, a glutathione conjugate, the mercapturic acid as well as a sulphate and dibenzothiazyl disulfide as metabolites of MBT in urine.