N-butylphosphorothioic triamide

Endpoint summary

Description of key information

No studies are available. Based on molecular structure, molecular weight, water solubility, and octanol-water partition coefficient it can be expected that oral absorption might be high, whereas dermal absorption rates might be moderate and uptake after inhalation is assumed to be low. Distribution in the body is wide and that elimination is assumed to occur mainly by kidney. The adverse effects seen in the oral 90-day study and 2-generation study confirm that the substance has at least moderate oral absorption rate.

Additional information

There were no experimental studies available investigating the toxicokinetic properties of N-(n-butyl) thiophosphoric triamide (NBPT). Therefore, whenever possible, toxicokinetic behavior was assessed taking into account the available information on physicochemical and toxicological characteristics of NBPT according to the “Guidance on information and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2009)”.

Absorption

NBPT (molecular weight of 167.16 g/mol) is a white to off-white crystalline solid with a water solubility of 43.04 g/L at 25°C. Its vapour pressure is estimated to be < 0.0011 Pa and its log Po/w is 0.44 at (20°C, pH 7.04-7.06).

The acute oral toxicity of NBPT has been investigated in rats (Glaza, 1994). The LD50 from this study was determined to be 2823 mg/kg bw for male and female animals. Mortality and general clinical signs commonly observed in acute oral toxicity studies were occured at doses above 2000 mg/kg bw.

In addition, slight signs of systemic toxicity were observed in rats in an oral subchronic study at 377 mg/kg bw/day. It is therefore assumed, that the test substance, or its possible metabolites, become systemically available after absorption along the gastro intestinal tract. The low molecular weight, the very high water solubility and the partition coefficient support the assumption that absorption of the test substance along the gastrointestinal tract is very likely. Furthermore, absorption after oral uptake was reported to be almost complete, reaching a total recovery of 80 to 90% within 48 h after administration to rats (NICNAS 2010). Therefore, the test substance and/or its metabolites are considered to be easily absorbable after oral ingestion at comparatively low systemic toxicity.

An acute inhalation test performed in rats revealed an LD50 of >2100 mg/m³ with an inhalable fraction of about 30% due to methodological restrictions (see summary and discussion of acute toxicity) (Griffiths, 2011). No mortality was observed and clinical signs were unspecific (increased respiratory rate, hunched posture, pilo-erection and wet fur). Taking the low amount of inhalable particles into consideration together with the low log Po/w and the high water solubility, it can be assumed, that uptake after inhalation is low and the rate of systemic uptake may be limited by the rate at which they partition out of the aqueous fluids (mucus) lining the respiratory tract and into the blood. The substance may be transported out of the deposition region with the mucus and swallowed or may pass across the respiratory epithelium via aqueous memebrane pores. As a consequence of the very low vapour pressure of < 0.0011 Pa, NBPT is essentially non-inhalable and exposure to humans via inhalation is unlikely to occur.

Dermal acute toxicity was assessed in an acute study (OECD 402) and an LD50 of >2000 mg/kg bw was determined (Glaza, 1994). No deaths were observed and soft stools were the only clinical sign seen on Day 1 and/or 2 after application. A Dermwin v2.0 QSAR modeling estimated a dermal permeability constant Kp of 0.000181 cm/h. Similar to the approach taken by Kroes et al. (2007), the maximum flux Imax (Imax = Kp [cm/h] x water solubility [mg/cm³]) was calculated, resulting in dermal absorption of 8 µg/cm²/h NBPT. Usually, this value is considered as indicator for a dermal absorption of 40% (“medium high”). Therefore, the test substance and/or its metabolites are considered to be absorbable after dermal application at comparatively low systemic toxicity.

Distribution

Since the molecule is relatively small, distribution in the body might occur. Uptake via aqueous channels and pores is supposed for this hydrophilic substance, whereas distribution into cells is rather unlikely. In a subchronic study with rats, effects on clinical chemistry and haematological parameters were observed in the highest dose group (5000 ppm) (Dunster et al., 1997). In a 2-generation study with rats, changes in the epididymis and in sperm parameters were observed, but no effects on the offspring (Myers, 1999). It is therefore assumed, that the test substance may at least reach the inner organs but probably not cross the placental barrier. Metabolism studies with radiolabelled NBPT indicated high amounts of NBPT in the cracass, liver and blood with minor amounts in the kidney, spleen and mesenteric fat (NICNAS 2010). After 7 days, 3% of the administered dose remained in the body.

Metabolism

According to the chemical structure of NBPT, it can be assumed that it will be metabolised in vivo. From the urine samples of rats that were orally treated with the test substance, two major metabolites were separated. One was the glucoronic acid conjugate of NBPT and the other one was N-(n-butyl)-thiophosphoric diamide (NICNAS 2010). Modeling of potential metabolites with the OECD toolbox Vs. 2.3, revealed 11 potential metabolites with the liver metabolism simulator.

Studies on genotoxicity (gene mutation in bacteria, chromosomal aberration and gene mutation in mammalian cells) were negative, indicating no reactivity of the test substance or its metabolites under the test conditions. The microbial metabolism simulator provided 13 potential and the skin metabolism simulator 2 metabolites. With respect to skin sensitisation data, there was no evidence of direct protein reactivity which would cause skin sensitisation.

Excretion

Since NBPT is a polar substance, highly water soluble and has a molecular weight of below 500, its elimination is assumed to mainly occur via kidney. However, elimination of NBPT from the blood stream was shown to follow linear declination with a t1/2 of 78 h (NICNAS 2010). After a single oral dose, 80% NBPT was eliminated within 7 days. It was mainly excreted via expired air (as CO2), urine and faeces with averages of 35, 24 and 9% of the administered dose, respectively.

Reference:

National Industrial Chemicals Notification and Assessment Scheme (NICNAS) of the Australian Government (Department of Health and Ageing) 2010: N-(n-butyl)thiophosphoric triamide (NBPT). Existing Chemical Secondary Notification Assessment. Draft Report. November 2010