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EC number: 244-848-1 | CAS number: 22224-92-6
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Link to relevant study record(s)
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
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