Phosphorothioic triamide, N-propyl-

Endpoint summary

Description of key information

Experimental logPow value is available for n-propyl phosphoro thioic triamide, being below 1. A bioaccumulation potential is therefore not expected for the substance.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Chemical and physico-chemical description of the substance

The target substance NPPT can be described as thiophosphoric triamide, an indirect urease inhibitor, and is a crystalline solid. It is a urease analogue that blocks three active sites of the urease enzyme (CAS-No. 916809-14-8).

According to the analytical investigations, the following major component / three minor components are present:

-         > 80.0 % (w/w) N-propyl-phosphorothioic triamide

-         ca. 10 % (w/w) N,N’-dipropylphosphorothioic triamide

-         ca. 2.5 % (w/w) N,N’-dipropylpropan-1-amine

-         ca. 1.0 % (w/w) propylamine

Description of the physico-chemical properties

-         Physical state (20 °C):                   solid

-         Vapour pressure (25 °C):             2.8 * 10^-6hPa

-         Molecular weight:                         153.19 g/mol

-         Log p_ow(24 °C):                               < 0.3

-         Water solubility (20 °C):              51.5 g/L

-         Melting point (1013 hPa):          91 °C

-         Boiling point (1013 hPa):            not applicable, substance decomposes before boiling

-         (Relative) Density (20 °C):           1.253 g/cm³

Toxicokinetic Assessment

No experimental data on absorption, metabolism, distribution and excretion are available for the substance. Therefore, the toxicokinetic behavior was evaluated based on the structure and the physico-chemical properties of the substance as well as data from experimental in vivo toxicity studies. Additionally, data from an experimental study with radiolabeled [¹⁴C]NBPT were taken into consideration for the assessment of NPPT.

Absorption

The molecular weight of 153.19 g/mol implies that the target substance is favourable for absorption after oral intake. Due to this comparatively low molecular weight in combination with the high water solubility, the substance may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. The rate of absorption will be limited because of the likely ionization of the molecule and the low log P_ow. The low log P_owalso is favourable for absorption by passive diffusion. With a water solubility of 51.5 g/L, the target substance is assumed to dissolve in the gastrointestinal fluid. In the acute oral toxicity study available for the reaction mass of the target substance and NBPT, a LD₅₀of > 2000 mg/kg bw was deduced. Clinical signs like impaired general state, dyspnea, reduced feces, staggering, salivation, exsiccosis and piloerection were observed. Therefore, it is assumed that absorption has occurred. In a short-term repeated dose toxicity study with the reaction mass of the target substance and NBPT in rats the substance caused signs of systemic toxicity like decreased food consumption and decreased body weight parameters, revealing that absorption has occurred. However, apart from that, no specific data concerning oral absorption of the test substance are available. Therefore, as a worst case an oral absorption of 100 % is assumed.

With regard to absorption after inhalation, the target substance has a low vapour pressure of 2.8 * 10^-6hPa and the boiling point is not applicable because the substance decomposes before boiling, indicating that inhalation as a vapour will be negligible. If the substance reaches the respiratory tract, passive diffusion is likely due to the low log P_owand the rather low molecular weight. Because of the good water solubility, the substance is likely to dissolve in the mucus of the upper respiratory tract, and consequently will at least partly be removed before reaching the lower respiratory tract. Due to the lack of data as a worst case 100 % absorption after inhalation is assumed as well.

The physical state of the target substance is solid, therefore the substance will have to dissolve into the surface moisture of the skin before uptake can begin. Due to the high water solubility and low log P_owthe substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Hence, dermal uptake for this substance is suggested to be low. In the acute dermal toxicity study available for the reaction mass of the target substance and NBPT, a LD₅₀of > 2000 mg/kg bw was deduced. As no systemic clinical signs were observed, it is assumed that the substance has only been partly absorbed. However, apart from that, no specific data concerning dermal absorption of the test substance are available. Therefore, a dermal absorption of about 10 % is assumed also based on an assessment using the DERMWIN software that calculated a K_p-value of 0.000343 cm/hr (with a worst case log K_owof 0.3) which is in line with a very low dermal absorption potential based on the user manual for the internet version of the Danish (Q)SAR database (Database Version 1 May 2005).

Distribution

The target substance is a small molecule and therefore wide distribution of the systemically available part could be assumed. In combination with the high water solubility diffusion through aqueous channels and pores is likely to occur. However, the rate at which the very hydrophilic molecule diffuses across membranes could limit its distribution. A bioaccumulation potential is not expected, considering the physico-chemical properties of the target substance. An experimental log P_owvalue for the target substance being below 1 confirms this assumption.

Metabolism

In an experimental toxicokinetic study with radiolabeled NBPT, the two major metabolites of NBPT N-(n-butyl)thiophosphoric diamide and the glucuronic acid conjugate of NBPT were found in the urine samples of treated rats. Therefore, NPPT is assumed to be biotransformated to N-(n-propyl)thiophosphoric diamide and the glucuronic acid conjugate of NPPT which then hydrolyzes to N-(n-propyl)thiophosphoric diamide. Both metabolites are assumed to be readily excreted in the urine. Therefore, NPPT and / or its metabolites are not expected to bioaccumulate.

Based on the results of the repeated dose oral toxicity study in the rat with NBPT that show some microscopic changes in the liver of rats that may be consistent with increased metabolism, NPPT is assumed to behave similar. This may be a consequence of amine oxidation.

Excretion

NPPT and its metabolites will mainly be excreted via the urine due to the low molecular weight and good water solubility. Because of these properties it is also unlikely that more than 5 – 10 % will be excreted in the bile. Any test material that is not absorbed following oral ingestion will be excreted in the feces.

In an experimental toxicokinetic study with radiolabeled NBPT, NBPT was eliminated mainly via expired air and via urine. Rat liver contained the highest level of radiolabel of all measured tissues, but still contained less than 0.29 % of the administered dose. No other tissue was found to contain residues above 0.10 % of the administered dose except carcass contained 2.49 %.