52-68-6

Name	Chlorophos
CAS	52-68-6
EINECS(EC#)	200-149-3
Molecular Formula	C4H8Cl3O4P
MDL Number	MFCD00055272
Molecular Weight	257.44
MOL File	52-68-6.mol

Chemical Properties

Appearance	Trichlorfon is a white to pale yellow crystalline solid.
Melting point	77-81 °C
Boiling point	100°C
density	1.73
vapor pressure	2.1×10^-4Pa (20 °C)
refractive index	1.3439
storage temp.	2-8°C
solubility	Freely soluble in water, very soluble in methylene chloride, freely soluble in acetone and in ethanol (96 per cent).
form	solid
pka	6 (est.)
color	Crystals
Water Solubility	Slightly soluble. 1-5 g/100 mL at 21 ºC
Merck	13,9696
BRN	1709434
Stability:	Light Sensitive
IARC	3 (Vol. 30, Sup 7) 1987
NIST Chemistry Reference	Metrifonate(52-68-6)
EPA Substance Registry System	Phosphonic acid, (2,2,2-trichloro-1-hydroxyethyl)-, dimethyl ester(52-68-6)

Safety Data

Hazard Codes	Xn,N
Risk Statements	22-43-50/53 less more
Safety Statements	24-37-60-61-2 less more
RIDADR	UN 3077 9/PG 3
WGK Germany	3
RTECS	TA0700000
HazardClass	6.1(b)
PackingGroup	III
HS Code	29319090
Safety Profile	Poison by ingestion, inhalation, inti-aperitoneal, subcutaneous, intravenous, and intramuscular routes. Moderately toxic by skin contact. Human systemic effects: true cholinesterase. Experimental teratogenic and reproductive effects. Questionable carcinogen with experimental carcinogenic and tumorigenic data. Human mutation data reported. An eye irritant. When heated to decomposition it emits very toxic fumes of Cland POx. less more
Hazardous Substances Data	52-68-6(Hazardous Substances Data)
Toxicity	LD50 in male, female rats (mg/kg): 630, 560 orally (Gaines) less more

Raw materials And Preparation Products

Hazard Information

Chemical Properties

white crystals or powder

Uses

anticholinergic, urinary incontenance therapy

Uses

One of the biologically active forms of nicotinic acid. Differs from NAD by an additional phosphate group at the 2?position of the adenosine moiety. Serves as a coenzyme of hydrogenases and dehydrogenases. Present in living cells primarily in the r

Uses

Trichlorfon is an irreversible organophosophate acetylcholinesterase inhibitor and the prodrug of Dichlorvos (D435950). Trichlorfon have also shown potential actions to be utilized as an effective org anophosphorus pesticide.

Definition

ChEBI: A phosphonic ester that is dimethyl phosphonate in which the hydrogen atom attched to the phosphorous is substituted by a 2,2,2-trichloro-1-hydroxyethyl group.

General Description

Chlorophos is a white crystalline solid. Chlorophos is a wettable powder. Chlorophos can cause illness by inhalation, skin absorption and/or ingestion. Chlorophos is used as a pesticide.

Air & Water Reactions

Chlorophos decomposes at higher temperatures in water and at pH <5.5. Chlorophos is sensitive to prolonged exposure to moisture. Chlorophos is unstable in alkaline solutions.

Reactivity Profile

Chlorophos is incompatible with alkalis. Chlorophos is corrosive to black iron and mild steel. Chlorophos is corrosive to metals. Chlorophos is subject to hydrolysis.

Health Hazard

INHALATION, INGESTION, AND SKIN ABSORPTION. Inhibits cholinesterase. Headache, depressed appetite, nausea, miosis are symptoms of light exposures. Moderate effects are peritoneal paralysis, diarrhea, salivation, lacrimation, sweating, dyspnea, substernal tightness, slow pulse, tremors, muscular cramps and ataxia. Severe symptoms are: pyrexia, cyanosis, pulmonary edema, areflexia, loss of sphincter control, paralysis, coma, heart block, shock and respiratory failure. EYES: Increases permeability of blood vessels in anterior eye. Reduces corneal sensitivity with glaucoma, abnormalities in intraocular tension or decreased visual acuity.

Fire Hazard

Combustible material: may burn but does not ignite readily. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form.

Potential Exposure

Trichlorfon is used as an agricultural and forest insecticide.

First aid

If this chemical gets into the eyes, remove any contact lenses at once and irrigate immediately for at least 15 minutes, occasionally lifting upper and lower lids. Seek medical attention immediately. If this chemical contacts the skin, remove contaminated clothing and wash immediately with soap and water. Speed in removing material from skin is of extreme importance. Shampoo hair promptly if contaminated. Seek medical attention immediately. If this chemical has been inhaled, remove from exposure, begin rescue breathing (using universal precautions, including resuscitation mask) if breathing has stopped and CPR if heart action has stopped. Transfer promptly to a medical facility. When this chemical has been swallowed, get medical attention. Give large quantities of water and induce vomiting. Do not make an unconscious person vomit. Medical observation is recommended for 2448 hours after breathing overexposure, as pulmonary edema may be delayed. As first aid for pulmonary edema, a doctor or authorized paramedic may consider administering a drug or other inhalation therapy.

Shipping

UN2783 Organophosphorus pesticides, solid, toxic, Hazard Class: 6.1; Labels: 6.1-Poisonous materials.

Incompatibilities

This chemical may be characterized as an organo-phosphate or-chlorine compound. Organophosphates are susceptible to formation of highly toxic and flammable phosphine gas in the presence of strong reducin g agents such as hydrideds and active metals. Partial oxidation by oxidizing agents may result in the release of toxic phosphorus oxides.Alkaline materials: lime, lime sulfur, etc. Corrosive to iron, steel and possibly to other metals.

Description

Trichlorfon is a colorless crystalline powder. It is soluble in water (120 g/L) and most organic solvents, except aliphatic hydrocarbons. Log Kow = 0.43. Trichlorfon is rapidly converted to dichlorvos by alkalis (2) and then hydrolyzed; DT₅₀ (22 ?C) values at pH 4, 7, and 9 are 510 d, 46 h, and <30 min, respectively.

Waste Disposal

Add a combustible solvent and burn in a furnace equipped with an afterburner and an alkali scrubber.In accordance with 40CFR165, follow recommendations for the disposal of pesticides and pesticide containers. Must be disposed properly by following package label directions or by contacting your local or federal environmental control agency, or by contacting your regional EPA office.

Antimicrobial activity

Useful activity is restricted to Schistosoma haematobium. It has little activity against other schistosomes. Although it exhibits activity against several other helminths, it is not used for their treatment.

Agricultural Uses

Insecticide, Anthelmintic: Not approved for use in EU countries . Registered for use in the U.S. except California. Trichlorfon has non-agriculture uses on golf course turf, home lawns and similar venues, and in non-food contact areas of food and meat processing plants. Also on ornamental shrubs and plants, and ornamental and bait fish ponds. Overseas, trichlorfon is used as cattle pour-on, which is classified as a food-use. It is used against insects such as lepidopteran larvae (caterpillars), white grubs, mole crickets, cattle lice, sod webworms, leaf miners, stink bugs, flies, ants, cockroaches, earwigs, crickets, diving beetles, water scavenger beetles, water boatman, backswimmers, water scorpions, giant water bugs and pillbugs. All food and feed uses in the U.S. were voluntarily canceled November 21, 1995. It was used on Brussels sprouts, barley, beets, blueberries, beans (dryand snap), corn, field corn, popcorn, sweet corn, cotton, cow peas, lima beans, tomatoes, cabbage, carrots (including tops), cauliflower, collards, cowpeas, southern peas, blackeyed peas, crowder peas, pumpkins, collards, lettuce and alfalfa, cotton, peanuts, peppers, pumpkins, tobacco, soybeans and treatment to manure. U.S. Maximum Allowable Residue Levels for the residues of Trichlorfon [40 CFR 180.198]: in or on the following raw agricultural commodities: cattle, fat 0.1ppm (negligible residue); cattle, meat byproducts 0.1ppm (negligible residue); and cattle, meat 0.1ppm (negligible residue)

Pharmaceutical Applications

An organophosphorus compound. It is soluble in water and stable at room temperature. At higher temperatures it decomposes to the insecticide dichlorvos.

Trade name

AEROL 1 (PESTICIDE)®; AGROFOROTOX®; ANTHON®; BAY 15922®; BAYER 15922®; BAYER L 13/59®; BILARCIL®; BOVINOX®[C]; BRITON®; BRITTEN®; CEKUFON®; CHLORAK®; CHLOROFTALM®; CICLO-SOM®; COMBOT®; COMBOT EQUINE®; DANEX®[C]; DEP®; DEPTHON®; DIMETOX®; DIPTEREX®; DIPTEREX® 50; DIPTEVU®; DITRIFON®; DYLOX®; DYLOX-METASYSTOX-R®; DYREX®; DYVON®; EQUINO-ACID®; EQUINO-AID®; FLIBOL E®; FLIEGENTELLE®; FOROTOX®; FOSCHLOR®; FOSCHLOR R®; FOSCHLOR R-50®; LEIVASOM®; LOISOL®; MASOTEN®[C]; MAZOTEN®; NEGUVON®; NEGUVON A®; PHOSCHLOR R50®; PROXOL®; RICIFON®; RITSIFON®; SATOX 20WSC®; SOLDEP®; SOTIPOX®; TRICHLORPHON FN®; TRINEX®; TUGON®; TUGON FLY BAIT®; TUGON STABLE SPRAY®; VERMICIDE BAYER 2349®; VOLFARTOL®; VOTEXIT®; WEC 50®; WOTEXIT®

Mechanism of action

In vivo, metrifonate rapidly rearranges to O,O-dimethyl O-(2,2-dichlorovinyl) phosphate, which is a potent inhibitor of schistosome acetylcholinesterase. This paralyzes the parasites because of the accumulation of acetylcholine, which functions as inhibitory transmitter . Trade name: Bilarcil (Bayer).

Pharmacokinetics

Metrifonate is rapidly absorbed after oral administration, achieving a peak concentration in plasma within 1–2 h. It undergoes chemical transformation to dichlorvos, which is the active molecule. Dichlorvos is rapidly and extensively metabolized and excreted mainly in the urine.

Clinical Use

Urinary schistosomiasis (especially mass chemotherapy control programs)

Carcinogenicity

When rats were fed diets that contained 0, 50, 100, 200, 250, 400, 500, or 1000 ppm (equivalent to about 0.5, 12.5, 25, or 50 mg/kg/day) for 17 or 24 months, no treatment-related effects occurred in those fed 50–250 ppm . Histopathological results suggested the occurrence of mammary tumors in rats fed 400, 500, and 1000 ppm. In another study, when rats were fed diets containing 0, 50, 250, 500, or 1000 ppm (equivalent to about 2.5, 12.5, 25, or 50 mg/kg/day) trichlorfon for 24 months, no treatment-related effects other than whole-blood cholinesterase depression at 1000 ppm occurred . There was no increase in the incidence of either benign or malignant tumors, including mammary tumors.

Environmental Fate

Soil. Trichlorfon degraded in soil to dichlorvos (alkaline conditions) and desmethyl dichlorvos (Mattson et al., 1955).
Plant. In cotton leaves, the metabolites identified included dichlorvos, phosphoric acid, O-demethyl dichlorvos, O-demethyl trichlorfon, methyl phosphate and dimethyl phosphate (Bull and Ridgway, 1969). Chloral hydrate and trichloroethanol were r
Pieper and Richmond (1976) studied the persistence of trichlorfon in various foliage following an application rate of 1.13 kg/ha. Concentrations of the insecticide found at day 0 and 14 were 81.7 ppm and 7 ppb for willow foliage, 12.6 ppm and 670 ppb for
Chemical/Physical. At 100°C, trichlorfon decomposes to chloral. Decomposed by hot water at pH <5 forming dichlorvos (Worthing and Hance, 1991).

Metabolic pathway

The metabolism of trichlorfon has been reviewed by Zayed et al. (1967), Sawicki (1973) and Zayed (1974). Trichlorfon is a non-systemic insecticide with favourable mammalian toxicity. There is considerable evidence that trichlorfon requires in vivu activation via dehydrochlorinatation to yield dichlorvos which is the active acetylcholinesterase inhibitor. This reaction is quite facile in slightly basic solution and the subsequent routes for the metabolism of trichlorfon are apparently the same as those of dichlorvos. However, there has been considerable controversy on the role played by this reaction in vivu since many workers have failed to identify dichlorvos as a metabolite in plants, mammals or insects treated with trichlorfon. It was realised that trichlorfon was a very much poorer inhibitor of acetylcholinesterase than dichlorvos and most considered that its insecticidal activity must be due to metabolism to dichlorvos as an activating step in an analogous way that phosphorothioates are metabolised to phosphates. Metcalf et al. (1959) and Miyamoto (1959) proposed that trichlorfon was totally inactive as an inhibitor of acetylcholinesterase and that any inhibition seen in vitru was due to some conversion to dichlorvos during the course of the assay for anticholinesterase activity. Metcalf et al. (1959) also reported the identification of dichlorvos in trichlorfon-treated houseflies. This conclusion was by no means universal and Arthur and Casida (1957) argued that trichlorfon was the active acetylcholinesterase inhibitor and the identification of a glucuronide conjugate of trichloroethanol was evidence that the primary route of stage I metabolism was hydrolysis of the P< bond. Other work, however, has provided evidence for the in vivu production of dichlorvos and it seems probable that the failure of some experiments to detect it is due to its rapid metabolism, resulting in a very low steadystate concentration. The metabolism of trichlorfon can be envisaged as being either through a deactivation route via demethylation and/or conjugation followed by breakdown of the demethylated products or an activation reaction to yield dichlorvos which is then degraded via a hydrolytic mechanism to yield dimethyl phosphate and dichloroacetaldehyde or demethylated by glutathione-S-methyl transferase. These competing reactions have been investigated in mammals and insects and it is the balance of activation and degradative metabolism which confers the favourable mammalian toxicity of trichlorfon in comparison with that of dichlorvos.

Metabolism

Trichlorfon administered to mammals is rapidly metabolized and excreted almost completely in the urine within 6 h. Majormetabolites are dimethyl hydrogen phosphate, methyl dihydrogen phosphate, and conjugates of dichloroacetic acid and trichloroethanol. Trichlorfon is rapidly broken down in soil.

Degradation

Trichlorfon is subject to hydrolysis and dehydrochlorination. Decomposition proceeds more rapidly with heating and above pH 6. It is rapidly converted by alkalis to dichlorvos (2) which is then hydrolysed. DT₅₀ s at pH 4,7 and 9 were 510 days, 46 hours and <30 min respectively at 20 °C. Photolysis is slow (PM).
Trichlorfon undergoes a facile rearrangement in the presence of mild base or heat to yield dichlorvos (2) and one mole of HCI (Barthel et al., 1955; Lorenz et al., 1955; Mattson et al., 1955). This reaction was shown to be first order in both trichlorfon concentration and [OH^-] with a calculated t_1/2 of 5 hours at pH 7.0 (37 °C) (Miyamoto, 1959). A mechanism for this reaction is shown in Scheme 1.

Toxicity evaluation

The acute oral LD₅₀ for rats is about 450 mg/kg. Inhalation LC50 (1 h) for rats is >0.5 mg/L air. NOEL (2 yr) for rats is 100 mg/kg diet (5 mg/kg/d). ADI is 0.01 mg/kg b.w.

Material Safety Data Sheet(MSDS)

Questions And Answer

Pharmacology and mechanism of action
Metrifonate is an organophosphorus compound, first introduced as an insecticide in 1952 and a little later as an anthelminthic. Early clinical studies have reported it to be effective against a wide number of helminthic infections including schistosomiasis, ascariasis, ancylostomiasis, and trichuriasis^[1] .The drug has been tried in onchocerciasis with limited success ^[2]. It is also an experimental drug in Alzheimer’s disease^[3]. Today, it is mainly used against Schistosoma (S) haematobium. The mechanism of action of metrifonate is unknown. The only pharmacological action described hitherto is its inhibitory effect on cholinesterases, which is due to its rearrangement product, dichlorvos. Dichlorvos, as a drug is used widely in veterinary medicine and has been given to man as a slow release preparation^{[4, 5]}. In vitro, metrifonate paralyses both S. haematobium and S. mansoni^[6]. However, clinically it is effective only against S. haematobium. Although this paradox has been explained to be due to the different locations of the two worms in man ^{[7, 8]}, recent reports suggest that S. haematobium may be more sensitive to metrifonate than S. mansoni because of much higher levels of cholinesterase activity in its tegument ^[9]. ;
Indications
For the treatment of Schistosoma haematobium infections. During mass treatment programmes, when cost is a major factor, metrifonate may be preferred over praziquantel. When radical treatment is desired and cost is not a problem, praziquantel is the first drug of choice, i.e. in places where re-infection is not expected. ;
Side effects
Despite extensive toxicological and clinical studies no major side effects have been observed with the recommended dose^{[10, 11]}. One of the most important side effects of the drug, is its effect on blood cholinesterases. Soon after its intake, both plasma and erythrocyte cholinesterase levels are inhibited to zero and to 80%, respectively. Normal plasma cholinesterase levels return after 4 weeks, but it takes longer for the recovery of the erythrocyte cholinesterase^[12]. Although no correlation seems to exist between the dose and the degree of cholinesterase inhibition, a good relationship was found between the occurrence of side effects and the plasma levels of the drug ^[13]. Side effects commonly reported include nausea, vomiting, headache, abdominal pain, vertigo, and fatigue. They are low in frequency and severity and they usually disappear spontaneously within a few hours after drug intake. In the case of metrifonate intoxication, pralidoxime iodide is used as an antidote (1 g is injected intravenously in 2 minutes. The dose may be repeated after 20 minutes if symptoms persist). In addition, atropine should be given in high doses, i.e. 2–4 mg i.v. every 3–10 minutes to a maximum daily dose of 50 mg. ;
Contraindications
Metrifonate should not be given to patients taking suxamthonium. In areas where organophosphorus insecticides have been sprayed, the community may already have low levels of blood cholinesterases. Special precautions are needed in such situations. ;
Interactions
Metrifonate prolongs the muscle-relaxing effect of succinylcholine.;
Preparations
• Bilarcil® (Bayer). Tablets 100 mg. ;
References
1. Cerf J, Lebrun A, Dierichx J (1962). A new approach to helminthiasis control: The use of an organophosphorus compound. Am J Trop Med Hyg, 11, 514–517.
2. Awadzi K, Gilles HM (1980). The chemotherapy of onchocerciasis, III: a comparative study of diethylcarbamazine DEC and metrifonate. Ann Trop Med Parasitol, 74, 210–217.
3. Moriearty PL, Womack CL, Dick BW, Colliver JA, Robbs RS, Becker RE (1991). Stability of peripheral hematological parameters after chronic acetylcholinesterase inhibition in man. Am J Hematol, 37, 280–282.
4. Cervoni WA, Oliver-Gonzalez J, Kaye S, Slomka MB (1969). Dichlorvos as a single-dose intestinal anthelminthic therapy for man. Am J Trop Med Hyg, 18, 912–919.
5. Chavarria APA, Swartzwelder JC, Villarejos VM, Kotcher E, Arguedas J (1969). Dichlorvos, an effective broad spectrum anthelminthic. Am J Trop Med Hyg, 18, 907–911.
6. Bueding E, Liu CL, Rogers SH (1972). Inhibition by metrifonate and dichlorvos of cholinesterases in schistosomes. Br J Pharmacol, 46, 480–487.
7. Forsyth DM, Rashid C (1967). Treatment of urinary schistosomiasis with trichlorofon. Lancet, ii, 909–912.
8. Feldmeier H, Doehring E, Daffalla AA, Omer AHS, Dietrich M (1982). Efficacy of metrifonate in urinary schistosomiasis: Comparison of reduction of Schistosoma haematobium and S. mansoni eggs. Am J Trop Med Hyg, 31, 1188–1194.
9. Camacho M, Tarrab-Hazdai R, Espinoza B, Arnon R, Agnew A (1994). The amount of acetylcholinesterase on the parasite surface reflects the differential sensitivity of schistosome species to metrifonate. Parasitology, 108, 153–160.
10. Holmstedt B, Nordgren I, Sandoz M, Sundwall A (1978). Metrifonate: Summary of toxicological and pharmacological information available. Arch Toxicol, 41, 3–29.
11. Davis A, Bailey DR (1969). Metrifonate in urinary schistosomiasis. Bull WHO, 41, 209–224.
12. Plestina R, Davis A, Bailey DR (1972). Effect of metrifonate on blood cholinesterases in children during the treatment of schistosomiasis. Bull WHO, 46, 747–759.
13. Aden Abdi Y, Villén T, Ericsson , Gustafsson LL, Dahl-Puustinen M-L (1990). Metrifonate in healthy volunteers: interrelationship between pharmacokinetic properties, cholinesterase inhibition and side effects. Bull WHO, 68, 731–736. ;

Spectrum Detail

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52-68-6

Chemical Properties

Safety Data

Raw materials And Preparation Products

Raw materials

Preparation Products

Hazard Information

Chemical Properties

Uses

Uses

Uses

Definition

General Description

Air & Water Reactions

Reactivity Profile

Health Hazard

Fire Hazard

Potential Exposure

First aid

Shipping

Incompatibilities

Description

Waste Disposal

Antimicrobial activity

Agricultural Uses

Pharmaceutical Applications

Trade name

Mechanism of action

Pharmacokinetics

Clinical Use

Carcinogenicity

Environmental Fate

Metabolic pathway

Metabolism

Degradation

Toxicity evaluation

Material Safety Data Sheet(MSDS)

Questions And Answer

Pharmacology and mechanism of action

Indications

Side effects

Contraindications

Interactions

Preparations

References

Spectrum Detail