Triclofos

SOL IN WATER /MONOSODIUM/

1 g in 250 ml alcohol; almost insol in ether

BLALOCK CC; DRUG EVALUATION DATA: TRICLOFOS SODIUM; DRUG INTEL CLIN PHARM 7 (MAR): 126-8 (1973). MONOGRAPH ON TRICLOFOS SODIUM INCLUDING CHEMISTRY, MECHANISM OF ACTION, TOXICOLOGY, BIOPHARMACEUTICS, MFR CLAIMS, SIDE EFFECTS & ADVERSE REACTIONS, DRUG INTERACTIONS, DOSAGE & ADMIN & COST IS PRESENTED.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

...TRICLOFOS.../IS/ SLOWLY HYDROLYZED IN STOMACH TO YIELD CHLORAL HYDRATE AND .../IT HAS/ BEEN SHOWN TO DECR WARFARIN HALF-LIFE BY INCR AMT OF UNBOUND WARFARIN AVAILABLE FOR METABOLISM.

...TRICLOFOS /IS/...METABOLIZED TO YIELD TRICHLOROETHANOL /WHICH/ WILL INTERACT WITH ALCOHOL.

It is proposed that a metabolite of triclofos (trichloroacetic acid) displaces warfarin from plasma protein binding.

TERRESTRIAL FATE: An estimated Koc of 352(1,2,SRC) indicates that triclofos will have moderate mobility in soil(3). Under alkaline soil conditions, hydrolysis of triclofos may be rapid and will be expected to be a major fate process for this compound; the rate of hydrolysis in neutral or slightly acid soil environments should be slower(4). Triclofos is not expected to volatilize from soil surfaces based on an estimated Henry's Law constant of 1.41X10-13 atm-cu m/mole(5).

AQUATIC FATE: Hydrolysis of triclofos, particularly in alkaline waters, will be a major fate process for this compound; in neutral or slightly acidic water, triclofos will hydrolyze less rapidly(1). Triclofos is not expected to volatilize from water surfaces based on an estimated Henry's Law constant of 1.41X10-13 atm-cu/mole(2). If released to an aquatic environment, triclofos is not expected to bioconcentrate with an estimated BCF value of 25(3,4,SRC).

ATMOSPHERIC FATE: Based on an estimated vapor pressure of 2.13X10-6 mm Hg at 25 °C(1,SRC), triclofos can exist in both the vapor phase and particulate phase in the ambient atmosphere(2,SRC). It will degrade fairly rapidly in the vapor phase by reaction with photochemically produced hydroxyl radicals with an estimated half-life of 10 days(3,SRC). Particulate phase triclofos may be removed physically from air by wet and dry deposition(SRC).

Using a regression-derived equation(1) and an estimated log Kow of 1.13(2), the Koc for triclofos was estimated as 98(SRC). According to a suggested classification scheme, this Koc value suggests that triclofos will have moderate mobility in soil(3). As triclofos should be fairly water soluble, leaching of this compound may occur under certain environmental conditions(SRC).

PRETERM INFANT WITH ACCIDENTAL TRICLOFOS SODIUM POISONING DEVELOPED DEEP COMA, SEVERE HYPOTHERMIA, HYPOTENSION & LACK OF PRIMITIVE & DEEP TENDON REFLEXES.

THIRTY PT COMPLAINING OF INSOMNIA WERE STUDIED IN DOUBLE-BLIND TRIAL WITH CROSSOVER OF FINORGAL, NITRAZEPAM & TRICLOFOS SODIUM. FINORGAL PRODUCED SIMILAR RESULTS TO TRICLOFOS SODIUM. SIDE-EFFECTS WERE NOT SERIOUS. NO DRUG TOXICITY DEVELOPED OVER THREE WK PERIOD OF TREATMENT.

The rate constant for the vapor phase reaction of triclofos with photochemically produced hydroxyl radicals has been estimated as 1.58X10-12 cu-cm/molecule-sec at 25 °C(1). This corresponds to an atmospheric half-life of about 10 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). Hydrolysis of triclofos is expected to be rapid. Hydrolysis of phosphate esters is generally promoted by alkaline conditions as the phosphate ester undergoes second order nucleophilic reactions involving cleavage of the O-P bond due to hydroxide ions(2). A half-life of 852 years has been reported for methyl phosphate in water at 25 °C and at a pH 4.17(3); the reaction rate was 2.57X10-11 1/sec(3). The three chlorines on the ethyl will act as electron withdrawing groups and will promote hydrolysis by OH-(2). In addition, monoalkyl phosphates, which exist as mono and dianions at common environmental pH's, are generally more susceptible to hydrolysis than the di- or triesters. Thus under alkaline conditions triclofos may hydrolyze fairly rapidly(2,SRC).

Triclofos's production and use as a medicinal drug may result in its release to the environment. If released to the atmosphere, triclofos will exist in both the vapor phase and particulate phase based on an estimated vapor pressure of 2.13X10-6 mm Hg at 25 °C. It will degrade in the vapor phase by reaction with hydroxyl radicals with a half-life of 10 days. Particulate phase triclofos may be removed physically from air by wet and dry deposition. In soil, triclofos is expected to have moderate mobility; some leaching may be possible as triclofos should be fairly water soluble. Hydrolysis of triclofos in soil may be an important fate process, particularly under alkaline soil conditions. In water, hydrolysis may be a major fate process for triclofos, particularly if the water is alkaline. An estimated Henry's Law constant of 5.64X10-7 atm-cu/mole indicates that this compound will not volatilize from water surfaces. Triclofos is not expected to bioconcentrate in aquatic organisms. (SRC)

N - Nervous system

QN - Nervous system

...IS RAPIDLY DEPHOSPHORYLATED, PRINCIPALLY IN GUT, TO TRICHLOROETHANOL... TRICLOFOS SODIUM PRODUCES A PEAK TRICHLOROETHANOL LEVEL IN 1 HR... /TRICLOFOS SODIUM/

METABOLISM OF CHLORAL HYDRATE AND TRICLOFOS SODIUM WAS COMPARED IN SEVEN HEALTHY PEOPLE WHO INGESTED 15 MG/KG & 22.5 MG/KG. TRICHLOROETHANOL WAS PRODUCED. AFTER 6 HR 4.6% OF TRICLOFOS SODIUM WAS RECOVERED IN URINE AS TRICHLOROETHANOL & TRICHLOROACETIC ACID.

HYDROLYSIS KINETICS WAS STUDIED AT PH 0-7.8, TEMP 80.1-98.4 °F & IONIC STRENGTH 0.02-1.50. VARIOUS MECHANISTIC POSSIBILITIES FOR THE DIFFERENT NATURES OF TRICLOFOS SODIUM AT THE VARYING RANGES OF PH, TEMPERATURE AND IONIC STRENGTH ARE DISCUSSED. /TRICLOFOS SODIUM MONOPHOSPHATE ESTER/

After 6 hr, 4.6% of 15 mg/kg and 22 mg/kg dose of triclofos sodium given orally to seven healthy people, was recovered in the urine.

HEMS ET AL, BRIT MED J 1, 1834 (1962).

Chloral is reduced with sodium borohydride and the resulting trichloroethanol is esterified with polyphosphoric acid to give the dihydrogen phosphate. The ester is then reacted with an equimolar quantity of sodium hydroxide. /Triclofos sodium/

Syrup: 500 mg/5 ml

Tablets: 750 mg; liquid: 100 mg/ml