Fenamiphos

Endpoint summary

Description of key information

The test substance is rapidly absorbed; widely distributed (not in compact bone structures, the spinal marrow and the brain, indicating minimal ability to cross the blood-brain barrier); has no potential for accumulation; extensively metabolised; excreted mostly renally.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The ADME of the test item was evaluated in the Directive 91/414 review (Gronberg (1969); Ecker et al. (1989); Weber (1988); Beaudoin (2015)). The provided information complies with the original dossier submitted in 2016 for inclusion of the test item to Annex I of Directive 91/414/EEC and has been previously evaluated in the Draft Assessment Report (DAR) and subject to peer review by EFSA and Member States in 2018.

 

Absorption
Absorption of radioactivity after oral administration of radiolabelled test substance (0.3-3 mg/kg bw) in rats was nearly complete and very rapid. Dermal absorption based on in vitro human skin data is 1% for the concentrate formulation (240 g/L) and 8% for spray dilution (12 g/L).

 

Toxicokinetics

	Males (0.3 mg/kg bw)	Females (0.3 mg/kg bw)
Cmax (ng /g)	72.1	117
Tmax (h)	1.00	0.25
AUCt (ng.h/g)	229	342
AUC (ng.h/g)	249	360
k (1/h)	0.3065	0.0968
t½ (h)	2.3	7.2

Distribution
In rats given 3 mg radiolabelled test substance/kg bw by gavage, autoradiography showed that within 0.5 h, radiolabel was distributed throughout the body, except for compact bone structures, the spinal marrow, and the brain, indicating minimal ability to cross the blood-brain barrier. The highest concentrations were seen in the contents of the stomach, some segments of the small intestine, the bladder as well as the kidney, indicating a high renal excretion. High concentrations were also found in the liver. Blood, lungs, salivary glands, parotids, hypophysis, and tissues with large amounts of connective tissue also had relatively high concentrations of radiolabel. Lower concentrations were found in the lymph, adrenal gland, and spleen. Low concentrations were observed in the muscles, fatty tissues, pancreas, and thymus. At 48 h, most of the levels in tissues and plasma were below the limit of quantification in rats given 0.4 mg/kg bw.

 

Metabolism
In rats, identified metabolites covered more than 93 % of the total radioactivity. The main groups of metabolites, comprising 80 % to 96 % of the recovered radioactivity, were the test substance-phenols (methylthiometacresol-derivatives (MTMC), M11, M12, M13) in different stages of oxidation at the sulphur atom and their respective sulphuric acid conjugates. Metabolic pathway in rats was oxidation of the thioether to the sulfoxide and sulfone, de-arylation to yield the methyl thioether phenol (or its sulfoxide and sulphide), and potential dealkylation of the ethyl, isopropyl, or isopropylamino moiety of the phosphate ester.

In urine and faeces, metabolites of toxicological relevance were detected in amounts of 0.3 to 1.3 % (test substance-sulfoxide, M01) and of 0.4 to 0.7 % (desisopropylfenamiphos-sulfoxide, M07). Parent compound or other oxidised and/or desisopropylated compounds were not detected above the limit of detection.

 

Excretion
Excretion of radioactivity after oral administration of radiolabelled test substance was nearly complete and very rapid. After 48 h, > 96% of the recovered radiolabel had been excreted by rats orally treated with 0.3 or 3 mg/kg bw, with 40-80% of the radiolabel being excreted renally within 4 h of treatment. Faecal elimination accounted for only 1.5-3.7% of the recovered radiolabel. The small amounts found in the faeces after intravenous administration indicate that a small amount of biliary excretion occurs. Only a very low fraction (<<0.1% of the total recovered radioactivity) was excreted via pulmonary ventilation (measured after a single oral dose of 3 mg/kg bw in males only). From 2 hours after administration of 3 mg radiolabeled test substance to rats, radiolabel was also found in the region of the hair follicles, suggesting slight elimination via this route.

In the first 4-8 h after administration, urinary excretion appeared to be slightly faster in males than females after oral dosing, and faster after 3 than after 0.3 mg/kg bw in females only. Prior treatment with unlabelled test substance resulted in a slightly faster urinary excretion in both males and females. There were no indications of accumulation of the parent compound or its metabolites.

 

References:

1. Gronberg R R (1969): The Metabolic Fate of Ethyl-4-(methylthio) m-tolyl isopropylphosphoramidate (BAY 68138), Ethyl 4-(methylsulfinyl)- m-tolyl isopropylphosphoramidate (BAY 68138 sulfoxide), and Ethyl 4~(methylsulfonyl)-m-tolylisopropylphosphoramidate (BAY 68138 sulfone) by White Rats, CHEMAGRO CORPORATION RESEARCH DEPARTMENT, Report No 26759

2. Ecker W, Weber H and Brauner A (1989): [Phenyl-l-14C] NEMACUR: General Metabolism Study in the Rat, Bayer AG Pflanzenschutz-Zentrum Monheim, Report No. 3175

3. Weber (1988): [phenyl-1- 14C] Nemacur: Whole-body autoradiographic distribution of the radioactivity in the rat, Bayer AG Sector 5, Agrochemicals CE, Institute for Metabolism Research PF Zentrum Monheim, Report No. 3055

4. Beaudoin L (2015): Pharmacokinetics after Single Oral and Intravenous Doses to Rats, Envigo CRS Limited, Report No. BDG0258