Absorption, Distribution and Excretion
We aimed to evaluate prognostic factors and toxicokinetics in acute fenitrothion self-poisoning. We reviewed 12 patients with fenitrothion self-poisoning admitted to the intensive care unit between 2003 and 2006. We compared the characteristics, initial vital signs, physiological scores, corrected QT interval on electrocardiogram and laboratory data (serum fenitrothion concentration and cholinesterase activity) of non-survivors and survivors. Furthermore, we evaluated the correlation between the prognostic factors and severity of poisoning (lengths of intensive care unit and hospital stays), and the toxicokinetics of the patients. In the 2 non-survivors, the estimated fenitrothion ingestion dose and the serum fenitrothion concentration at the emergency department and at 24 hr after ingestion were significantly higher than those in the 10 survivors. (p=0.008, 0.003, and 0.04, respectively). In the 10 survivors, the serum fenitrothion concentration at 24 hr after ingestion was significantly correlated with the lengths of intensive care unit and hospital stays (p=0.004 and 0.04, respectively); however, the initial vital signs, physiological scores, corrected QT interval on electrocardiogram at the emergency department, and serum cholinesterase activity did not show any correlation. In five patients successfully fitted to a two-compartment model, the distribution and elimination half-lives were 2.5 and 49.8 hr, respectively, which is compatible with the slow and prolonged clinical course of fenitrothion poisoning. Estimated fenitrothion ingestion dose and serum fenitrothion concentration at the emergency department and at 24 hr after ingestion may be useful prognostic factors in acute fenitrothion self-poisoning. Furthermore, we should take care for the patients whose serum fenitrothion concentration is high.
An unblinded crossover study of fenitrothion 0.18 mg/kg/day [36 times the acceptable daily intake (ADI)] and 0.36 mg/kg/day (72 X ADI) administered as two daily divided doses for 4 days in 12 human volunteers was designed and undertaken after results from a pilot study. On days 1 and 4, blood and urine samples were collected for analysis of fenitrothion and its major metabolites, as well as plasma and red blood cell cholinesterase activities, and biochemistry and hematology examination. Pharmacokinetic parameters could only be determined at the higher dosage, as there were insufficient measurable fenitrothion blood levels at the lower dosage and the fenitrooxone metabolite could not be measured. There was a wide range of interindividual variability in blood levels, with peak levels achieved between 1 and 4 hr and a half-life for fenitrothion of 0.8-4.5 hr. Although based on the half-life, steady-state levels should have been achieved; the area under the curve (AUC)(0-12 hr) to AUC(0-(infinity) )ratio of 1:3 suggested accumulation of fenitrothion. There was no significant change in plasma or red blood cell cholinesterase activity with repeated dosing at either dosage level of fenitrothion, and there were no significant abnormalities detected on biochemical or hematologic monitoring.
The purpose of this study was to characterize tissue esterase activity and blood fenitrothion concentrations in the rat dam and fetus following in-utero exposure to the organophosphate insecticide fenitrothion. Time-mated, 8-week-old rats were gavaged on gestation day 19 with 0, 5, or 25 mg fenitrothion/kg. Fenitrothion was absorbed rapidly from the gastrointestinal tract, with peak maternal and fetal blood levels observed 0.5-1.0 hr after dosing. Fenitrothion concentrations in maternal and fetal blood were virtually identical and demonstrated a non-linear dose-response relationship. Acetylcholinesterase and carboxylesterase activities in maternal liver and blood and in fetal liver and brain decreased within 30-60 min of fenitrothion exposure. Esterase inhibition occurred at a fenitrothion dose (5 mg/kg) that has not been previously associated with reproductive toxicity, suggesting that esterase inhibition should be considered as the critical effect in risk assessments for this pesticide.
... Rapid absorption through skin.
For more Absorption, Distribution and Excretion (Complete) data for Fenitrothion (17 total), please visit the HSDB record page.

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Metabolism / Metabolites
Fenitrothion is metabolized unremarkably in the goat. The metabolites result from one or more of the following pathways: reduction of the nitro-group to an amine followed by conjugation with sulfate or acetate; formation of oxon; O-demethylation.
After exposure of rats and guinea pigs to sumithion, desmethyl analog, dimethyl phosphorothioate, dimethyl phosphate, and 4 unidentified compounds were found.
In comparative study of biotransformations in mice of sumithion ... and methyl parathion ... similar urinary metabolites resulted. They included methyl phosphorothioates, ... dimethyl phosphates ... and methyl phosphates ... and together with dimethyl phosphorothionate, dimethylphosphate, methyl phosphate and phosphate.
After the beetle Tribolium castaneum was topically treated with fenitrothion, main hydrolytic metabolite was o-demethyl analog. Dimethyl thiophosphate and dimethyl phosphate were also found. Fenitroxon and ... phenol were observed. Application of formic, acetic or n-propionic acid to tribolium castaneum inhibited formation of oxon and desmethyl analogs.
For more Metabolism/Metabolites (Complete) data for Fenitrothion (14 total), please visit the HSDB record page.
Metabolism of organophosphates occurs principally by oxidation, by hydrolysis via esterases and by reaction with glutathione. Demethylation and glucuronidation may also occur. Oxidation of organophosphorus pesticides may result in moderately toxic products. In general, phosphorothioates are not directly toxic but require oxidative metabolism to the proximal toxin. The glutathione transferase reactions produce products that are, in most cases, of low toxicity. Paraoxonase (PON1) is a key enzyme in the metabolism of organophosphates. PON1 can inactivate some organophosphates through hydrolysis. PON1 hydrolyzes the active metabolites in several organophosphates insecticides as well as, nerve agents such as soman, sarin, and VX. The presence of PON1 polymorphisms causes there to be different enzyme levels and catalytic efficiency of this esterase, which in turn suggests that different individuals may be more susceptible to the toxic effect of organophosphate exposure.

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Biological Half-Life
Following administration of 10 or 3 mg fenitrothion/kg body weight per day to male native Japanese rabbits for 6 months, blood, skeletal muscle, and abdominal fat were analyzed by gas chromatography for fenitrothion and fenitrooxon. In most cases, blood and muscle did not contain any detectable amounts of either compound (detection limit for fenitrothion 0.005 or 0.002 mg/kg, and that of fenitrooxon, 0.01 mg/kg). Averages of 0.131 mg fenitrothion/kg (0.243 mg/kg maximum) and of 0.045 mg/kg were measured in the fat of rabbits dosed at 10 and 3 mg/kg body weight per day, respectively, while muscle contained a maximum of 0.006 mg fenitrothion/kg. No fenitrooxon was detected.
.... We reviewed 12 patients with fenitrothion self-poisoning admitted to the intensive care unit between 2003 and 2006 ... In five patients successfully fitted to a two-compartment model, the distribution and elimination half-lives were 2.5 and 49.8 hr, respectively, which is compatible with the slow and prolonged clinical course of fenitrothion poisoning ...

Toxicity Summary
IDENTIFICATION AND USE: Fenitrothion is a yellow-brown liquid. It is used as an insecticide (acaricide). HUMAN EXPOSURE AND TOXICITY: The signs and symptoms of poisoning in humans were those of parasympathetic stimulations. It has been suggested that the slow release of the insecticide from adipose tissue can give rise to a protracted clinical course or late symptoms of intoxication. In some cases, contact dermatitis has been attributed to exposure to this insecticide. There is no evidence of delayed neurotoxicity or of an association with Reye's syndrome. Moderate poisoning of 25 workers was reported, where a formulation containing 50% fenitrothion was applied by aircraft during a strong wind. Onset of poisoning developed 2.5-6 hr after inhalation and the symptoms were typical. Whole blood ChE activity was decreased by 48%. Recovery required 3 days of treatment with atropine. In another study, Cholinesterase activity was significantly reduced at the end of the working week in 3 out of 28 fenitrothion workers in Haiti. ANIMAL STUDIES: In experimental animals, fenitrothion causes cholinesterase activity depression in plasma, red blood cells, and brain and liver tissues. It is metabolized to fenitrooxon, which is more acutely toxic. Its toxicity may be potentiated by some other organophosphate compounds. Fenitrothion is only minimally irritating to the eyes and is nonirritating to the skin. A single oral dose of 250 mg fenitrothion/kg resulted in a slight decrease in a number of biochemical indices of liver function in rats, including mitochondrial ATPase activity, cytochrome P450 content, aniline hydroxylase activity, and aminopyrine N-demethylase activity. A dose of 25 mg/kg also had a slight effect on P450 content and xenobiotic metabolism, while 5 mg/kg did not have any significant effects. The magnitude of the effects was greater in females than in males. Mice that received fenitrothion at dietary level of 1000 ppm (about 12.8 mg/kg/day) developed symptoms within a week and at the end of a 20 day feeding period had cholinesterase activity in brain, red cells, and plasma reduced to 45, 26, and 5% of normal, respectively; body weight and liver weight were not affected. Prenatal administration in rats at 5, 10 and 15 mg/kg from days 7 to 15 of gestation, resulted in dose related decrease in open field activity and motor coordination in the offspring treated with the two higher doses. Long lasting alterations in the acquisition and extinction of a conditioned escape response, as well as increased social interactions were observed in the adult offspring. No embryotoxic or teratogenic effects were observed in mice or rats. Fenitrothion was found to be non-mutagenic in Salmonella typhimurium strains of TA98, TA1535 and TA1537 and in Escherichia coli WP2uvrA both with and without S9 mix, while weak mutagenicity was observed only in Salmonella typhimurium TA100 and enhanced by the addition of S9 mix. ECOTOXICITY STUDIES: The unexpectedly high sensitivity of Australian marsupials to fenitrothion was described. Signs of intoxication in mallards and pheasants from acute oral administration: regurgitation (in mallards), ataxia, high carriage, wing-drop, wing shivers, falling, salivation, tremors, loss of righting reflex, tetanic seizures, dyspnea, miosis, lacrimation, and wing-beat convulsions. Short term fenitrothion treatment in bluerock pigeons (Columba livia Gmelin) resulted in a reduction of total count of peripheral erythrocytes, hemoglobin content, hematocrit and total spleen cell count, but an increase in total peripheral leukocyte count, with marked heterophilia along with lymphopenia and monocytopenia. Also, there was consistent prolongation of both bleeding and clotting time in the experimental birds. Fenitrothion appears to have anti-androgenic effects on both the physiology and behavior of the male stickleback. Fenitrothion was highly toxic to crayfish, a nontarget organism that can be used for monitoring of environmental effects. Prawns exposed to fenitrothion showed alterations in enzymes involved in the production of energy (LDH and IDH) possibly in an attempt to cope with additional energetic demands. Pregnant female guppies were exposed to 10 mg fenitrothion/liter for 4 hr, 5, 10, or 15 days before the next parturition. Half of the females gave premature birth when exposed 5 or 10 days before parturition, and only 32 or 63%, respectively, of the eggs were delivered alive. The females exposed to the fenitrothion 15 days before parturition had normal births and only 9.4% of the offspring were stillborn. The body lengths of the young produced by the females after exposure were significantly shorter than those produced before exposure in all the studies.
Fenitrothion is a cholinesterase or acetylcholinesterase (AChE) inhibitor. A cholinesterase inhibitor (or 'anticholinesterase') suppresses the action of acetylcholinesterase. Because of its essential function, chemicals that interfere with the action of acetylcholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Nerve gases and many substances used in insecticides have been shown to act by binding a serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. Acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the enzyme. The structural requirements are a phosphorus atom bearing two lipophilic groups, a leaving group (such as a halide or thiocyanate), and a terminal oxygen.

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Toxicity Data
LC50 (rat) > 2,200 mg/m3/4h

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Interactions
... The present study was carried out to evaluate the effects of palm oil tocotrienol-rich fraction (TRF) in reducing the detrimental effects occurring in spermatozoa of FNT-treated rats. Adult male Sprague-Dawley rats were divided into four equal groups: a control group and groups of rats treated orally with palm oil TRF (200 mg/kg), FNT (20 mg/kg) and palm oil TRF (200 mg/kg) combined with FNT (20 mg/kg). The sperm characteristics, DNA damage, superoxide dismutase (SOD) activity, and levels of reduced glutathione (GSH), malondialdehyde (MDA), and protein carbonyl (PC) were evaluated. Supplementation with TRF attenuated the detrimental effects of FNT by significantly increasing the sperm counts, motility, and viability and decreased the abnormal sperm morphology. The SOD activity and GSH level were significantly increased, whereas the MDA and PC levels were significantly decreased in the TRF+FNT group compared with the rats receiving FNT alone. TRF significantly decreased the DNA damage in the sperm of FNT-treated rats. A significant correlation between abnormal sperm morphology and DNA damage was found in all groups. TRF showed the potential to reduce the detrimental effects occurring in spermatozoa of FNT-treated rats.
The effects of pesticide mixtures on cholinesterase activity in aggregate cultures of neural cells were investigated; it was also determined whether exogenous rat-liver microsomal fraction (S-9) might be used in conjunction with the cultures to mimic the in vivo activation of pesticides such as malathion. Studies of the effects of pesticide mixtures on the cholinesterase activity of cultures demonstrated that a hepatic microsomal fraction (S-9) played a major role in the nature of the interaction between combinations of malathion and fenitrothion or carbofuran. In the absence of S-9, malathion potentiated the anticholinesterase effect of fenitrothion, while neither synergistic nor antagonistic interactions occurred with mixtures of carbofuran and malathion. When S-9 was added to cultures with the pesticide mixtures, malathion's interaction with fenitrothion was antagonistic, and a synergistic response was observed for the mixtures of malathion and carbofuran. The antagonistic interaction of mixtures of fenitrothion and carbofuran was demonstrated to be independent of exogenously added S-9. Neither antagonistic nor synergistic interactions were observed for mixtures of triallate and fenitrothion or carbofuran. The data indicate that the addition of exogenous S-9 may be used to mimic certain aspects of the in vivo biotransformation of pesticides in aggregate cultures of neural cells from rat brain. Furthermore, the effects on cholinesterase activity of several of the pesticide mixtures tested were dependent upon the presence of exogenous S-9.
Depletion of hepatic glutathione in the mouse by pretreatment with diethyl maleate is known to potentiate the acute toxicities of many dimethyl substituted organothiophosphate insecticides. However, certain studies have raised doubts regarding the participation of glutathione in the detoxification of methyl parathion in the mouse, and hence the putative mechanism of action of diethyl maleate induced potentiation of this insecticide. The present study evaluates the hypothesis that diethyl maleate potentiates the acute toxicities of methyl parathion, methyl paraoxon, and fenitrothion by a mechanism other than glutathione depletion. One hour following pretreatment of mice with diethyl maleate (0.75 ml/kg ip) glutathione was markedly depleted and the acute toxicities of methyl parathion, methyl paroxon and fenitrothion were potentiated. Administration of glutathione monoethyl ester (20 mmol/kg po) to diethyl maleate pretreated mice attenuated diethyl maleate depletion of hepatic glutathione, or maintaining glutathine at or above control levels. However, glutathione monoethyl ester did not alter the diethyl maleate induced potentiation of the lethality of these insecticides. Furthermore, administration of glutathione monoethyl ester to naive mice increased hepatic glutathione levels, but did not affect the percentage of animals succumbing to a challenge dose of methyl parathion, methyl paraoxon, or fenitrothion. These data indicate that diethyl maleate potentiates the toxicity of methyl parathion, methyl paraoxon or fenitrothion by a mechanism unrelated to hepatic glutathione content.
The effects of a combination of fenitrothion with malathion in male rats were more than additive. The potentiation was most pronounced (half of the expected LD50) with a combination rate of 1:1. No potentiation was observed with other tested organophosphates, ie bromophos, amidithion, 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 Non-Human Toxicity Values (Complete) data for Fenitrothion (12 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 oil. Used as a selective acaricide and a contact and stomach insecticide against chewing and sucking insects on rice, orchard fruits, vegetables, cereals, cotton and forest. Also used against flies, mosquitoes, and cockroaches. (EPA, 1998)
Fenitrothion is an organic thiophosphate that is O,O-dimethyl O-phenyl phosphorothioate substituted by a methyl group at position 3 and a nitro group at position 4. It has a role as an EC 3.1.1.7 (acetylcholinesterase) inhibitor, an agrochemical, an acaricide, an EC 3.1.1.8 (cholinesterase) inhibitor and an insecticide. It is an organic thiophosphate and a C-nitro compound. It is functionally related to a 4-nitro-m-cresol.
Fenitrothion is a synthetic organophosphate acetylcholinesterase inhibitor and endocrine disrupter that is used as a pesticide. It is characterized as a volatile yellow brown oily liquid, and exposure occurs by inhalation, ingestion, or contact.
Fenitrothion is an organophospahate insecticide that has been used since 1959 to control insects on rice, cereals, fruits, vegetables, stored grains, cotton, to control insects in forests and for fly, mosquito, and cockroach control in public health programs. Between 15 000 and 20 000 tons of fenitrothion are produced per year. The health effects of finitrothion are consistent with those of other organophosphates and are the result of cholinesterase inhibition.
An organothiophosphate cholinesterase inhibitor that is used as an insecticide.

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Mechanism of Action
Cholinesterase inhibitor.
Fenitrothion is not a strong inhibitor of AChE in vitro, but is much more so in vivo. The compound converted in the animal body to the active esterase inhibitor, fenitrooxon (O,O-dimethyl O-(3-methyl-4-nitrophenyl)phosphate), by the action of microsomal mixed function monooxygenase in liver and other tissues.
... /Authors/ concluded that dealkylation was an important factor among the many that contribute to the lower mammalian toxicity of fenitrothion compared with that of methylparathion. For example, the cholinesterase inhibition of fenitrooxon is less, the activation by conversion of P=S to P=O, slower, the translocation of fenitrothion more rapid, and the detoxification rate of fenitrothion, higher. Comparison of metabolites, at equitoxic doses in white mice (i.e., 17 mg methylparathion/kg and 850 mg fenitrothion/kg) showed that demethylation is the major detoxification path for fenitrothion at high doses (200-850 mg/kg), but not for methylparathion. However, inherently, demethylation of both compounds proceeds in a similar way and both fenitrothion and methylparathion are metabolized at a similar rate in vivo. ... /It was/ concluded that the relatively poorer penetration of fenitrooxon into the brain explained the selectively lower toxicity of fenitrothion rather than the dealkylation detoxification mechanism.

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.)