National Toxicology Program

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. ¹

Names (NTP)

• Trichlorfon
• (2,2,2-TRICHLORO-1-HYDROXYETHYL)PHOSPHONIC ACID DIMETHYL ESTER (9CI)

Human Toxicity Excerpts

• HUMAN EXPOSURE STUDIES: Cholinesterase activity measurements for 542 California agricultural pesticide applicators under medical supervision during the first 9 months of 1985 were analyzed. Medical records of applicators were used if the subject had been exposed for over 3 hr in a 30 day period to category I and II organophosphate and carbamate pesticides. Employers of all workers with cholinesterase activity depressions that fell to 70% or less of the workers's plasma or RBC(/red blood cell/) baselines were contacted to obtain a list of pesticides handled in the 2 wk interval preceding the greatest reported cholinesterase activity depression. In evaluating pesticide exposure data, it was not possible to distinguish listed pesticides primarily or cumulatively responsible for the observed cholinesterase activity depressions from those not responsible for the cholinesterase activity depression, but coincidentally used during the same period. The pesticides associated with plasma or RBC cholinesterase activity depressions to 70% of baseline or lower are listed. Trichlorfon usage in California for 1985 was 35,700 lb. The frequency of trichlorfon exposure as measured by "% depression from chloinesterase baseline activity" was 0 for plasma (< 50% reduction) and 3 and 1 for RBC (< 70% and 60% reductions, respectively). Twenty-six workers, 4.8% of the sample, had cholinesterase values at or below the California action limit value for removal from continued exposure to cholinesterase-inhibiting pesticides. Eight of these 26 workers (31.5%) had pesticide-related illnesses. [Ames RG et al; Am J Ind Med 15 (2): 143-50 (1989) ]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: Five people exposed to high levels of Ditriphon 50, a Hungarian insecticide preparation containing trichlorfon as the active ingredient and other unknown constituents /were studied/. /Results indicated/ an excess incidence of short lived chromosome breaks and exchange figures relative to karyotypes of 15 healthy volunteers matched for age only. A significant increase in stable chromosome alterations was also found among the people exposed to Ditriphon 50. [National Research Council. Drinking Water and Health, Volume 6. Washington, D.C.: National Academy Press, 1986., p. 399]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: The characteristic clinical features of dipterex-induced delayed neurotoxicity in humans showed 3 stages: (1) acute encephalopathy, (2) followed by recovery without any residual symptoms, (3) followed by delayed neuropathy, 2-3 weeks later. All cases showed motor dominant polyneuropathy, but the most severe case developed myeloneuropathy. The histological evaluation of the sural nerve showed axonal change. [Shiraishi S et al; J Uoeh 5 (Suppl): 125-32 (1983) ]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: 1. Nausea is often the first symptom, followed by vomiting, abdominal cramps, diarrhea, and excessive salivation (sialorrhea). Hypothermia has been reported in animals and at least once in man as an early sign. 2. Headache, giddiness, vertigo, and weakness. 3. Rhinorrhea and a sensation of tightness in the chest are common in inhalation exposures. 4. Blurring or dimness of vision, miosis (with fixed pinpoint pupils), tearing, ciliary muscle spasm, loss of accommodation, and ocular pain. None of these eye effects are diagnostically dependable except in primary ocular exposures. Indeed, mydriasis is sometimes seen, probably due to sympatho-adrenal discharge. 5. Bradycardia or tachycardia. Varying degrees of AV heart block are described, as well as atrial arrhythmias. 6. Loss of muscle coordination, slurring of speech, fasciculations and twitching of muscles (particularly of the tongue and eyelids), and generalized profound weakness. 7. Mental confusion, disorientation, and drowsiness. 8. Difficulty in breathing, excessive secretion of saliva and of respiratory tract mucus, oronasal frothing, cyanosis, pulmonary rales and rhonchi, and hypertension presumably due to asphyxia). 9. Random jerky movements, incontinence, convulsions and coma. 10. Death primarily due to respiratory arrest arising from failure of the respiratory muscles, intense bronchoconstriction, or all three. /Parathion/ [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-340]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: Accumulation of acetylcholine in CNS is believed to be responsible for tension, anxiety, restlessness, insomnia, headache, emotional instability, and neurosis, excessive dreaming and nightmares, apathy, and confusion ... described after organophosphate poisoning. /Organophosphate insecticides/ [Doull, J., C.D.Klassen, and M.D. Amdur (eds.). Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986., p. 528]**PEER REVIEWED**
  
• CASE REPORTS: A 50-year-old man, suspected of ingesting organophosphorus insecticides, was found dead in a graveyard. In the gas chromatography-mass spectrometric screening, trichlorfon and methidathion were detected in his gastric contents. The quantitative analysis for trichlorfon and methidathion was carried out by high-performance liquid chromatography. The concentrations (microg/ml or microg/g) of trichlorfon and methidathion were 409 and 1.9 in the heart blood, 281 and 0.4 in the femoral vein blood, 430 and 5.8 in the cerebrum, 385 and 5.1 in the brain stem, 256 and 2.8 in the right apex of lung, 449 and 15.1 in the left basal of lung, 856 and 131.0 in the liver, 460 and 1.6 in the right kidney, 390 and 1.9 in the left kidney, 524 and 3.4 in the spleen, 152 and 0.6 in the thigh muscle, 207 and 0.9 in the urine, 20,000 and 19,400 in the gastric contents, respectively. According to the autopsy finding and toxicological analysis, the cause of death was judged to be acute trichlorfon and methidathion poisoning. [Arao T et al; Leg Med (Tokyo) 4 (3): 182-6 (2002) ]**PEER REVIEWED** PubMed Abstract
  
• CASE REPORTS: A 76-year-old male, who had attempted suicide by ingesting about 50 mL of trichlorfon, died approximately 8 hours later. The trichlorfon concentration was found to be 215 ug/g in a blood sample and 15.0 mg/g in a gastric lavage liquid sample, both of which were collected about 1 hour after intake. [WHO; Environ Health Criteria 132: Trichlorfon p. 39 (1992) ]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: Of 15 live births in one Hungarian village in 1989-90, 11 (73%) were affected by congenital abnormalities and 6 were twins. Of the 11, 4 had Down's syndrome. Likely causes of such clusters (known teratogenic factors, familial inheritance, consanguinity) were excluded. A case control study and environmental investigations pointed the finger of suspicion at the excessive use of trichlorfon at local fish farms. The content of this chemical was very high in fish (100 mg/kg) and several pregnant women, including all mothers of babies with Down syndrome, had consumed contaminated fish in the critical period for the congenital abnormalities observed. [Czeizel AE et al; Lancet 341 (8844): 539-42 (1993) ]**PEER REVIEWED**
  
• EPIDEMIOLOGY STUDIES: Thirty cysticercous patients were treated with metrifonate in doses of 7.5 mg/kg given for five consecutive days, with intervals of two weeks until completion of six series. The symptoms originated by drug reaction were mild and transitory. The results obtained after treatment demonstrated the effectivity in cerebral ocular and musculocutaneous cysticercosis, corroborated by clinical evaluations like: neurological, ophtalmological and psychiatric examinations; routine laboratory tests; special examinations like indirect immunofluorescence and hemagglutination, immunoglobulin quantitation and cholinesterase activity and by special cabinet studies like electroencephalogram, retinal fluorangiography, axial computerized tomography. The postreatment observation time varied from six months to nine years; in no case reactivation was observed. [Trujillo-Valdes VM et al; Arch Invest Med (Mex) 12 (1): 15-28 (1981) ]**PEER REVIEWED** PubMed Abstract
  
• BIOMONITORING: Historical surveillance data were collected from 1977 to 1982 and compared with the results of a cross-sectional study conducted in 1983-4 in a dipterex (trichlorfon) packing plant. The number of employees varied from 36 to 110 workers per year. For the period 1977-82, mean air concentrations ranged from 0.95 - 3.30 mg/cu m. Review of surveillance data showed a trend of declining air concentrations and declining incidence of poisoning cases but no apparent change in blood cholinesterase activity over the same period. There was a statistically significant (p<0.01) difference in incidence rates of poisoning + suspected poisoning by season. During the study period (1983-4), air concentrations were near or below 1.0 mg/cu m and calculated dermal conentrations ranged from 0.50-5.92 ug/cu cm of skin surface. In study subjects, blood cholinesterase activity was consistently significantly (p<0.05) inhibited after 3 months of employment as compared with their pre-exposure values. [Hu X et al; Br J Ind Med 43: 414-19 (1986) ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: Skin sensitivity has been reported in humans ... . [Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974., p. 615]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: Significant and persistent increases (lasting at least 180 days after exposure) in aneuploidy in lymphocytes of individuals who attempted suicide by using trichlorfon (Ditriphon-50) were reported. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:933]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: 379 cases of trichlorfon poisoning /were reviewed/ and found that in some cases (3%), acute poisonings were accompanied by "mental disturbance" (described as loss of memory and problem-solving ability, delirium, depression and anxiety, psychomotor stimulation, hallucinations, and paranoid delusions); and in other cases (21%), poisoning was accompanied by a delayed type polyneuropathy. It is not clear, however, whether these symptoms were due to trichlorfon itself or to some contaminant in the ingested material. Estimates of dosages associated with poisonings suggested that ingestion of 40 mg/kg causes light to moderate poisoning, ingestion of 80-700 mg/kg causes severe poisoning, and ingestion of 30,000-90,000 mg/kg causes death. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:933]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: Consumption of trichlorfon-poisoned fish by women in a small Hungarian village has been associated with trisomy resulting from an error of meiosis II in oogenesis. [Yin H et al; Chromosoma 107 (6-7): 514-22 (1998) ]**PEER REVIEWED** PubMed Abstract
  

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Non-Human Toxicity Excerpts

• LABORATORY ANIMALS: Acute Exposure: In rats given daily oral doses of 300 mg/kg body weight technical trichlorfon for 5 days, brain edema, congestion of organs, fatty degeneration, and glycogen depletion of the liver, glycogen depletion of the heart muscle and emphysema and local inflammation in the lungs were observed. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V30 215 (1983)]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Trichlorfon (200 mg/kg, orally) decreased blood acetylcholinesterase and pseudocholinesterase activities in dogs by up to approximately 3.5 and approximately 4 fold, respectively, within 0.5 hours of its administration. [FLORES A ET AL; ARCH MED VET 14 (1): 23-7 (1982) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: When rats were given single oral doses of 10, 30, and 100 mg/kg trichlorfon, the 100-mg/kg dose of trichlorfon caused salivation, tremor, diarrhea, ptosis, flat body, decreased body temperature, and decreased pentylenetetrazole seizure threshold, whereas the 30- or 10-mg/kg doses did not. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:927]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Trichlorfon ... was a moderate contact allergen in the skin. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:928]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: Acute toxicity tests were conducted to determine (a) the individual and interactive effects of water temperature (7, 12, 17deg C), pH (6.5, 7.5, 8.5, 9.5), and time on the toxicity of terbufos, trichlorfon, 4-nitrophenol, and 2,4-dinitrophenol to rainbow trout (Oncorhynchus mykiss) and the amphipod Gammarus pseudolimnaeus, and (b) the individual and interactive effects of water temperature and pH on chemical bioconcentration during acute tests with rainbow trout and Gammarus exposed to terbufos, 4-nitrophenol, and 2,4-dinitrophenol. The toxicity of all four chemicals was significantly affected by pH in all tests, except for Gammarus exposed to terbufos. The toxicity of terbufos to rainbow trout and Gammarus was less at pH 7.5 than at higher or lower pH. The toxicity of both nitrophenols decreased as pH increased, whereas the toxicity of trichlorfon increased with pH. The effect of pH on trichlorfon toxicity decreased with temperature. Temperature significantly affected the toxicity of all four chemicals to both species. Toxicity increased with temperature in all tests, except for rainbow trout exposed to nitrophenols; toxicity decreased as temperature increased for rainbow trout. Chemical bioconcentration was also significantly affected by temperature and pH and was directly related to toxicity in most tests. Significant interactive effects between toxicity-modifying factors were also frequently observed. Temperature and pH effects on chemical toxicity need to be considered in chemical hazard assessment to ensure adequate protection of aquatic organisms. [Howe GE et al; Environ Toxicol Chem 13 (1): 51-66 (1994) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Acute Exposure: When applied to eyes of rabbits it has short lasting miotic effect and produces little or no irritation. [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 933]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Rats (13/sex per group) were fed trichlorfon at dietary levels of 0, 20, 100, or 300 mg/kg diet for 16 weeks. Significant cholinesterase depression was noted at 300 mg/kg. No effects were observed at the 100 mg/kg level on growth, behavior, food consumption, or on gross and microscopic examination of tissues. [WHO; Environ Health Criteria 132: Trichlorfon p. 53 (1992) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Rats (10/sex per group) were exposed for 6 hours a day over a 3-week period (total of 15 exposures) to an atmosphere containing trichlorfon at concentrations of 0, 12.7, 35.4, and 103.5 mg/cu m. ... Body weight gain, parameters of hematological and clinical chemistry examinations, and urinalyses were not influenced at any exposure level. Cholinesterase inhibition of 42, 31, and 22% was found in the plasma, erythrocytes, and the brain, respectively, in male animals at 103.5 mg/cu m; female animals showed dose-dependent inhibition values of 39, 26, and 26% at 35.4 mg/cu m and 48, 44, and 47% at 103.5 mg/cu m in the plasma, erythrocyte, and brain, respectively. The only significant alteration in relative organ weight was found in male animals showing dose-related increases in relative spleen weights of about 20 and 25% at the 35.4 and 103.5 mg/cu m exposure levels, respectively. No abnormal histological findings were observed in any of the tissues examined microscopically. [WHO; Environ Health Criteria 132: Trichlorfon p. 54 (1992) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Trichlorfon does not have a cumulative effect. Repeated intraperitoneal doses of 50 mg/kg/day ... (about one-fourth of the ip LD50) for a period of 60 days had no effect on mortality. But repeated doses of 100 mg/kg/day (about one-half LD50) produced 40% mortality by 60 days, and repeated doses of 150 mg/kg produced 100% mortality by 60 days. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:928]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: When rats were given diets that contained 100, 500, or 2500 ppm trichlorfon (about 6-7, 31-35, and 165-189 mg/kg/day) for 13 wk, cholinergic toxicity and inhibition of RBC and brain cholinesterase activities occurred in male rats given 2500 ppm, and RBC and brain cholinesterase inhibition occurred in females given 500 or 2500 ppm. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:928]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: No signs of cholinergic or other toxicity were seen in dogs fed 42 mg/kg/day trichlorfon for 6 days/wk for 3 mo or in dogs given diets that contained 50, 200, or 500 ppm trichlorphon for 12 wk. The dietary level of 500 ppm (about 10.5 mg/kg/day) inhibited RBC cholinesterase activity. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:928]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Changes of serum C-reactive protein (CRP) levels in rainbow trout (Oncorhynchus mykiss) were studied after exposure to formalin, metriphonate or potassium permanganate, which are used in aquaculture as anti-ectoparasitic chemicals. The CRP level in normal trout sera is 88+/-5 microg ml(-1) according to sandwich enzyme-linked immunosorbent assay. CRP levels increased to a maximum at six or nine days after exposure to formalin for 3.5 h at 300 ppm or 9.5 h at 30 ppm, respectively; these levels are 4.3 and 18 times higher than normal. At 18 days after treatment, the CRP level had decreased to significantly below the normal level. After exposure to metriphonate (0.4 ppm for 30 min), the CRP level increased significantly to a maximum at three days after exposure (9.9 times higher than normal), then decreased to below normal. With exposure to potassium permanganate at 40 ppm for 45 min, fish showed significantly lower CRP levels than the normal level at 14 days after exposure. Fish reared at a water temperature of 16.5-19.5 degrees C showed significantly higher CRP levels than those reared at 13 degrees C. Measurement of CRP levels in trout serum can be used as a bioindicator of the health condition of the fish. [Kodama H et al; Fish Shellfish Immunol 16 (5): 589-97 (2004) ]**PEER REVIEWED** PubMed Abstract
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Spraque Dawley rats (25 of each sex) /were given/ diets containing 0 to 1,000 ppm concentrations of technical grade trichlorfon. The dosing was intended to last for 24 mo, but it was shortened to 17 mo in males (due to mortality). Males in the 1000 ppm (100 mg/kg/day) group failed to gain weight equivalent to other groups, and life span was shortened in both sexes at the high dose. Serum cholinesterase, but not brain, submaxillary gland, or red blood cell cholinesterase, was inhibited by 25% in the group fed 250 ppm (25 mg/kg/day). Vascular lesions, including fibrous changes and necrotizing inflammation, were reported, but the dosing group in which they occurred was not identified. Histopathology was done on only five rats of each sex from each dose group. [National Research Council. Drinking Water and Health, Volume 6. Washington, D.C.: National Academy Press, 1986., p. 401]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: /Investigators administered/ Sprague-Dawley rats (25 males and 50 females per group) 100, 200, or 400 ppm concentrations of technical grade trichlorfon in feed. The study was intended to last 18 months, but was apparently curtailed at about 70 weeks due to mortality in both the treated and control groups. There was a sex difference in cholinesterase inhibition: slight depression of RBC/(red blood cell)/ cholinesterase occurred in males at 200 ppm but not at 100 ppm (10 mg/kg/day), whereas there was "very slightly" depressed RBC cholinesterase in females fed 100 ppm. Spleen and liver weights were reported to be reduced in the 400 ppm group (40 mg/kg/day), and four females in the high dose group had pulmonary changes. [National Research Council. Drinking Water and Health, Volume 6. Washington, D.C.: National Academy Press, 1986., p. 402]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: No increased incidence in malignant tumors /was found/ in Long Evans rats given up to 1000 ppm concentrations of trichlorfon in feed for 2 yr. Forty Wistar rats (unspecified sex) /were gavaged/ with 15 mg/kg doses of trichlorfon twice weekly for life. The average life span for treated animals was shortened, and 7 of 28 treated animals had malignant tumors (of unspecified type) as compared to no tumors in controls. Benign tumors were found in 19 of 28 rats and in 3 of 36 controls. [National Research Council. Drinking Water and Health, Volume 6. Washington, D.C.: National Academy Press, 1986., p. 405]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Technical grade Trichlorfon (Dylox), less than or equal to 97.3% purity, was fed in the diet for 104 weeks at 0, 300, 900, and 2700 ppm (nominal) to 50 CD-1 mice/sex/group. ... Plasma and red blood cell cholinesterase inhibition occured at 900 to 2700 ppm. NOEL for effects other than cholinesterase inhibition was 300 ppm (liver relative weight increases in females at 900 to 2700 ppm). Common findings at 2700 ppm included increased urine staining in males, possibly caused by cholinesterase inhibition. Mammary tumors (adenomas, adenocarcinomas, or adenoacanthomas) were elevated in high dose females: incidences of 0, 300, 900, and 2700 ppm females were 1,2,0, and 8, respectively. These are considered treatment-related and thus a possible adverse effect. [California Environmental Protection Agency/Department of Pesticide Regulation; Toxicology Data Review Summaries. Available from: http://www.cdpr.ca.gov/docs/toxsums/pdfs/88.pdf on Trichlorfon as of February 23, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: There were no effects on mortality or body weights nor was there any cholinergic toxicity in dogs given diets that contained 0, 50, 250, 500, or 1000 ppm (equivalent to 0, 1.25, 6.25, 12.5, or 25 mg/kg/day, respectively) for 1 yr. There was mild to moderate enlargement of the spleen in dogs fed the 1000-ppm diet, as well as congestion of the spleen and lymphoid atrophy and foci of inflammatory liver cells. Dogs given the 500- or 1000-ppm diet exhibited decreases in RBC cholinesterase activity. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:931]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: When dogs were fed diets that contained 0, 50, 200, 800, or 3200 ppm for 4 yr, dogs fed the 50-ppm diet were unaffected; dogs fed the 200-ppm diet had depressed RBC cholinesterase activity; dogs fed the 800- or 3200-ppm diet had depressed RBC cholinesterase activity, reduced food intake, retarded body weight gain, and increased mortality; and dogs fed the 3200-ppm diet also exhibited tremors, cramps, and salivation. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:931]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Trichlorfon, 98.6% purity, was administered 6 days/week for 10 years by imbibition from a syringe at 0 (Tang orange-flavored drink), 0.2, 1.0, or 5.0 mg/kg/day with 5/sex/group. No adverse chronic effect. Cholinesterase NOEL = 0.2 mg/kg/day (dose-related cholinesterase inhibition, over 20% in RBC and brain in both sexes, and in plasma of males). Brain cholinesterase inhibition at 10-yr termination was noteworthy: at dose levels of 1 and 5 mg/kg/day, respectively, brain cholinesterase inhibition was 53 and 83% of controls in males, and 24 and 78% of controls in females. Cholinesterase-related clinical signs NOEL = 1.0 mg/kg/day, based on pupillary constriction (2 high dose females only, both limited to the first month of study), muscle fasciculations (limited to 1 high dose female on one occasion: day 15 of study), and a noticeable increase in incidence of soft stools or diarrhea in high dose monkeys throughout the study, in comparison with other groups. There were no gross or microscopic findings attributed to treatment, despite periodic biopsies of liver tissue during the first 3 years of the study, and complete gross and histopathology examinations at termination. Thus the NOEL for chronic effects (other than those plausibly related to cholinesterase inhibition) was > 5 mg/kg/day. [California Environmental Protection Agency/Department of Pesticide Regulation; Toxicology Data Review Summaries. Available from: http://www.cdpr.ca.gov/docs/toxsums/pdfs/88.pdf on Trichlorfon as of February 23, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: In Sprague Dawley rats, 50-150 mg/kg by ip route, daily for 60 days: 0/15 had tumors. In BD rats, 50 mg/kg by sc route for 800 days induced 2/24 injection site sarcomas; in Wistar rats, 30 mg/kg, 3 times weekly, no route given, for up to 705 days induced 3/52 papilloma of forestomach. /From table, control data not reported/ [Searle, C. E. (ed.). Chemical Carcinogens. ACS Monograph 173. Washington, DC: American Chemical Society, 1976., p. 170]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: In AB mice skin application and promotion with croton oil at 30 mg/kg, 3 times weekly for up to 781 days induced 1/19 liver carcinoma, 2/19 papillomas of forestomach and 1/19 local sarcoma. /From table, control data not reported/ [Searle, C. E. (ed.). Chemical Carcinogens. ACS Monograph 173. Washington, DC: American Chemical Society, 1976., p. 170]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: A group of 30 male and 28 female 8 week old AB/JENA strain mice received 30 mg/kg body weight trichlorfon ... by gavage twice weekly for 75 weeks, with a 2 week break after the 45th week (cumulative dose: males, 157.5 mg; females, 154 mg). All surviving animals were sacrificed at 80 weeks. A group of 30 male and 29 female mice served as controls. There was no significant difference in the incidence of tumors between treated and control mice. A group of 30 male and 35 female 10 week old albino rats received 22 mg/kg body weight trichlorfon ... in saline by gavage twice weekly for 90 weeks; all surviving animals were killed at 118 weeks (cumulative dose: males, 2.08 g; females, 1.98 g). A group of 25 male and 26 female control rats were given saline. There was no significant difference in the incidence of tumors between treated and control groups. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V30 212 (1983)]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: A group of 30 male and 30 female 8 week old AB/JENA mice received 28.2 mg/kg body weight trichlorfon ... by ip injection twice weekly for 75 weeks, with a 2 week break at 45 weeks. The cumulative doses were 160.8 mg in males and 149.7 mg in females. All surviving animals were killed at 80 weeks. A group of 30 male and 30 female controls were given saline by ip injections. There was no significant difference in the incidence of tumors between treated and control mice. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V30 213 (1983)]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: A group of 30 male and 35 female 10 week old albino rats were given 12 mg/kg body weight trichlorfon ... by ip injection twice weekly for 90 weeks. The average cumulative dose was 1.16 g in males and 1.1 g in females. A group of 25 male and 25 female controls received saline injections. All surviving animals were killed at 118 weeks. No statistically significant difference was found in the incidence of tumors between treated and control rats. A group of 23 male and 25 female Syrian golden hamsters, 7 to 8 weeks of age, were given 20 mg/kg body weight trichlorfon ... as a 2% soln in isotonic saline by ip injection once weekly for 90 weeks. A group of 22 male and 23 female controls received saline injections. All surviving animals were killed at 100 weeks. There was no significant difference in the incidence of tumors between treated and control hamsters. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V30 213 (1983)]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Trichlorfon technical, 99% purity, was administered by gavage to 20 to 25 artificially inseminated American Dutch female rabbits per group on gestation days 6-18 at 0 (distilled water), 10, 35, and 110 mg/kg/day. By gestation day 18, 14 of 25 inseminated females at 110 mg/kg/day died. Maternal clinical symptoms at 35 and 110 mg/kg/day included tremors, rapid respiration, ataxia, salivation, and prostration. No Adverse effects. Maternal NOEL = 10 mg/kg/day (clinical symptoms of ChE inhibition in the mid and high dose groups). Developmental NOEL = 35 mg/kg/day (reduced fetal weights and increased resorptions at 110 mg/kg/day). [California Environmental Protection Agency/Department of Pesticide Regulation; Toxicology Data Review Summaries. Available from: http://www.cdpr.ca.gov/docs/toxsums/pdfs/88.pdf on Trichlorfon as of February 23, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Animals considered pregnant (30) were dosed at 400 mg/kg/day during days 7-11 of gestation and subsequently, lower dose levels were added (20, 5, 25, 10 at 0-gavaged with distilled water, 100, 200, 300 mg/kg/day) and additional hamsters (23) were administered 400 mg/kg/day only on day 8 to determine fetal sensitivity to exposure on a single day of gestation. There was an increase in fetal malformations at the highest dosage (400 mg/kg/day, days 7-11), primarily edema, cleft palate, patagium (fold of skin connecting forelimbs and hindlimbs), and fused ribs. Increases in fetal death, also an increase in the numbers of runted fetuses and a decrease in mean fetal weight (all significant, p < 0.05) were noted at 400 mg/kg/day. The parental NOEL was apparently 100 mg/kg/day, as signs of cholinesterase inhibition were observed at 200 mg/kg/day. Food intake of dams was decreased in a dose-related fashion at 300 to 400 mg/kg/day. The high dosages administered were made possible by giving the daily dose in three portions, 3.5 hours apart. [California Environmental Protection Agency/Department of Pesticide Regulation; Toxicology Data Review Summaries. Available from: http://www.cdpr.ca.gov/docs/toxsums/pdfs/88.pdf on Trichlorfon as of February 23, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Trichlorfon technical, 98.5% purity, was administered in the diet to 30 Sprague-Dawley rats/sex/group at nominal doses of 0, 150, 500 and 1750 ppm beginning at seven weeks of age for the F0 parents and at weaning for the F1 parents. Treatment-related reductions in birth weight in F1a pups continued into adulthood with F1 adults showing lower premating and gestation body weight; food consumption was reduced in F0 and F1 dams during lactation. Dose-related kidney effects dilated renal pelves were seen in F1a (F1a + F1 = 5, 7, 10 and 23 at 0, 150, 500 and 1750 ppm) and F2a pups (F2a = 2, 8, 6 and 31 at 0, 150, 500 and 1750 ppm). Gross and microscopic lesions were noted in the lungs (eg pneumonia) and kidneys (eg chronic nephropathy and hydronephrosis) of high-dose F0 and F1 adults. Cholinesterase (ChE) was inhibited in adult brain, plasma and RBC (NOEL = 150 ppm) and in pup brain and plasma at the high-dose. Possible Adverse Effect: Reduction in the birth and viability indices together with reductions in weight and kidney lesions in pups; Reproductive NOEL = 500 ppm. [California Environmental Protection Agency/Department of Pesticide Regulation; Toxicology Data Review Summaries. Available from: http://www.cdpr.ca.gov/docs/toxsums/pdfs/88.pdf on Trichlorfon as of February 23, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ...We examined cytogenetic and developmental effects on early mouse zygotes exposed to trichlorfon in vivo. Pregnant female mice were intraperitoneally administered a single dose of trichlorfon (100 or 200mg/kg) at 6h post presumed conception and either sacrificed on day of gestation (dg) 3, 9 or 17 to assess the developmental toxicity and mutagenic effects on embryos.Mean cell number (dg 3) and somite number (dg 9) of embryos in the two trichlorfon-treated groups were significantly fewer than in the control group and the mean micronucleus (MN) number (dg 3) and the frequency of mosaic aneuploidies including monosomic or trisomic cell lines (dg 9) was significantly increased in both trichlorfon-treated groups compared with the control group. However, there was no difference in fetal body weight (dg 17) between the control and trichlorfon-treated groups and no increased incidence of external malformations was observed in the trichlorfon-treated groups. [Tian Y et al; Mutat Res 471 (1-2): 37-44 (2000) ]**PEER REVIEWED** PubMed Abstract
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Dipterex was teratogenic after admin by gavage /3 times per day/ at a dose level of 480 mg/kg/day to CP rats on days 6 through 15 of gestation, but not when admin only on days 8 or 10 of gestation. Positive teratogenic response also occurred in the hamster after admin on days 7 through 11 of gestation at 400 mg/kg/day; The apparent no-effect level for the criteria studied was 200 mg/kg/day. Embryotoxicity, but not teratogenicity, occured after admin of 400 mg/kg/day on day 8 of gestation. The mouse was less susceptible to dipterex than were the rat and hamster, but a significant increase in the incidence of cleft palates resulted from exposure on days 10 through 14, or on days 12 through 14 of gestation. [STAPLES RE, GOULDING EH; ENVIRON HEALTH PERSPECT 30: 105 (1979) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: A single 80 mg/kg body weight dose admin to rats orally by gavage on day 13 of pregnancy caused an increased number of embryonic deaths, a decreased number of live fetuses and increased fetal anomalies, such as exencephaly and failure of eyelids to close; admin of 8 mg/kg body weight throughout pregnancy produced no teratogenic manifestations. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V30 216 (1983)]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Daily oral admin of 1,2, or 5 mg chlorophos/kg, or admin of 5 mg/kg in weekly intervals, for 6 months caused hemodynamic disturbances in the brain and other organs of bulls, and dystrophic changes in the liver, kidneys, spleen, lungs, and testicles. The severity of the pathological changes depended on the dose. Swelling and hyperplasia of the interstitial tissue occured in the testicles. Spermatogenic epithelium desquamated from the seminiferous tubules. Ejaculate vol decreased, the proportion of pathological spermatozoids increased, sperm respiration was inhibited, and fertility decreased. Admin of 1-2 mg chlorophos/kg caused no pathological changes. Tolerance threshold of chlorophos is 2 mg/kg feed. [KHAITOV RK ET AL; TR UZNIVI 32 (1): 127-30 (1982) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: /Chlorophos/ was given to pregnant hamsters and mice during active organogenesis (300 mg/kg daily). Low incidences of cleft palate and some skeletal defects in hamster fetuses were found. All of these abnormal fetuses occurred in hamsters treated on day 8. Neither embryotoxicity nor teratogenicity was found in mice. [Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986., p. 339]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Pregnant guinea pigs were administered trichlorfon at doses of of 0 or 100 mg/kg body weight on days 36, 37, 38, 51, 52, and 53 of gestation. The number of abortions and still-born fetuses, and the mean fetal wt, were lower than in controls. Some pups from different litters had marked trembling and locomotor disturbances. Symmetrical atrophy of the skeletal muscles, and cardiovascular abnormalities were found in the treated group. There was a decrease in total brain and cerebellum weights. The activities of choline-acetyl transferase and glutamate decarboxylase were both significantly reduced in the cerebellum, as compared to control values. [Berge GN et al; Arch Toxicol 59: 30-5 (1986) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Trichlorfon was evaluated for its teratogenic potential in the mouse (200, 300, or 400 mg/kg/day) after administration by gavage on days 7-16 of gestation. /The cmpd/ was teratogenic, fetotoxic, and lethal at the two highest doses which were also maternally lethal. There was a decr in the number of calcified centers in the forepaws and hindpaws indicating fetotoxicity and a delay in maturation. /Trichlorfon/ was administered (50, 100, or 200 mg/kg/day) to rats by gavage on gestational days 7-19 or 8-20 ( groups A and B respectively). In both groups the highest dose was maternally lethal. In group A, /the cmpd/ was teratogenic with a shift in rib profile. In group B, /the cmpd/ was teratogenic with an increased incidence in malformations of the urinary system. /Trichlorfon/ was fetotoxic with reduced ossification of the skulls at the lowest and highest dose levels. [Courtney KD et al; J Environ Sci Health Part B, B21 (3): 207-27 (1986) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: When rats were fed diets that contained 0, 300, 1000, or 3000 ppm for three generations, 3000 ppm (about 150 mg/kg/day) caused a marked decrease in the pregnancy rate and early deaths in pups, 1000 ppm (about 50 mg/kg/day) caused reduced numbers of pups per litter and weight of individual pups, and 300 ppm (about 15 mg/kg/day) had no detectable effect on reproduction. There was no indication of teratogenesis, even at dosages that were highly toxic. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:930]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: A review of this insecticide and anthelmintic demonstrated a potent developmental toxicity profile in laboratory animals such as the rat (oral and inhalation), mouse (oral), and hamster (oral), but teratogenicity was not noted if the exposure was via the intraperitoneal route. [Krieger, R. (ed.). Handbook of Pesticide Toxicology. Volume 1, 2nd ed. 2001. Academic Press, San Diego, California., p. 399]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: When trichlorfon (125 mg/kg/day) ... was administered to guinea pigs between day 42 and 46 of gestation, offspring exhibited severe reductions in brain weight that was most pronounced in the cerebellum, medulla oblongata, thalamus/hypothalamus, and quadrigemina. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:930]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Adult white leghorn hens were given oral or sc doses of 50-300 mg/kg. Signs of neurological dysfunction (ataxia, paralysis) appeared 12-28 days later. Multifocal neuropathy affecting CNS and peripheral nervous system was observed about 1 month after dosing. [OLAJOS EJ ET AL; ECOTOXICOL ENVIRON SAF 3 (3): 245 (1979) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Changes in the elctrophysiologic activity of the rat sciatic nerve were examined after repeated dosing with parathion and trichlorfon. Trichlorfon produced dose-dependent changes in the duration, rise time, relative area, and refractory period of the sciatic nerve cmpd action potential. The observed changes indicated an increased excitability of the nerve. During the early development of these electrophysiologic changes there were no accompanying histololgic changes in the nerve. This suggests that changes in nerve excitability may be a sensitive indicator of neurotoxicity, and that continued trichlorfon exposure may lead to a cumulative alteration in nerve function. [AVERBOOK BJ, ANDERSON RJ; ARCH TOXICOL 52 (3): 167-72 (1983) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: The aim of these experiments was to assess whether the clinically validated cognition enhancers donepezil (Aricept, E2020) and metrifonate antagonize scopolamine-induced deficits in the cone field, a complex spatial discrimination task. The cone field task allows measurement of the effects of experimental manipulations on working and reference memory (WM and RM), search strategies, and on the speed and latency to execute the task. The effects of a single administration of donepezil (0.1, 0.3, and 1.0 mg kg(-1), p.o.) and metrifonate (30, 60, and 120 mg kg(-1), p.o.) were investigated in adult Harlan-Wistar rats trained to a stable level of performance and pretreated with scopolamine (0.5 mg kg(-1), i.p. 30 min before training). Scopolamine impaired WM without inducing overt non-cognitive side-effects. Donepezil did not antagonize the scopolamine-induced deficits, whereas metrifonate antagonized the WM deficits at the dose of 60 mg kg(-1), but not at 30 or 120 mg kg(-1). Thus, a cholinesterase inhibitor with proven clinical efficacy can antagonize scopolamine-induced spatial memory deficits. [Van der Staay FJ, Bouger PC; Behav Brain Res 156 (1): 1-10 (2005) ]**PEER REVIEWED** PubMed Abstract
  
• LABORATORY ANIMALS: Neurotoxicity: Trichlorfon technical (Dylox purity of 98.4%, dissolved in corn oil) was administered in the feed to 18 Fischer 344 rats/sex/dose at 0, 100, 500 and 2500 ppm for 13 weeks. Clinical observations (at 2500 ppm) consisted of perianal stain (males) and increased incidence of urine stain (females). High-dose males showed lower body weights (4-5%) compared to controls lower during most of the study. Functional Observational Battery (FOB) high-dose males had perianal staining (week 4) and decreased righting response (week 8); females at this level showed increased urine stain for weeks 8 and 13. Reduced motor and locomotor activity (18 to 28%) was noted during weeks 4 and 8 for 2500 ppm males and during week 4 for 2500 ppm females. ChE Inhibition High-dose rats showed >20% reductions in plasma, erythrocyte and brain ChE activity and reductions in plasma and erythrocyte ChE at 4 weeks were similar in magnitude to those at 13 weeks. At 500 ppm, inhibitions of plasma and erythrocyte ChE ranged from 22-31% during week 4. NOEL(M/F)=100 ppm,((M)=6 mg/kg, (F)=7 mg/kg, based on ChE inhibition). Microscopic lesions (segmental, ballooning separation of myelin lamellae from the axon, ie, primary myelinopathy) were reported in the cervical and lumbar spinal nerve roots of high-dose rats. [NOAEL(M/F)=500 ppm; (M)=35 mg/kg/day, (F)=31 mg/kg/day] based on degeneration of myelin in cervical and lumbar spinal nerve roots. [California Environmental Protection Agency/Department of Pesticide Regulation; Toxicology Data Review Summaries. Available from: http://www.cdpr.ca.gov/docs/toxsums/pdfs/88.pdf on Trichlorfon as of February 23, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Technical trichlorfon (purity = 98.8%) was given to White Leghorn hens by gavage for 90 consecutive days at dose levels of 0 (vehicle = corn oil:acetone 9:1), 3, 9 or 18 mg/kg/day (12/group). TOCP was used as a positive control. No adverse effect. NOEL for delayed neurotoxicity parameters = 18 mg/kg/day (no clinical signs of delayed neurotoxic damage, no related histopathology findings, no alterations seen in ladder and turf test). There was no "NOEL" for whole blood cholinesterase inhibition (consistently reduced by about 20-30% at 9-18 mg/kg/day: slight but statistically significant reduction at 3 mg/kg/day in latter weeks of the study). Clinical signs typical of cholinesterase inhibition (ataxia and decreased activity) were common at 18 mg/kg/day. Hypertrophy of the esophagus (and often in one or more structures of the upper alimentary tract such as the crop, gizzard or proventriculus) was the only histopathology change, occurring at 18 mg/kg/day. [California Environmental Protection Agency/Department of Pesticide Regulation; Toxicology Data Review Summaries. Available from: http://www.cdpr.ca.gov/docs/toxsums/pdfs/88.pdf on Trichlorfon as of February 23, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: The toxicity of trichlorfon (purity not stated), reported to elicit delayed neurotoxicity in humans and chickens, was studied by administering single subcutaneous doses of 100 or 300 mg/kg to adult White Leghorn hens. At 24 hours post-treatment, hens were observed for visible signs of neurotoxicity, were euthanized, and samples of blood plasma, brain and spinal cord (cervical and thoracic regions) were obtained for quantification of cholinesterase and neurotoxic esterase (NTE) activities. In subacute studies, hens were dosed with trichlorfon (100 mg/kg) every 72 hours for a total of 6 doses. 72 hours after the final dose, the hens were euthanized and the brains, spinal cords and distal sciatic nerves were removed for enzymatic and/or histological examination. ... Trichlorfon markedly inhibited tissue cholinesterase activities but elicited /no/ significant NTE inhibition. ...Trichlorfon caused little or no obvious neurotoxicity, an observation that was supported by minimal morphological changes and impairment of walking ability and no inhibition of brain or spinal cord NTE. [California Environmental Protection Agency/Department of Pesticide Regulation; Toxicology Data Review Summaries. Available from: http://www.cdpr.ca.gov/docs/toxsums/pdfs/88.pdf on Trichlorfon as of February 23, 2006. ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Neurotoxicity: Measurements of plasma cholinesterase (pl.ChE), brain cholinesterase (Br.ChE) and brain Neuropathy Target Esterase (Br.NTE) were made in three different lineages of chickens. All birds received toxicants through gavage in a single oral dose between 08:00 and 09:00 h, after overnight fast. Babcock chickens were treated with 800 mg/kg tri-ortho-cresyl phosphate (TOCP) or 80 mg/kg trichlorfon. The TOCP group had 82% Br.NTE inhibition, when compared to the control group, and no birds displayed symptoms of clinical organophosphate-induced delayed neuropathy (OPIDN). Hy-line w36 lineage chickens were given 1600 mg/kg TOCP and despite this higher dose, Br.NTE inhibition was similar that presented by Babcock chickens. Isabrown chickens were given 1600 mg/kg TOCP or 80 mg/kg trichlorfon. At 36 h all trichlorfon treated birds had from 80 to 90% inhibition of Pl.ChE and Br.ChE, when compared to controls. However, Br.NTE was inhibited less than 20%, and there were no clinical signs of OPIDN. All TOCP treated isabrown chickens had more than 80% Br.NTE inhibition while one of them exhibited just light signs of OPIDN, two chickens became totally paralyzed. This finding suggested that chicken strain was important in the appearance of OPIDN. In addition, 70-80% of NTE inhibition was necessary but was not sufficient to produce OPIDN in chickens, since babcock and hy-line w36 chickens exhibited NTE inhibition in the range of 70-80% without clinical signs of OPIDN. [Honorato de Oliveira G et al; Toxicol Lett 136 (2): 143-150 (2002) ]**PEER REVIEWED** PubMed Abstract
  
• GENOTOXICITY: Trichlorfon (purity not specified) did not induce mutation in Drosophila malanogaster, but because of high toxicity, only low doses could be tested. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V30 218 (1983)]**PEER REVIEWED**
  
• GENOTOXICITY: Trichlorfon (98.5% purity) was administered to 5 male Chinese hamsters/dose/sampling period through single intraperitoneal injections of 0 (0.5% aqueous Cremophor) or 100 mg/kg; sampling of gonadal cells was performed 6, 24, and 48 hours after treatment (24 hr only for controls). No Adverse effects: no increases in chromosomal aberrations were reported. [California Environmental Protection Agency/Department of Pesticide Regulation; Toxicology Data Review Summaries. Available from: http://www.cdpr.ca.gov/docs/toxsums/pdfs/88.pdf on Trichlorfon as of February 23, 2006. ]**PEER REVIEWED**
  
• GENOTOXICITY: Trichlorfon, 98.9% purity, single dose administered by gavage at 0 (distilled water), 30, 100, and 300 mg/kg with 6 Chinese hamsters/sex/group. Bone marrow of 5/sex/group was sampled at 24 hours (colcemide 2.5 hours prior to sacrifice). No increase in sister chromatid exchange frequency. [California Environmental Protection Agency/Department of Pesticide Regulation; Toxicology Data Review Summaries. Available from: http://www.cdpr.ca.gov/docs/toxsums/pdfs/88.pdf on Trichlorfon as of February 23, 2006. ]**PEER REVIEWED**
  
• GENOTOXICITY: Trichlorfon technical /in a/ gene mutation, Salmonella (TA1535, TA1537, TA1538, TA98, and TA100) and E. coli WP2 (uvrA). 0-10,000 ug/plate. Repeat trials with TA100 and with E. coli WP2 (uvrA). Increases in revertants with TA100 and with E. coli WP2 (uvrA) at higher concentrations, but not with other Salmonella strains. [California Environmental Protection Agency/Department of Pesticide Regulation; Toxicology Data Review Summaries. Available from: http://www.cdpr.ca.gov/docs/toxsums/pdfs/88.pdf on Trichlorfon as of February 23, 2006. ]**PEER REVIEWED**
  
• GENOTOXICITY: Trichlorfon induces gene mutation in S. typhimurium and E. coli and in S. cerevisiae. It also induces a mitotic crossing over, gene conversion, and mitotic recombination. The positive results in microorganisms indicate that trichlorfon induces mainly base-pair substitution or mutation in the absence of metabolic activation. Trichlorfon also induces a chlorophyll mutation and chromosomal damage in plants. [WHO; Environ Health Criteria 132: Trichlorfon p. 60-1 (1992) ]**PEER REVIEWED**
  
• GENOTOXICITY: In a recombinant DNA study, trichlorfon did not inhibit the growth of Bacillus subtillis ... Trichlorfon was inactive in inducing unscheduled DNA synthesis in rat hepatocytes up to levels of severe cytoxicity ... [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:932]**PEER REVIEWED**
  
• GENOTOXICITY: Under physiological conditions, trichlorfon alkylates DNA (through its conversion to dichlorvos which is more easily demethylated) ... In mice that received a single dose of trichlorfon, liver DNA adducts increased maximally 6 hr after dosing, were substantially reduced 24 hr after dosing, and were undetectable by 48 hr after dosing. Increases in sister chromatid exchanges occurred in the bone marrow of mice treated 24 hr earlier with 120 mg/kg, but not with 30 or 50 mg/kg trichlorfon ... No chromosomal aberrations occurred in the bone marrow or spermatogonia of mice treated with acute doses of 100 mg/kg trichlorfon, and dominant lethal mutations did not significantly increase in mice given 5 ppm trichlorfon for 5 days/wk for 7 wk. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:932]**PEER REVIEWED**
  
• GENOTOXICITY: Trichlorfon, technical /was studied with/ Saccharomyces cerevisiae D3 /in a/ mitotic recombination test. Two trials with and without rat liver activation at 0.1, 0.5, 1.0, 2.0, 4.0 or 5.0 % concentration; clear and dose-related increase in mitotic recombinants with and without activation/was observed/. [California Environmental Protection Agency/Department of Pesticide Regulation; Toxicology Data Review Summaries. Available from: http://www.cdpr.ca.gov/docs/toxsums/pdfs/88.pdf on Trichlorfon as of February 23, 2006. ]**PEER REVIEWED**
  
• GENOTOXICITY: Rat hepatocytes were tested for unscheduled DNA synthesis at 0-50 ug/mL (100 ug/mL was toxic), 20 hours, counted grains in 3x50 cells per concentration. No evidence of UDS /was observed/. [California Environmental Protection Agency/Department of Pesticide Regulation; Toxicology Data Review Summaries. Available from: http://www.cdpr.ca.gov/docs/toxsums/pdfs/88.pdf on Trichlorfon as of February 23, 2006. ]**PEER REVIEWED**
  
• GENOTOXICITY: Dylox technical (purity = 97.3%) was tested in a sister chromatid exchange assay using Chinese hamster ovary cells at 0 (vehicle = distilled water), 10, 25, 50 and 100 ug/mL (no S-9) or 0, 30, 75, 150 and 300 ug/mL (with S-9). Possible adverse effect. Under conditions of this study, Dylox technical produced a statistically significant increase in sister chromatid exchange both with S-9 (> 75 ug/mL) and without S-9 (> 50 ug/mL). Positive controls functioned as expected. [California Environmental Protection Agency/Department of Pesticide Regulation; Toxicology Data Review Summaries. Available from: http://www.cdpr.ca.gov/docs/toxsums/pdfs/88.pdf on Trichlorfon as of February 23, 2006. ]**PEER REVIEWED**
  
• GENOTOXICITY: Mouse lymphoma 0 - 125 (-S9) and 0 -145 (+S9) ug/mL, cytotoxic at concentrations higher than these; 4 hours incubation, two trials. A significant increase in mutation frequency occurred with and without activation in both trials. [California Environmental Protection Agency/Department of Pesticide Regulation; Toxicology Data Review Summaries. Available from: http://www.cdpr.ca.gov/docs/toxsums/pdfs/88.pdf on Trichlorfon as of February 23, 2006. ]**PEER REVIEWED**
  
• GENOTOXICITY: Trichlorfon ... produced aneuploidy in genetically engineered human lymphoblastoid cell lines. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:933]**PEER REVIEWED**
  
• GENOTOXICITY: ... In the present EU research project, DNA-probes for mouse chromosomes 8, X and Y were employed each labelled with different colours. Male mice were treated with the test chemicals and sperm were sampled from the Caudae epididymes 22-24 days later to allow spermatocytes exposed during meiosis to develop into mature sperm. [Adler ID et al; Mutat Res 504 91-2): 173-82 (2002) ]**PEER REVIEWED**
  
• GENOTOXICITY: Trichlorfon is genotoxic in cultured mammalian cells. It induced unscheduled DNA synthesis in a human epithelloid cell line and in W138 human fibroblasts with and without an uninduced mouse liver microsomal preparation. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V30 218 (1983)]**PEER REVIEWED**
  
• GENOTOXICITY: Twelve organophosphorus insecticides, including trichlorfon, were tested for toxicity and mutagenicity in the foward mutation test system at the Adeo locus of Schizosaccharomyces pombe. Trichlorfon showed a linear dose-response relation. Trichlorfon tested in combination with malathion, methyl parathion, or azinphos-methyl, produced clearly synergistic effects for toxicity and mutagenicity. [GILOT-DEHALLE J ET AL; MUTAT RES 117 (1-2): 139-48 (1983) ]**PEER REVIEWED**
  
• GENOTOXICITY: Insecticides ... were examined for their ability to induce chromosomal aberrations in the bone marrow cells of Syrian hamster (Mesocricetus auratus) treated in vivo. Mutagenicity of commercial preparations were examined at four doses: LD50; 1/2, 1/5, 1/10 LD50. The positive control was an ip injection of cyclophosphamide to hamsters at a dose of 40 mg/kg body weight. ... Trichlorfon ... was negative in this test. [Dzwonkowska A, Hubner H; Arch Toxicol 58 (3): 152-6 (1986) ]**PEER REVIEWED**
  
• ALTERNATIVE IN VITRO TESTS: To assess the aneugenic activity of TCF in oogenesis, we presently analysed maturation, spindle assembly, and chromosome constitution in mouse oocytes maturing in vitro in the presence of 50 or 100 microg/ml TCF for 16 h or in pulse-chase experiments. TCF stimulated maturation to meiosis II at 50 microg/ml, but arrested meiosis in some oocytes at 100 microg/ml. TCF at 100 microg/ml was aneugenic causing non-disjunction of homologous chromosomes at meiosis I, a significant increase of the hyperploidy rate at metaphase II, and a significant rise in the numbers of oocytes that contained a 'diploid' set of metaphase II chromosomes (dyads). TCF elevated the rate of precocious chromatid segregation (predivision) at 50 and 100 microg/ml. Pulse-chase experiments with 100 microg/ml TCF present during the first 7 h or the last 9 h of maturation in vitro did not affect meiotic progression and induced intermediate levels of hyperploidy at metaphase II. Exposure to > or =50 microg/ml TCF throughout maturation in vitro induced severe spindle aberrations at metaphase II, and over one-third of the oocytes failed to align all chromosomes at the spindle equator (congression failure). These observations suggest that exposure to high concentrations of TCF induces non-disjunction at meiosis I of oogenesis, while lower doses may preferentially cause errors in chromosome segregation at meiosis II due to disturbances in spindle function, and chromosome congression as well as precocious separation of chromatids prior to anaphase II. The data support evidence from other studies that TCF has to be regarded as a germ cell aneugen. [Cukurcam S et al; Mutat Res 564 (2): 165-78 (2004) ]**PEER REVIEWED** PubMed Abstract
  
• ALTERNATIVE IN VITRO TESTS: The ability of the carbamate pesticide carbaryl (CB) and the organophosphate pesticide trichlorphon (TCL) to inhibit the outgrowth of axon-like processes was studied using mouse N2a neuroblastoma cells induced to differentiate by serum withdrawal. At concentrations of 1 and 2 mug/ml (4.97 and 9.94 muM), CB did not cause cell death but inhibited the outgrowth of axon-like processes from N2a cells. This effect was noted as early as 24 h after exposure of the cells to CB. A similar effect was observed with TCL at concentrations of 1 and 2 mug/ml (3.89 and 7.78 muM). Western blot analysis of cell extracts treated with the pesticides showed decreased cross reactivities with the monoclonal antibody RMd09 compared to control extracts. The results indicate that CB and TCL are both able to inhibit axon development and that this effect is associated with reduced levels of the neurofilament high molecular weight protein subunit (NFH). [Flaskos J et al; toxicol Lett 110 91-2): 79-84 (1999) ]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: The oral toxic dose for calves is 5-10 mg/kg, for cattle is 50-100 mg/kg and for sheep is 100-200 mg/kg. A 1% spray is non-toxic to calves. While single doses of up to 125 mg/kg of trichlorophon are non-toxic, 150 mg/kg will produce intoxication in horses. Single exposure to sprays was non-toxic up to 240 mg/kg. [Humphreys, D.J. Veterinary Toxicology. 3rd ed. London, England: Bailliere Tindell, 1988., p. 171]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: Muscarinic signs of /organophosphorus cmpd/ ... consist of hypersalivation, lacrimation, sweating and nasal discharge. Miosis, dyspnea, vomiting, diarrhea and frequency of urination ... nicotinic effects consist of fasciculation of muscles, weakness and paralysis. CNS effects include nervousness, apprehension, ataxia, convulsions and coma. Death is due to respiratory failure, or sometimes cardiac arrest. There is little diference between signs produced by different ... cmpd, but route of absorption may influence one system more than another. /organophosphorus cmpd/ [Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981., p. 153]**PEER REVIEWED**
  
• OTHER TOXICITY INFORMATION: Mouse oocytes exposed for 3 hr during fertilization to 50 ug/ml trichlorfon /were examined/. Spindle morphology was not visibly altered by the pesticide. Chromosomes segregated normally at anaphase II with no induction of aneuploidy. However, formation of a spindle was disturbed in many oocytes resuming meiosis I in the presence of trichlorfon. In spite of the spindle aberrations and the failure of bivalents to align properly at the equator, oocytes did not become meiotically arrested but progressed to metaphase II. At this stage, spindles were highly abnormal, and chromosomes were often totally unaligned, unattached or dispersed on the elongated and disorganized spindle. By causing spindle aberrations and influencing chromosome congression, trichlorfon appears, therefore, to predispose mammalian oocytes to random chromosome segregation, especially when they undergo a first division and develop to metaphase II during exposure. [Yin H et al; Chromosoma 107 (6-7): 514-22 (1998) ]**PEER REVIEWED** PubMed Abstract
  

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Human Toxicity Values

• None found

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Non-Human Toxicity Values

• LD50 Rat oral 438 mg/kg [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 1001]**PEER REVIEWED**
  
• LD50 Rat weanling ip 190 mg/kg [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 1001]**PEER REVIEWED**
  
• LD50 Rat adult ip 250 mg/kg [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 1001]**PEER REVIEWED**
  
• LD50 Mouse oral 579 mg/kg [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 1001]**PEER REVIEWED**
  
• LD50 Mouse ip 500 mg/kg [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 1001]**PEER REVIEWED**
  
• LD50 Guinea pig ip 300 mg/kg [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 1001]**PEER REVIEWED**
  
• LD50 Calf oral 600 mg/kg [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 1001]**PEER REVIEWED**
  
• LD50 Chicken oral 125 mg/kg [Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991., p. 1001]**PEER REVIEWED**
  
• LD50 Rat male oral 630 mg/kg [O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1716]**PEER REVIEWED**
  
• LD50 Rat female oral 560 mg/kg [O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1716]**PEER REVIEWED**
  
• LD50 Rat (male and female) percutaneous >5000 mg/kg/24 hr [Tomlin CDS, ed. Trichlorfon (52-68-6). In: The e-Pesticide Manual, 13th Edition Version 3.2 (2005-06). Surrey UK, British Crop Protection Council. ]**PEER REVIEWED**
  
• LD50 Rat oral 250 mg/kg [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3529]**PEER REVIEWED**
  
• LD50 Rat ip 160 mg/kg [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3529]**PEER REVIEWED**
  
• LD50 Rat sc 400 mg/kg [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3529]**PEER REVIEWED**
  
• LD50 Rat im 395 mg/kg [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3529]**PEER REVIEWED**
  
• LD50 Mouse oral 300 mg/kg [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3529]**PEER REVIEWED**
  
• LD50 Mouse ip 196 mg/kg [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3529]**PEER REVIEWED**
  
• LD50 Mouse sc 267 mg/kg [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3529]**PEER REVIEWED**
  
• LD50 Mouse iv 290 mg/kg [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3529]**PEER REVIEWED**
  
• LC50 Rat (male and female) inhalation >2.3 mg/L air/4 hr [Tomlin CDS, ed. Trichlorfon (52-68-6). In: The e-Pesticide Manual, 13th Edition Version 3.2 (2005-06). Surrey UK, British Crop Protection Council. ]**PEER REVIEWED**
  
• LC50 Rat inhalation 533 mg/cu m/4hr [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:770t]**PEER REVIEWED**
  
• LD50 Rat (female) oral 136 mg/kg [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:770t]**PEER REVIEWED**
  
• LD50 Rat (male) oral 173 mg/kg [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:770t]**PEER REVIEWED**
  
• ED50 Rat (3-month old) oral 90 mg/kg; effect: inhibition of brain cholinesterase activity [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:927]**PEER REVIEWED**
  
• ED50 Rat (3-month old) oral 80 mg/kg; effect: inhibition of RBC and plasma cholinesterase activities [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:927]**PEER REVIEWED**
  
• LD50 Rabbit oral 160 mg/kg [Verschueren, K. Handbook of Environmental Data on Organic Chemicals. Volumes 1-2. 4th ed. John Wiley & Sons. New York, NY. 2001, p. 946]**PEER REVIEWED**
  

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Absorption, Distribution and Excretion

• Absorbed by skin. [Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993, p. 1169]**PEER REVIEWED**
  
• Trichlorfon ...is not readily absorbed by cotton leaves. [White-Stevens, R. (ed.). Pesticides in the Environment: Volume 1, Part 1, Part 2. New York: Marcel Dekker, Inc., 1971., p. 176]**PEER REVIEWED**
  
• In cow, (32)P-labeled trichlorfon administered orally .../was/ eliminated in urine, about 65% of administered dose .../was/ excreted in 12 hr. ...75% ...of compound of unknown structure. ...Less than 0.2% of administered dose ...in milk ... Blood contained ...max of 15.1 ug equivalent 2 hr after administration, decreased ...to about 1 ug equivalent after 24 hr. [White-Stevens, R. (ed.). Pesticides in the Environment: Volume 1, Part 1, Part 2. New York: Marcel Dekker, Inc., 1971., p. 175]**PEER REVIEWED**
  
• The absorption, distribution, and excretion of trichlorfon in mammals is rapid: about 70-80% of a dose administered orally to mice was excreted during the first 12 hr after treatment. The biological half-life of trichlorfon was 80 min. ...3 hr after an iv injection of (14)CH3O-trichlorfon to rats, trace amounts of radioactivity were found in the liver, lungs, kidney, heart, spleen and blood. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V30 216 (1983)]**PEER REVIEWED**
  
• Toxicants can be absorbed by inhalation, ingestion, and skin penetration. ...All undergo hydrolytic degradation in liver and other tissues, usually within hr of absorption. Degradation products are of low toxicity, and are excreted in urine and feces. /Organophosphate cholinesterase-inhibiting pesticides/ [Morgan, D.P. Recognition and Management of Pesticide Poisonings. EPA 540/9-80-005. Washington, DC: U.S. Government Printing Office, Jan. 1982., p. 2]**PEER REVIEWED**
  
• They: ...are rapidly absorbed through mucous membrane of digestive system, respiratory system and the skin, and conveyed by the blood to various body tissues. ...The main route of elimination .../is/ the kidneys. /Organophosphorus pesticides/ [International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I&II. Geneva, Switzerland: International Labour Office, 1983., p. 1638]**PEER REVIEWED**
  
• Radiolabelled trichlorfon ... was administered by stomach tube to pregnant guinea pigs on days 37 and 52 of gestation and examined by the whole body autoradiography method. The results /indicated/ that the radiolabelled cmpd was rapidly distributed to the main organs of the dam and the highest concentrations /were found/ in the liver, kidney, and lung. No substantial concn of radioactivity occurred in the fetuses until 30 minutes after administration. The uptake in the fetuses was more pronounced at the later gestational stage when the concn in the fetal liver equalled that of the placenta. [Berge GN, Nafstad I; Arch Toxicol 59 (1): 26-9 (1986)]**PEER REVIEWED**
  
• Organophosphates are efficiently absorbed by inhalation, injestion, and skin penetration. /Organophosphate pesticides/ [Morgan, D.P. Recognition and Management of Pesticide Poisonings. EPA 540/9-80-005. Washington, DC: U.S. Government Printing Office, Jan. 1982., p. 2]**PEER REVIEWED**
  
• In animals, degraded rapidly in the blood. Excretion in the urine is more or less complete within 6 hr. [Hartley, D. and H. Kidd (eds.). The Agrochemicals Handbook. 2nd ed. Lechworth, Herts, England: The Royal Society of Chemistry, 1987., p. A408/Aug 87]**PEER REVIEWED**
  
• After humans were exposed to 7.5 to 10 mg/kg dose of trichlorfon, presumably by the oral route, peak plasma levels of the compound were detected in plasma in 1 hr. [National Research Council. Drinking Water and Health, Volume 6. Washington, D.C.: National Academy Press, 1986., p. 397]**PEER REVIEWED**
  
• In rats iv injected with (14)CH3 labeled trichlorfon, radioactivity /was found/ in liver, lung, kidney, heart, spleen, and blood. The inhibition of esterases in the spinal cord and brain of hens suggest that trichlorfon or an active metabolite also enters the CNS. [National Research Council. Drinking Water and Health, Volume 6. Washington, D.C.: National Academy Press, 1986., p. 397]**PEER REVIEWED**
  
• Dichlorvos was detected in the brain of mice after ip injection of trichlorfon. Following dermal and intragastric application of trichlorfon to cows, the parent compound and dichlorvos were detected in the milk up to 22 days after application. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V30 216 (1983)]**PEER REVIEWED**
  
• Peak concentrations in plasma of metrifonate (30 uM) and of dichlorvos (0.3 uM) are reached within 1 hr after a single oral dose of metrifonate (10 mg/kg). [Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1133]**PEER REVIEWED**
  
• Trichlorfon is rapidly and completely absorbed via oral exposure and is extremely rapidly metabolized and excreted. Once absorbed following a 133 mg/kg oral dose, trichlorfon was not detected, but dichlorvos (a nonenzymatic breakdown product of trichlorfon) was distributed primarily in blood, adipose tissue, muscle, and liver. Peak concentrations occurred 1, 7, 7, and 7 days after exposure, respectively. Dichlorvos was undetected at 20 days. Calculated half-lives in blood, adipose tissue, muscle, and liver were 7, 11, 10, and 12 days, respectively. /Rats/ [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:929]**PEER REVIEWED**
  
• Regardless of whether rats were given single or repeated oral doses or single iv doses of trichlorfon, 80-90% of the dose was excreted within 24 hr. The major route of excretion was via the urine, followed by feces and expired air. About 1 to 2% of the dose was found in the tissues after 96 hr. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:929]**PEER REVIEWED**
  
• Metrifonate concentrations in plasma, its inhibition of blood cholinesterase, and side-effects were studied in 16 healthy volunteers who received a single oral dose of 2.5, 5, 7.5 or 15 mg/kg in a randomized double blind study (4 subjects for each dose). Metrifonate was determined by a gas chromatographic method. Peak plasma levels were reached within 2 hr; the half life in plasma, oral clearance, and normalized Cmax and area under the concentration time curves did not differ significantly between the four groups. Plasma cholinesterase was inhibited to low levels in all subjects, while erythrocyte cholinesterase was affected in a dose dependent fashion. The occurrence of side effects correlated strongly with peak plasma levels but not with maximum erythrocyte cholinesterase inhibition or with increase in salivation. This study shows that the absorption of metrifonate was not significantly different for doses between 2.5 and 15 mg/kg. The plasma levels of this drug correlated with the occurrence of side effects. [Aden-Abdi Y et al; Bull World Health Organ 68 (6): 731-6 (1990)]**PEER REVIEWED**
  
• Metrifonate--via its pharmacologically active metabolite DDVP--is an inhibitor of cholinesterase effective in the treatment of Alzheimer's disease. Two separate studies were performed to investigate the influence of food and time of administration, respectively, on the concentration vs. time profiles of metrifonate and DDVP and cholinesterase inhibition. METHODS: In study I, a single dose of metrifonate 50 mg tablet was administered either in the fasting condition or within 5 min after completion of an American breakfast. In study II, a single dose of metrifonate 80 mg tablet was given either at 8:00 a.m. after overnight fasting, 7:00 p.m. (7 h after lunch) or 10:00 p.m. (4 h after dinner). Both studies were performed in a non-blind, randomized, single-centre, cross-over design in healthy Caucasian volunteers. AUC and Cmax of metrifonate and DDVP as primary parameters were compared between treatments by ANOVA and acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition vs. time profiles were assessed. RESULTS: In study I a high-fat/high-calorie breakfast had no effect on the AUC of DDVP, while its Cmax was decreased to 56% and tmax was prolonged, compared to the fasting condition. The effects on metrifonate were similar. In study II bioequivalence was shown for AUC and Cmax of DDVP when comparing administration of metrifonate at 8:00 a.m. and 7:00 p.m. Administration at 10:00 p.m. also had no effect on AUC of DDVP while a reduction in rate of absorption was observed. In both studies the equivalence in AUC of DDVP was paralleled by equivalent effects on BChE inhibition. Following single metrifonate administration little inhibition of AChE was observed. Metrifonate was well tolerated. CONCLUSIONS: Delayed gastric emptying is likely to cause the reduced rate of absorption of metrifonate with food. In view of unchanged bioavailability of its active metabolite, this food effect is considered to be without clinical relevance and metrifonate can be administered with or without food. The decrease in rate of absorption following administration of the drug at 10:00 p.m. is either a protracted food effect or an effect of time. As the bioavailability of DDVP as well as pharmacodynamic profiles were independent of the time of administration it is concluded that metrifonate can be taken in the morning or evening without compromising its safety or efficacy. [Heinig R, Sachse R; Int J Clin Pharmacol Ther 37 (9): 456-64 (1999) ]**PEER REVIEWED** PubMed Abstract
  

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Metabolism/Metabolites

• Dichlorvos was detected in the brain of mice after ip injection of trichlorfon. Following dermal and intragastric application of trichlorfon to cows, the parent compound and dichlorvos were detected in the milk up to 22 days after application. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V30 216 (1983)]**PEER REVIEWED**
  
• After ip injections of (32)P labeled trichlorfon into rats, urine was collected and analyzed. Major detoxification product was dimethyl phosphate. Some monomethyl phosphate, orthophosphate, o-demethyl trichlorfon, and 2 unknowns ...one ...characterized as glucuronide containing trichlorfon but not further identified. [Menzie, C. M. Metabolism of Pesticides, An Update. U.S. Department of the Interior, Fish, Wild-life Service, Special Scientific Report - Wildlife No. 184, Washington, DC: U.S. Government Printing Office, l974., p. 370]**PEER REVIEWED**
  
• In cow, (32)P labeled trichlorfon administered orally ...of total radioactivity, <1% appeared to be unchanged trichlorfon and about 17% was tentatively identified as dimethyl phosphoric acid. Less than 0.2% ...found in milk. Of this, only 10% partitioned in favor of chloroform indicating that radioactivity was largely in form of hydrolyzed ionic products. [White-Stevens, R. (ed.). Pesticides in the Environment: Volume 1, Part 1, Part 2. New York: Marcel Dekker, Inc., 1971., p. 175]**PEER REVIEWED**
  
• ...Dog treated iv ...urine contained 63% ...in form of glucuronide of trichloroethanol indicating cleavage of carbon-phosphorus bond. Approximately 77% of (32)P in urine collected during first 6 hr ...in form of hydrolyzed products of unknown structure and 23% passed through as unchanged trichlorfon. [White-Stevens, R. (ed.). Pesticides in the Environment: Volume 1, Part 1, Part 2. New York: Marcel Dekker, Inc., 1971., p. 175]**PEER REVIEWED**
  
• Recent studies in rat indicate that o-demethylation of trichlorfon is important metabolic route in mammals. As much as 27% of injected dose of methoxy labeled (14)C trichlorfon has been recovered as (14)CO2 within 10 hr, presumably by o-demethylation to form methyl alcohol and subsequent oxidation... . [White-Stevens, R. (ed.). Pesticides in the Environment: Volume 1, Part 1, Part 2. New York: Marcel Dekker, Inc., 1971., p. 177]**PEER REVIEWED**
  
• Tests with microorganisms showed that Aspergillus niger, Penicillium notatum, and Fusarium sp hydrolyzed trichlorfon. One compound was identified as o-methyl-2,2,2-trichloro-1-hydroxyethyl phosphonic acid. Other is believed to be 2,2,2-trichloro-1-hydroxyethyl phosphonic acid. [Menzie, C.M. Metabolism of Pesticides. U.S. Department of the Interior, Bureau of Sport Fisheries and Wildlife, Publication 127. Washington, DC: U.S. Government Printing Office, 1969., p. 323]**PEER REVIEWED**
  
• The fate of trichlorfon in pH 7.4 buffer and the soluble fractions from cow and chicken liver homogenates prepared in the same buffer was studied. In pH 7.4 buffer, trichlorfon was readily converted into dichlorvos. With the enzyme systems, the insecticide was metabolized into both dichlorvos and demethyltrichlorfon. The rate of degradation of trichlorfon in enzyme systems was greater than that in buffer. Cow liver soluble fraction metabolized trichlorfon at a slightly higher rate than chicken liver preparation. [Akhtar MH; J Agric Food Chem 30 (3): 551-4 (1982) ]**PEER REVIEWED**
  
• Trichlorfon is metabolized quickly. In cows, 65% of administered (32)P-trichlorfon was excreted in the urine in 12 hr. The urinary metabolites were found to contain a small amount (17%) of dimethylphosphate. /It was shown/ that in rats the O-dimethylation process is an important degradation mechanism. In brain homogenates, trichlorfon is rapidly metabolized to desmethyltrichlorfon, monomethylphosphate, and 2,2,2-trichlor-1-hydroxyethylphosphoric acid. In vivo studies ... showed recovery of 60% of the (14)C in urine and in the expired air after administration of (14)C trichlorfon. Similarly with (32)P trichlorfon, 75-85% of the radioactivity /was found/ in the urine in 48 hr. Mono- and dimethylphosphate were the major metabolites in the urine. With respect to insects ... /it was/ found that the cotton leafworm (Prodenia lituria), which is quite resistant to trichlorfon, degraded it to desmethyltrichlorfon, a glucuronic conjugate of 2,2,2-trichloro-1-hydroxethylphosphoric acid (about 68%), monomethylphosphone acid (5%), and dimethylphosphoric acid (27%), and (14)C labeled carbon dioxide. Similarly, in the cotton plant (32)P trichlorfon is metabolized into monomethylphosphate, dimethylphosphate, and phosphoric acid. [Matsumura, F. Toxicology of Insecticides. 2nd ed. New York, NY: Plenum Press, 1985., p. 255]**PEER REVIEWED**
  
• In plant tissues, dehydrochlorination leads to the formation of dichlorvos, which is presumably then hydrolyzed to phosphoric acid and dichlorovinyl alcohol, sometimes with dichloroacetaldehyde being split off. ... The major metabolites /in animals/ are dimethylphosphoric acid, phosphoric acid, demethyldichlorvos, and monomethyl phosphoric acid. [Hartley, D. and H. Kidd (eds.). The Agrochemicals Handbook. 2nd ed. Lechworth, Herts, England: The Royal Society of Chemistry, 1987., p. A408/Aug 87]**PEER REVIEWED**
  
• Trichlorfon, dichlorvos, dimethylphosphate, and demethyltrichlorfon were detected in human serum incubated with (14)C trichlorfon. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V30 220 (1983)]**PEER REVIEWED**
  
• After an ip Injection of 5 mg (32)P trichlorfon to rats, trichlorfon (0.7%), dimethyl phosphate (35.7%), phosphoric acid and methyl phosphate (0.8%), O-demethyltrichlorfon (1.4%) and O-demethyldichlorvos (0.8%) were found in the urine. After ip administration of trichlorfon, (14)C labelled at the two methyl groups, 24% of the dose was recovered as (14)CO2 in the expired air within 10 hours; 32% was recovered in urine as formate (7-15%) and dimethyl phosphate (65-75%) in the first 24 hr after the administration. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V30 216 (1983)]**PEER REVIEWED**
  
• Trichlorfon and dichlorvos levels were followed in plasma and RBCs of 7 individuals given single oral doses of 7.5-10 mg/kg trichlorfon repeated after 2 wk for treating schistosomiases. The relationship of dichlorvos to trichlorfon in plasma and RBCs was about 1%. A biphasic curve for the elimination of trichlorfon in plasma developed; the first phase had a half-life fo 0.4 to 0.6 hr, and the second phase had a half-life of about 3 hr. Clearance of trichlorfon was primarily due to formation of dichlorvos. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:929]**PEER REVIEWED**
  
• ... Trichlorfon (and its decomposition product dichlorvos) is very rapidly absorbed and cleared in humans. After acute oral treatment of healthy male volunteers with a 2, 5, 7.5, or 12 mg/kg dose of trichlorfon (metrifonate), the maximum blood concentration of trichlorfon was obtained between 12 min and 2 hr and the half-life in blood was about 2 hr. The concentrations of dichlorvos ... closely followed those of trichlorphon at a constant ratio of about 1 to 100. the concentrations of trichlorfon were detectable up to 8 hr, but those of dichlorvos had fallen bellow the level of detection by then. Both plasma and RBC cholinesterases were readily inhibited and were still low after 24 hr--none of the volunteers complained of side effects (and the half-life of ... dichlorvos was about 3.8 hr). [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:929]**PEER REVIEWED**
  
• The predominant metabolic pathway that involves cleavage of the P-C phosphonate bond that generates trichloroethanol and dimethyl phosphate which are then excreted in urine. Quantitatively minor pathways of metabolism include demethylation ... and (nonenzymatic) dehydrochlorination of dichlorvos which is rapidly metabolized to dichloroethanol and dimethyl phosphate which are then excreted in urine. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 7:929]**PEER REVIEWED**
  

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Footnotes

¹ Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.