N-butylphosphorothioic triamide

Endpoint summary

Description of key information

NBPT appears to be biotransformed to N-(n-butyl)thiophosphoric diamide and the glucuronic acid conjugate of NBPT which then hydrolyzes to N-(n-butyl)thiophosphoric diamide. Both metabolites appear to be readily excreted in the urine.
Therefore NBPT and/or its metabolites are not expected to bioaccumulate.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Introduction

The study was conducted according to the requirements of the the guideline EPA OPPTS 870.7485 (Metabolism and Pharmacokinetics) of the United States of America. The study was designed to estimate the extent and rate of elimination of radiolabel in expired air, urine, feces and cage rinses from male Sprague-Dawley rats that received a singlp oral dose of [¹⁴C]-N-(n-butyl) thiophosphoric triamide. The liver, mesenteric fat, kidneys, spleen, whole blood and residual carcass also were analyzed for radiolabel content. The study also was designed to generate the blood pharmacokinetic data. In addition, metabolites of NBPT in the urine were characterized and identified.

Method

In the pilot experiment, a single oral dose of [¹⁴C]-N-(n-butyl) thiophosphoric triamide (¹⁴C]NBPT) was administered at an average of 269 mg/kg body weight (263 µCi/kg body weight) to two male Sprague-Dawley rats. Expired air from each animal was passed through two CO₂traps and one volatile organics trap. An average of 40.22 percent of the administered dose (% AD) was excreted as¹⁴CO₂during, 48 hours after dosing, while an average of 0.01% AD was excreted as volatile organics. Averages of 25.20 and 5.44% AD were excreted in urine and feces, respectively, during 48 hours after dosing. An average of 8.03% AD was recovered in cage rinses during 48 hours after dosing. The total excretion of radiolabel averaged 78.88% AD. The total recovery of radiolabel from each animal averaged 86.43% AD.

In the main experiment, a single oral dose of [¹⁴C]NBPT was administered at an average of 252 mglkg body weight (206 µCi/kg body weight) to 8 male Sprague-Dawley rats. An average of 35.42% AD was excreted as¹⁴CO₂during 168 hours after dosing. Averages of 24.39 and 8.65% AD were excreted in urine and feces during 168 hours after dosing. An average of 11.67% AD was recovered in the cage rinses during 168 hours after dosing. The total excretion of radiolabel averaged 80.12% AD. Whole blood, spleen, kidneys, liver, mesenteric fat and carcass were analyzed for radiolabel content. Radiolabel in whole blood, spleen, kidneys, liver, mesenteric fat and carcass averaged 2.96,5.05,6.34, 12.64,9.88 and 5.83 µg-equiv/g, respectively. The %AD in whole blood, spleen, kidneys, liver, mesenteric fat and carcass averaged 0.10,0.01,0.03,0.29,0.01 and 2.49%, respectively. The total recovery of radiolabel averaged 83.04% AD.

Four of the eight rats had jugular cannulae surgically implanted prior to dosing. Blood samples were collected from each animal through the cannulae at 1,2,4,6,8, 10, 12, 16, 24, 48, 72, 96 and l20 hours after dosing, and through the dorsal aorta at termination 168 hours after dosing, and then analyzed for radiolabel content. The peak concentration (C_max) observed at any of the sampling times averaged 80.18 flg-equiv/g. The sampling time at which the peak concentration was observed (t_max), was 1 or 2 hours after dosing.

Results:

After the t_maxthe blood level rapidly decreased to less than 14% of the C_maxby 24 hours after dosing and then declined to less than 5% by 168 hours.

Two major metabolites of NBPT were found in the urine samples from rats which had been treated with [¹⁴C]NBPT. The metabolites were N-(n-butyl)-thiophosphoric diamide and the glucuronic acid conjugate of NBPT

[¹⁴C]NBPT was eliminated from male Sprague-Dawley rats during 168 hours after a single oral dosing, mainly via expired air as¹⁴CO₂and via urine, with averages of 35.42 and 24.39% AD, respectively. The total excretion of radiolabel was an average of 80.12% AD during 168 hours after dosing. Rat liver contained the highest level of radiolabel of all measured tissues (12.64 µg-equiv/g), but still contained less than 0.29% AD. No other tissue was found to contain residues above 10 µg-equiv/g or 0.10% AD except carcass contained 2.49% AD (5.83 µg-equiv/g).

There was a rapid absorption of [¹⁴C]NBPT equivalent residues into the systemic circulation following dosing. After the peak blood level. the blood level indicated a biphasic declination. The first phase was rapid and the second was slower.

Conclusion

NBPT appears to be biotransformed to N-(n-butyl)thiophosphoric diamide and the glucuronic acid conjugate of NBPT which then hydrolyzes to N-(n-butyl)thiophosphoric diamide. Both metabolites appear to be readily excreted in the urine.