Absorption, Distribution and Excretion
We aimed to assess the prognostic factors and toxicokinetics of acute benzylphos poisoning. We retrospectively analyzed 12 patients admitted to the intensive care unit (ICU) between 2003 and 2006 with benzylphos poisoning. We compared characteristics, initial vital signs, physiological scores, corrected QT intervals on electrocardiograms, and laboratory data (serum benzylphos concentration and cholinesterase activity) between deceased and surviving patients. Furthermore, we assessed the correlation between prognostic factors and the severity of poisoning (ICU stay and length of hospital stay) and patient toxicokinetics. In the two deceased patients, the estimated benzylphos intake dose and serum benzylphos concentrations at the emergency room and 24 hours after ingestion were significantly higher than in the 10 surviving patients (p values were 0.008, 0.003, and 0.04, respectively). Among the 10 survivors, serum fenthion concentration 24 hours after ingestion was significantly correlated with intensive care unit (ICU) and hospital stay (p = 0.004 and 0.04, respectively); however, initial vital signs, physiological scores, emergency ECG corrected QT interval, and serum cholinesterase activity showed no correlation. In the 5 patients who successfully fitted the two-compartment model, the distribution half-life and elimination half-life were 2.5 hours and 49.8 hours, respectively, consistent with the slow and sustained clinical course of fenthion poisoning. The estimated fenthion ingestion dose and serum fenthion concentrations in the emergency room and 24 hours after ingestion may be useful prognostic factors for acute fenthion poisoning. Furthermore, patients with high serum fenthion concentrations should be monitored. A crossover trial designed based on preliminary results enrolled 12 healthy volunteers who received fenthion twice daily for four consecutive days. The doses were 0.18 mg/kg/day (equivalent to 36 times the Acceptable Daily Intake (ADI)) and 0.36 mg/kg/day (equivalent to 72 times the ADI). Blood and urine samples were collected on days 1 and 4 for analysis of fenthion and its major metabolites, plasma and erythrocyte cholinesterase activity, and biochemical and hematological parameters. Because the plasma concentration of fenthion in the low-dose group was insufficient for detection, and its metabolite fenthionoxone could not be determined, pharmacokinetic parameters were only measured in the high-dose group. Significant individual variability was observed in blood drug concentrations, with peak concentrations reached within 1 to 4 hours after administration. The half-life of fenthion ranged from 0.8 to 4.5 hours. Although steady-state concentrations were presumed to have been reached based on the half-life, the ratio of the area under the curve (AUC) (0–12 hours) to AUC (0–∞) was 1:3, suggesting accumulation of fenthion. Repeated administration at both dose levels showed no significant changes in plasma or erythrocyte cholinesterase activity, and no significant abnormalities were detected in biochemical or hematological monitoring. This study aimed to characterize changes in tissue esterase activity and blood fenthion concentration in rat mothers and fetuses after intrauterine exposure to the organophosphate insecticide fenthion. Eight-week-old female rats were administered 0, 5, or 25 mg/kg of fenthion by gavage on day 19 of gestation. Fenthion was rapidly absorbed from the gastrointestinal tract, reaching peak maternal and fetal blood concentrations within 0.5–1.0 hours after administration. Maternal and fetal blood concentrations were almost identical, exhibiting a non-linear dose-response relationship. Acetylcholinesterase and carboxylesterase activities in maternal liver and blood, as well as fetal liver and brain tissue, decreased within 30–60 minutes after exposure to parathion. Esterase inhibition was observed at parathion doses (5 mg/kg) previously not associated with reproductive toxicity, suggesting that esterase inhibition should be considered a key effect in the risk assessment of this pesticide. …rapid absorption via the skin. For more complete data on the absorption, distribution, and excretion of parathion (17 species), please visit the HSDB record page. Metabolites/Metabolites Parathion is metabolized normally in goats. Its metabolites originate from one or more of the following pathways: nitro reduction to amine, followed by conjugation with sulfate or acetate; formation of oxo derivatives; O-demethylation. In rats and guinea pigs exposed to thiophosphates, demethylated analogs, dimethyl thiophosphate, dimethyl phosphate, and four unidentified compounds were found. Similar urinary metabolites were produced in a comparative study of the biotransformation of thiophosphate and methyl parathion in mice. These metabolites include methyl thiophosphate, dimethyl phosphate, and methyl phosphate, as well as dimethyl thiophosphate, dimethyl phosphate, methyl phosphate, and phosphate esters.
After topical treatment of Triticum aestivum with fenthion, the main hydrolytic metabolite is an O-demethyl analog. Dimethyl thiophosphate and dimethyl phosphate were also found. Fenthion and phenol were observed. Treatment of Triticum aestivum with formic acid, acetic acid, or propionic acid inhibits the formation of oxyphosphorus and its demethylated analogs.
For more complete data on the metabolism/metabolites of fenitrothion (14 metabolites in total), please visit the HSDB record page.
The metabolism of organophosphates mainly occurs through oxidation, esterase hydrolysis, and reactions with glutathione. Demethylation and glucuronidation may also occur. Oxidation of organophosphate pesticides can produce moderately toxic products. Generally, thiophosphates themselves are not directly toxic and require oxidative metabolism to be converted into proximal toxins. Products produced by glutathione transferase reactions are generally less toxic. Paraoxyphosphatase (PON1) is a key enzyme in organophosphate metabolism. PON1 can inactivate certain organophosphates through hydrolysis. PON1 can hydrolyze active metabolites of various organophosphate pesticides and nerve agents (such as soman, sarin, and VX). The existence of PON1 polymorphism leads to differences in the enzyme activity level and catalytic efficiency of this esterase, suggesting that different individuals may be more susceptible to the toxic effects of organophosphate poisons.

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Biological half-life
After male Japanese rabbits were administered 10 or 3 mg/kg body weight of fenthion daily for 6 consecutive months, the contents of fenthion and fenthion oxide in blood, skeletal muscle, and abdominal fat were analyzed by gas chromatography. In most cases, neither compound was detected in blood or muscle (the detection limit for fenthion was 0.005 or 0.002 mg/kg, and the detection limit for fenthion oxide was 0.01 mg/kg). In rabbits administered doses of 10 and 3 mg/kg body weight daily, the mean phenylthionine content in adipose tissue was 0.131 mg/kg (maximum 0.243 mg/kg), and the mean phenylthionine content in muscle tissue was 0.045 mg/kg, with a maximum value of 0.006 mg/kg. Phenylephrine oxychloride was not detected. ...We reviewed 12 patients admitted to the intensive care unit between 2003 and 2006 with phenylthionine poisoning...In the 5 patients who successfully fitted the two-compartment model, the distribution half-life and elimination half-life were 2.5 hours and 49.8 hours, respectively, consistent with the slow and persistent clinical course of phenylthionine poisoning...

Toxicity Summary
Identification and Uses: Fenitrothion is a yellowish-brown liquid used as an insecticide (acaricide). Human Contact and Toxicity: Signs and symptoms of human poisoning include parasympathetic nervous system excitation. Studies have shown that slow release of the insecticide from adipose tissue may lead to prolonged illness or delayed symptoms. In some cases, contact dermatitis has been attributed to exposure to the insecticide. There is currently no evidence of delayed neurotoxicity or association with Reye's syndrome. One report described 25 workers with moderate poisoning caused by an aircraft spraying a formulation containing 50% Fenitrothion in strong winds. Symptoms appeared 2.5–6 hours after inhalation and were typical. Whole blood cholinesterase activity decreased by 48%. Patients recovered after 3 days of atropine treatment. Another study found that among 28 workers in Haiti who used Fenitrothion, 3 had significantly reduced cholinesterase activity at the end of the work week. Animal studies: In laboratory animals, fenthion leads to decreased cholinesterase activity in plasma, erythrocytes, and brain and liver tissues. It is metabolized into the more toxic fenthionoxonium. Certain other organophosphate compounds may enhance its toxicity. Fenthion has minimal eye irritation and is non-irritating to the skin. A single oral dose of 250 mg/kg fenthion in rats resulted in a slight decrease in several liver function biochemical indicators, including mitochondrial ATPase activity, cytochrome P450 content, aniline hydroxylase activity, and aminopyrine N-demethylase activity. A dose of 25 mg/kg had a slight effect on P450 content and the metabolism of exogenous substances, while a dose of 5 mg/kg had no significant effect. Female mice were more significantly affected than male mice. Mice fed with 1000 ppm (approximately 12.8 mg/kg/day) of fenitrothion developed symptoms within one week. After a 20-day feeding period, cholinesterase activity in their brains, erythrocytes, and plasma decreased to 45%, 26%, and 5% of normal, respectively; body weight and liver weight were unaffected. In rats, administration of doses of 5, 10, and 15 mg/kg between days 7 and 15 of gestation resulted in a dose-dependent decrease in open-field activity and motor coordination in offspring, with the higher dose groups showing a more significant decrease. Adult offspring exhibited persistent alterations in the acquisition and extinction of conditioned escape responses and increased social interaction. No embryotoxicity or teratogenicity was observed in mice and rats. No mutagenicity was found in Salmonella Typhimurium strains TA98, TA1535, and TA1537, or Escherichia coli WP2uvrA, with or without the addition of the S9 mixture. Weak mutagenicity was observed only in Salmonella Typhimurium TA100, with increased mutagenicity upon the addition of the S9 mixture. Ecotoxicity studies described the unexpectedly high susceptibility of Australian marsupials to phosmet. Symptoms of acute oral poisoning in mallards and pheasants included: rumination (mallards), ataxia, high leg raising, drooping wings, wing tremors, falling, salivation, tremors, loss of righting reflex, tonic spasms, dyspnea, miosis, lacrimation, and wing flapping twitches. Short-term treatment with fenthion resulted in a decrease in the total number of erythrocytes, hemoglobin content, hematocrit, and total number of spleen cells in peripheral blood, but an increase in the total number of leukocytes in peripheral blood, accompanied by significant heterophile granulocytosis, lymphopenia, and monopenia. Furthermore, bleeding and clotting times in the experimental group of birds were persistently prolonged. Fenthion appears to have anti-androgenic effects on the physiology and behavior of male sticklebacks. Fenthion is highly toxic to crayfish (a non-target organism used to monitor environmental impacts). Enzymes involved in energy production (lactate dehydrogenase and isoprene dehydrogenase) in crayfish exposed to fenthion were altered, possibly in response to increased energy demands. Pregnant female guppies were exposed to 10 mg/L fenthion solutions for 4 hours, 5 days, 10 days, or 15 days prior to their next spawning. In female fish exposed to fenthion 5 or 10 days before spawning, half experienced premature birth, with only 32% and 63% of eggs surviving, respectively. Female fish exposed to fenthion 15 days before spawning gave birth normally, with only 9.4% of fry stillborn. In all studies, fry born after exposure were significantly shorter in body length than those born before exposure. Fenthion is a cholinesterase or acetylcholinesterase (AChE) inhibitor. Cholinesterase inhibitors (or "anticholinesterases") inhibit the activity of acetylcholinesterase. Because acetylcholinesterase has crucial functions, 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. Neurotoxins and substances in many pesticides have been shown to exert their effects by binding to serine residues at the active site of acetylcholinesterase, thereby 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 continuous nerve impulse transmission and an inability to stop muscle contraction. The most common acetylcholinesterase inhibitors are phosphorus-containing compounds designed to bind to the active site of the enzyme. The structural requirements are: 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
LC50 (Rat)> 2,200 mg/m³/4h

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Interactions
…This study aimed to evaluate the effect of a palm oil fraction rich in tocotrienols (TRF) on reducing the harmful effects of FNT treatment in rat sperm. Adult male Sprague-Dawley rats were randomly divided into four groups of equal size: a control group, rats orally administered palm oil TRF (200 mg/kg), FNT (20 mg/kg), and rats orally administered palm oil TRF (200 mg/kg) combined with FNT (20 mg/kg), respectively. This study evaluated sperm characteristics, DNA damage, superoxide dismutase (SOD) activity, and levels of reduced glutathione (GSH), malondialdehyde (MDA), and protein carbonyl (PC). TRF supplementation significantly improved sperm count, motility, and viability, and reduced sperm morphological abnormalities, thereby mitigating the harmful effects of FNT. Compared with rats treated with FNT alone, the TRF+FNT group showed significantly increased SOD activity and GSH levels, while MDA and PC levels were significantly decreased. TRF significantly reduced DNA damage in the sperm of FNT-treated rats. A significant correlation was found between sperm morphological abnormalities and DNA damage in all groups. TRF demonstrates the potential to reduce the harmful effects of FNT-treated rat sperm. This study investigated the effects of pesticide mixtures on cholinesterase activity in neural cell aggregate cultures. It also determined whether exogenous rat liver microsomal fraction (S-9) could be used in combination with culture media to mimic the in vivo activation process of pesticides such as malathion. The effect of pesticide mixtures on cholinesterase activity in the culture medium showed that liver microsomal fraction (S-9) plays an important role in the interaction between malathion and combinations of fenthion or carbofuran. In the absence of S-9, malathion enhanced the anticholinesterase activity of fenthion, while the mixture of carbofuran and malathion did not show synergistic or antagonistic effects. When S-9 was added to the culture medium containing pesticide mixtures, the interaction between malathion and fenthion showed antagonism, while the mixture of malathion and carbofuran showed synergistic effects. The study indicated that the antagonistic effect of the fenthion and carbofuran mixture was independent of the exogenously added S-9. No antagonistic or synergistic effects were observed between trimethyl ester and mixtures of fenthion or carbofuran. Data indicate that the addition of exogenous S-9 can be used to mimic certain aspects of pesticide biotransformation in rat brain nerve cell aggregate cultures. Furthermore, the effect of several tested pesticide mixtures on cholinesterase activity depends on the presence of exogenous S-9. It is known that pretreatment of mice with diethyl maleate depletes hepatic glutathione, thereby enhancing the acute toxicity of many dimethyl-substituted organothiophosphate insecticides. However, some studies have questioned the involvement of glutathione in the detoxification of methyl parathion in mice, thus also questioning the hypothetical mechanism by which diethyl maleate induces enhanced toxicity of this insecticide. This study verifies that the mechanism by which diethyl maleate enhances the acute toxicity of methyl parathion, methyl parathion, and fenthion is not through glutathione depletion. One hour after intraperitoneal injection of diethyl maleate (0.75 ml/kg) into mice, glutathione levels were significantly reduced, and the acute toxicity of methyl parathion, methyl parathion, and fenthion was also significantly enhanced. Oral administration of glutathione monoethyl ester (20 mmol/kg) to mice pre-injected with diethylmaleate reduced hepatic glutathione depletion caused by diethylmaleate, or maintained glutathione levels at or above control levels. However, glutathione monoethyl ester did not alter the enhancing effect of diethylmaleate on the lethality of these insecticides. Furthermore, injection of glutathione monoethyl ester into untreated mice increased hepatic glutathione levels, but did not affect the mortality rate of mice at challenge doses of methyl parathion, methyl parathion, or fenthion. These data suggest that diethylmaleate enhances the toxicity of methyl parathion, methyl parathion, or fenthion through a mechanism independent of hepatic glutathione levels. In male rats, the combined effect of fenthion and malathion far exceeded the additive effect. This enhancing effect was most significant (reaching half of the expected LD50) when the combined ratio was 1:1. No synergistic effect was observed compared to other tested organophosphate compounds (such as bromophos, amitraz, and trichlorfon).

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Non-human toxicity values
LD50 rat (female) acute oral 800 mg/kg
LD50 rat (male) acute dermal 890 mg/kg
LD50 rat (female) acute dermal 1200 mg/kg
LD50 rat (oral) 500 mg/kg
For more complete non-human toxicity data for fenthion (12 in total), please visit the HSDB record page.

[1]. Impact of Exposure to Fenitrothion on Vital Organs in Rats. J Toxicol. 2016;2016:5609734.

[2]. A microcosm study on bioremediation of fenitrothion-contaminated soil using Burkholderia sp. FDS-1. International Biodeterioration & Biodegradation.

Fenitrothion is a brownish-yellow oily substance. It is a selective acaricide and also a contact and stomach poison insecticide used to control chewing and sucking pests in rice, orchard fruits, vegetables, grains, cotton, and forests. It is also used to control flies, mosquitoes, and cockroaches. (EPA, 1998)
Phosphosphate is an organothiophosphate with the structure O,O-dimethyl-O-phenylthiophosphate, substituted with a methyl group at the 3-position and a nitro group at the 4-position. It has multiple functions, including as an EC 3.1.1.7 (acetylcholinesterase) inhibitor, agricultural chemical, acaricide, EC 3.1.1.8 (cholinesterase) inhibitor, and insecticide. It is an organothiophosphate and C-nitro compound. Its function is similar to 4-nitro-m-cresol.
Phosphosphate is a synthetic organophosphate acetylcholinesterase inhibitor and endocrine disruptor used as an insecticide. It is a volatile, yellowish-brown, oily liquid that can enter the human body through inhalation, ingestion, or contact. Phosphate is an organophosphate insecticide that has been used since 1959 to control pests on rice, cereals, fruits, vegetables, stored grains, cotton, and forest pests, and in public health programs to control flies, mosquitoes, and cockroaches. Annual production of phosphate is between 15,000 and 20,000 tons. The health effects of phosphate are consistent with other organophosphate insecticides; its mechanism of action is the inhibition of cholinesterase. Phosphate is an organothiophosphocholinesterase inhibitor used as an insecticide. Mechanism of Action: Cholinesterase inhibitor. Phosphate does not show strong inhibitory activity against acetylcholinesterase (AChE) in vitro, but its inhibitory activity is much stronger in vivo. In animals, this compound is converted to the active esterase inhibitor fenprophosoxygenone (O,O-dimethyl-O-(3-methyl-4-nitrophenyl)phosphate) by microsomal mixed-function monooxygenases in the liver and other tissues. .../The author/ concludes that dealkylation is one of many factors contributing to the lower mammalian toxicity of fenprophos compared to methyl parathion. For example, fenprophos exhibits weaker cholinesterase inhibition, a slower activation process for the conversion of P=S to P=O, faster transport, and a higher detoxification rate. In mice, comparison of metabolites at equivalent toxic doses (i.e., 17 mg/kg methyl parathion and 850 mg/kg fenprophos) revealed that demethylation was the primary detoxification pathway for high doses (200-850 mg/kg) of fenprophos, but not for methyl parathion. However, the demethylation processes of the two compounds are essentially similar, and the metabolic rates of fenprophos and methyl parathion in vivo are also similar. ...The conclusion was ultimately drawn that the relatively poor brain permeability of fennitrophos, rather than its dealkylation detoxification mechanism, was the reason for its low selective toxicity.

C9H12NO5PS

277.23

277.017

122-14-5

Fenitrothion-d6;203645-59-4

31200

Colorless to light yellow liquid

1.4±0.1 g/cm3

349.5±52.0 °C at 760 mmHg

3.4°C

165.2±30.7 °C

0.0±0.7 mmHg at 25°C

1.570

3.24

0

6

4

17

313

0

CC1=CC(=CC=C1[N+](=O)[O-])OP(=S)(OC)OC

ZNOLGFHPUIJIMJ-UHFFFAOYSA-N

InChI=1S/C9H12NO5PS/c1-7-6-8(4-5-9(7)10(11)12)15-16(17,13-2)14-3/h4-6H,1-3H3

dimethoxy-(3-methyl-4-nitrophenoxy)-sulfanylidene-λ5-phosphane

Nuvanol; Arbogal; Fenitrothion

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.

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

Ethanol : ~100 mg/mL (~360.71 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.02 mM) (saturation unknown) in 10% EtOH + 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 EtOH 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 (9.02 mM) (saturation unknown) in 10% EtOH + 90% (20% SBE-β-CD in 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 EtOH 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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 (Please use freshly prepared in vivo formulations for optimal results.)