Absorption, Distribution and Excretion
Pyridinephosphine methyl is known to be absorbed through intact skin, the gastrointestinal tract, and inhalation. In five male rats, oral administration of 0.6 mg/kg body weight of 2-(14)C ring-labeled pyridinephosphine methyl resulted in a mean urinary excretion rate of 80.7% and a mean fecal excretion rate of 7.3% within 24 hours, indicating rapid absorption. After 96 hours, 86.0% and 15.2% of the administered dose were excreted in urine and feces, respectively. Nine (unidentified) metabolites were detected in urine. In female rats, after oral administration of 7.5 mg/kg body weight of 2-(14)C-pyridinephosphine methyl, cardiac blood samples were collected at 0.5, 1, 3, 5, 7, or 24 hours post-administration (3 rats at each time point). Peak plasma concentrations (0.5 hours) were 2–3 μg/mL, decreasing by 50% after 1 hour. Twenty-four hours later, the concentration of (14)C in the blood was 0.2-0.3 μg/mL, and the concentration of pyridinium methyl was 0.01-0.02 μg/mL. Rats were treated with 2-(14)C-pyridinium methyl at a dose of 7.5 mg/kg body weight/day for four consecutive days and were sacrificed every 24 hours. The results showed that the blood concentration did not increase over time. The total radioactivity concentration in the liver, kidney and adipose tissue was generally less than 2 mg pyridinium methyl equivalent/kg tissue (the concentration of unmetabolized pyridinium methyl was less than 0.15 mg/kg tissue) within 4 days. No signs of tissue accumulation were found. Adult male Wistar rats were administered (14)C-labeled pyridinium methyl via endotracheal intubation at a dose of 1 mg/kg body weight/day. The rats were divided into four groups of three and administered the drug for 3, 7, 14 or 21 days, and were sacrificed 24 hours after the last administration. Five additional groups of three rats each were administered the same dose for 28 days and sacrificed on days 1, 3, 7, 14, or 28 after administration. One rat in each group of nine served as a control, having not received pyridinium methyl treatment. After sacrifice, liver, kidney, muscle, fat, erythrocyte, and plasma samples were collected for analysis. Urine and feces were collected from two rats within 24 hours of the seventh administration. 14C-labeled pyridinium methyl was added to the control tissues; the 14C recovery rate was 96.9 ± 5.2%. Radioactivity concentrations were extremely low, close to or below the detection limit, in all tissue samples collected at all time intervals. Repeated administration did not lead to increased concentrations. Liver concentrations were fairly stable (0.03 ppm), and similar concentrations were detected in some kidney samples. In other tissues, radioactivity concentrations were generally below the detection limit (0.04–0.06 ppm). Radioactivity was detected in the kidney of one animal three days after drug withdrawal. No residues were detected after 7 days. After seven consecutive administrations, excretion was 70% to 80% of the single dose, indicating rapid metabolism and elimination, rather than poor absorption. For more complete data on the absorption, distribution, and excretion of pyridinium methyl (6 metabolites), please visit the HSDB record page.
Metabolism/Metabolites
Twelve pyridinium methyl metabolites were isolated from the urine of rats and dogs by thin-layer chromatography. No unmetabolized compounds were detected, and none of the metabolites exhibited anticholinesterase activity. In short, the PO bond was extensively cleaved, and the next step in the metabolism of the pyrimidine leaving group is N-dealkylation and/or conjugation. The mechanism by which high-dose repeated administration of methylpyrimidine methyl pyrimidine reduces hemoglobin in rats is unclear. This is likely due to 2-diethylamino-4-hydroxy-6-methylpyrimidine, a metabolite produced by both mammals and plants. Although the acute toxicity of this metabolite is on the same order of magnitude as the parent compound, unlike the parent compound, rats tolerated it after continuous administration at a dose of 400 mg/kg for 2 weeks; even so, its hematologic effects manifested as reticulocytosis and lymphopenia. The metabolism of organophosphates mainly occurs through oxidation, esterase hydrolysis, and reactions with glutathione. Demethylation and glucuronidation may also occur. Oxidation of organophosphate pesticides may produce moderately toxic products. Generally, thiophosphate compounds themselves are not directly toxic and require oxidative metabolism to be converted into proximal toxins. The products produced by glutathione transferase reactions are generally less toxic. Paraoxygenase (PON1) is a key enzyme in organophosphate metabolism. PON1 can inactivate some organophosphate compounds through hydrolysis. PON1 can hydrolyze active metabolites in many organophosphate pesticides and nerve agents (such as soman, sarin, and VX). The presence of PON1 polymorphism leads to differences in the enzyme level and catalytic efficiency of this esterase, which in turn suggests that different individuals may be more susceptible to the toxic effects of organophosphate exposure.

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Biological half-life
Female rats were orally administered 7.5 mg/kg body weight of 2-(14)C-pyridinium methyl phosphine, and cardiac blood samples were collected at 0.5, 1, 3, 5, 7, or 24 hours post-administration (3 rats per time interval). Peak plasma concentration (0.5 hours post-administration) was 2–3 μg/mL, decreasing by 50% at 1 hour post-administration.

Toxicity Summary
Methylpyrimidine phosphorus is a cholinesterase, or acetylcholinesterase (AChE) inhibitor. Cholinesterase inhibitors (or "anticholinesterases") inhibit the activity of acetylcholinesterase. Because acetylcholinesterase plays a vital physiological role, chemicals that interfere with its activity are potent neurotoxins; even low doses can cause excessive salivation and lacrimation, followed by muscle spasms and ultimately death. Substances used in nerve gases and many pesticides have been shown to exert their effects by binding to serine residues at the active site of acetylcholinesterase, thus completely inhibiting the enzyme's activity. Acetylcholinesterase breaks down the neurotransmitter acetylcholine, which is released at the neuromuscular junction, causing muscle or organ relaxation. Inhibition of acetylcholinesterase results in the accumulation and sustained action of acetylcholine, leading to the continuous transmission of nerve impulses and the inability to stop muscle contractions. The most common acetylcholinesterase inhibitors are phosphorus-containing compounds designed to bind to the enzyme's active site. Its structural requirements include a phosphorus atom with two lipophilic groups, a leaving group (e.g., a halide or thiocyanate), and a terminal oxygen atom.

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Toxicity Data
LC (Rats)> 5040 mg/m³/4h

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Interactions
This study investigated the effects of L-ascorbic acid supplementation on the toxicity of imidacloprid methyl-induced albino rats. Biochemical parameters were measured in rats orally administered 100 and 200 mg/kg body weight of insecticide, respectively, as well as rats simultaneously supplemented with 200 mg/kg body weight of L-ascorbic acid. Biochemical parameters included brain and plasma cholinesterase activity, ascorbic acid content in the liver, kidneys, and adrenal glands, and ascorbic acid and glucuronic acid content in urine. Results showed that rats supplemented with ascorbic acid exhibited lower levels of cholinesterase inhibition. Furthermore, in rats treated with the insecticide, the levels of ascorbic acid and glucuronic acid in urine were significantly increased. The results of this study indicate that L-ascorbic acid supplementation can partially counteract the toxicity caused by imidacloprid methyl. Female rats were administered dermal dressings at doses of 100 mg/kg/day and 250 mg/kg/day, alone or in combination, for 7, 15, or 30 days. The results showed that the rats exhibited symptoms of poisoning, pathological morphological changes in vital organs, and significant alterations in liver and serum enzyme activity. The changes produced by the combined use of the two compounds did not show an enhancing effect at the tested dose levels. To determine the potential genotoxicity of the benzimidazole fungicide benomyl and the organophosphate insecticide imidacloprid methyl, the two were tested in a 6:1 ratio (a common ratio in food residue analysis). The effects were assessed using a micronucleus assay on cultured rat hepatocytes stimulated by epidermal growth factor (EGF). Adult rat hepatocytes were exposed in vitro to escalating non-cytotoxic doses for 48 hours, doses selected based on cytotoxicity assays such as LDH and neutral red assays. Benomyl significantly increased micronucleus frequency in a dose-dependent manner; in contrast, imidacloprid showed no genotoxicity at any of the tested doses. When hepatocytes were simultaneously exposed to both pesticides with gradually increasing doses, the increase in micronucleus frequency was similar to that observed with benomyl alone, indicating no interaction between the two at this ratio and at non-cytotoxic doses (benomyl up to 25 μg/mL + methylpyrimidine 4.2 μg/mL).

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Non-human toxicity values
Rats oral LD50 1250 mg/kg
Mice oral LD50 1180 mg/kg
Rabbit oral LD50 1150 mg/kg
Guinea pig oral LD50 1000 mg/kg
For more complete non-human toxicity data for methylpyrimidine (15 in total), please visit the HSDB records page.

[1]. Detection of Pirimiphos-Methyl in Wheat Using Surface-Enhanced Raman Spectroscopy and Chemometric Methods. Molecules. 2019 Apr 30;24(9):1691.

[2]. In Vitro Toxicity of Pirimiphos-Methyl in Atlantic Salmon Hepatocytes. Toxicol In Vitro. 2017 Mar;39:1-14.

[3]. Atmospheric Degradation of the Organothiophosphate Insecticide - Pirimiphos-methyl. Sci Total Environ. 2017 Feb 1;579:1-9.

Methylpyrimidine phosphate is a yellow liquid, corrosive to tin and low-carbon steel, and is used as an insecticide. Methylpyrimidine phosphate is an organothiophosphate with the structure O,O-dimethyl-O-pyrimidin-4-ylthiophosphate, substituted with a methyl group at position 6 and a diethylamino group at position 2. It is an EC 3.1.1.7 (acetylcholinesterase) inhibitor, acaricide, agricultural chemical, insecticide, and also an environmental pollutant. It is an organothiophosphate and aminopyrimidine compound with a structure similar to 2-diethylamino-6-methylpyrimidin-4(1H)-one. Methylpyrimidine phosphate was an organophosphate fumigant insecticide, now discontinued. It was once used to control various insects and mites in shops, livestock sheds, residences, and industrial sites. It is considered an acetylcholinesterase (AChE) inhibitor with contact and respiration effects. It is one of several compounds used to control the vector of kissing bugs.

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Mechanism of Action
Imidacloprid methyl exerts its effect through systemic inhibition of cholinesterase, which is the only known mechanism of its toxicity. Although it is rapidly absorbed, obvious toxic symptoms did not appear in rats until 24 hours after administration of a dose of 1450 mg/kg, at which point brain cholinesterase activity was inhibited by 46%. Cholinesterase activity began to recover after 72 hours; plasma enzyme activity fully recovered after 96 hours, but erythrocyte enzyme activity recovered more slowly.Mechanism of Action

C11H20N3O3PS

305.33

305.096

29232-93-7

Pirimiphos-methyl-d6;1793055-06-7

34526

Light yellow to yellow liquid

1.2±0.1 g/cm3

386.5±52.0 °C at 760 mmHg

15°C

187.6±30.7 °C

0.0±0.9 mmHg at 25°C

1.555

4

0

7

7

19

310

0

CCN(CC)C1=NC(=CC(=N1)OP(=S)(OC)OC)C

QHOQHJPRIBSPCY-UHFFFAOYSA-N

InChI=1S/C11H20N3O3PS/c1-6-14(7-2)11-12-9(3)8-10(13-11)17-18(19,15-4)16-5/h8H,6-7H2,1-5H3

4-dimethoxyphosphinothioyloxy-N,N-diethyl-6-methylpyrimidin-2-amine

AI3-27699 Actelic Pirimiphos-methyl

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~163.76 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.19 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (8.19 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (8.19 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)