Ammonium 2-amino-4-(hydroxymethylphosphinyl)butyrate

Endpoint summary

Description of key information

Absorption:

GA was poorly absorbed in rats following a single low (2 mg/kg bw), intermediate (20 and 30 mg/kg bw) or high (500 mg/kg bw) oral dose, or following repeated oral doses of 2, 10 or 100 mg/kg bw/d.

The rate of absorption estimated from the renal excretion indicated low absorption of 5-13% of the dose administered.

GA was rapidly absorbed in rats. Following a single oral dose of 2 or 800 mg/kg bw, maximum blood concentrations in rats were reached 0.5-1 hrs after administration. Blood levels were detectable up to 3 hrs in low dose males and 8 hrs in low dose females and for up to 24 hrs (last sampling point) post-dose in high dose animals. Half-lives in the 4 to 5 hrs range were calculated for the first elimination phase following oral administration of either low or high dose.

As observed in rats, GA was poorly absorbed in dogs following a single oral dose of 8 mg/kg bw or following repeated oral doses of 1 or 8 mg/kg bw/d. The rate of absorption estimated from the renal excretion indicated low absorption of 9.2-17% of the dose administered.

GA was rapidly absorbed in dogs. Following a single oral dose of 8 mg/kg bw, maximum blood concentrations in dogs were reached 2-4 hrs after administration. The estimated half-lives were in the range of 9 to 14 hrs.

Additionally: GA was as poorly absorbed in rabbits; however, better than in rats and dogs. Approximately 27-28% of a single dose of around 6.1 mg/kg bw was absorbed in female rabbits, based solely on excretion in urine.

Distribution:

Concentrations of radioactive residues in selected organs/tissues in rats were low at time of sacrifice (4 or 7 days) after a single low (2 mg/kg bw), intermediate (30 mg/kg) or high (500 mg/kg bw) oral

dose, or following repeated oral dose of 2 mg/kg bw/d. The total radioactive residues in rats amounted to 0.1-1.3% of the administered dose. Highest concentrations of radioactive residues were found in liver (0.024-0.29 µg eq/g), kidneys (0.014-0.36 µg eq/g) and testes (0.068-0.3 µg eq/g) following a single administration of 2 or 30 mg/kg bw. Concentrations of radioactive residues were low in brain (below 0.05 µg eq/g). No accumulation was observed in rats after repeated oral administration.

Concentrations of radioactive residues in selected organs/tissues in dogs were low at time of sacrifice (6 or 24 hrs post-dose) after a single oral dose of 8 mg/kg bw. Highest concentrations of radioactive residues were found in kidneys (1.2-2.4 µg eq/g) and liver (1.23-1.25 µg eq/g) 24 hrs post-dose (last sampling point). The concentrations of radioactive residues were low in different brain regions (0.021 -0.070 µg eq/g) following single oral administration. Following repeated oral doses of 1 or 8 mg/kg bw/d, highest concentrations of radioactive residues were found in kidneys (0.5-

6.4 µg eq/g) and liver (0.4-3.6 µg eq/g) 24 hrs post-dose. Concentrations of radioactive residues in different brain regions were 0.263-0.573 µg eq/g following repeated oral doses of 8 mg/kg bw/d at 24 or 48 hrs post-dose. No accumulation was observed in dogs after repeated oral administration.

Excretion:

GA was rapidly excreted in rats following a single low (2 mg/kg bw), intermediate (20 and 30 mg/kg bw) or high (500 mg/kg bw) oral dose, or following repeated oral doses of 2, 10 or 100 mg/kg bw/d. Complete excretion (above 95% of the dose) is achieved within 96 hrs following single oral dose administration. The faeces were the major routes of excretion (73-95% of the administered dose). Only 5-13% of the administered dose was eliminated via urine. The majority of the applied radioactivity was eliminated in the 0-24 h interval (74-97%). Based upon a study where exhaled radioactivity was examined in rats, there is no evidence of elimination in expired air.

After iv administration of a single low (2 mg/kg bw) dose to rats, renal excretion was predominant, accounting for about 85-93% of the administered dose. 8-18% of the administered dose was found in the faeces.

As observed in rats, GA was rapidly excreted in dogs following a single oral dose of 8 mg/kg bw or following repeated oral doses of 1 or 8 mg/kg bw/d. The faeces were the major route of excretion (82 - 84% of the administered dose). Only 10-14% of the administered dose was eliminated via urine. The majority of the radioactivity was eliminated in the 0-24 h interval (about 95%).

The rate and route of excretion was neither sex- nor dose-dependent in rats or dogs. Repeated administration had no influence on the excretion pattern.

Addtionally: Following administration of an oral dose of 6 mg/kg bw to female rabbits excretion was complete after 10 days. 27.7 % of the dose was excreted with the urine and 70.2% with the faeces.

Metabolism:

GA is readily excreted without intensive metabolisation from rats, presumably due to its polar character. Only a small fraction is metabolised via oxidative deamination as occurs normally in the degradation sequence of natural amino acids. The intermediate compound, 4-methylphosphinico-2 -oxo-butanoic acid (PPO) is rapidly decarboxylated. The major metabolites identified in excreta in rat studies are 3-methylphosphinico-propionic acid (MPP) and disodium L-2-acetamido-4 -methylphosphinato-butyrate (NAG), with minor amounts of 2-hydroxy-4-methylphosphinico-butanoic acid (MHB), 4-methylphosphinico-butanoic acid (MPB) and traces of 2-methylphosphinico-acetic acid (MPA) identified in some substrates in more recent work utilising more sophisticated HPLC methods. Both early and recent studies show very low transfer to tissues/organs in which low levels of parent compound (GA) and MPP were consistently found.

Following a single low (2 mg/kg bw) oral dose or high (500 mg/kg bw) oral dose of GA in rats, the majority of the radioactivity found in excreta was identified as parent GA (about 4-5% (urine) and 66-83% (faeces) of the administered dose). In urine MPP was the main metabolite (1-2% (low dose group) and 0.5-1% (high dose group) of the administered dose). Additionally, MPB (1.5% (low dose group) and 0.2% (high dose group) of the administered dose), MHB (0.14% of the administered dose, low dose group), NAG (0.08% (low dose group) and 0.03% (high dose group) of the administered dose) and MPA (0.1% of the administered dose, low dose group) was detected in the urine. In the faeces, NAG was the main metabolite (7-8% (low dose group) and 1-1.5% (high dose group) of the administered dose). Additionally, MHB (3-4% (low dose group) and 0.1-0.2% (high dose group) of the administered dose), MPP (1% of the administered dose, low and high dose groups) and MPB (0.4% (low dose group and 0.1-0.2% (high dose group) of the administered dose) was detected in the faeces.

The main component detected in the kidneys and liver in rats treated orally or by ingestion was GA.

MPP was identified as a major metabolite. Traces of MPB were also detected. In brain extracts (iv, rats) GA was the major component while MPP was the main metabolite.

Following a single oral dose (8 mg/kg bw) or following repeated oral doses (1 or 8 mg/kg bw/d) of glufosinate-ammonium (GA), parent compound (GA) was the only substance observed in faecal extracts of dogs. In urine, the metabolite MPP represented 0.3-1.2% of the administered dose. In animals administered repeated oral doses of GA, the metabolite MPP was the predominant residue in liver and kidneys representing 30-70% of the sample radioactivity. In animals given a single oral dose, parent compound (GA) was the only detectable compound in liver, kidneys and blood plasma.

Additionally: Following administration of an oral dose to rabbits (6 mg/kg bw) the metabolic profiles in the urine and faeces samples were similar to those found in earlier rat studies. The parent compound was the major radioactive compound excreted.