TRICHLORFON

Comments:

The 60th & 66th Committees reviewed further information on trichlorfon's pharmacokinetics and genotoxic, reproductive and developmental toxicity, and neurotoxicity. The information did not provide evidence that any of these effects was more sensitive than inhibition of acetylcholinesterase activity, and the Committee concluded that inhibition of acetylcholinesterase is the most relevant end-point for establishing an ADI. The 54th Committee meeting established the ADI for trichlorfon on the basis of a NOEL of 0.2 mg/kg bw/d in a clinical study with Alzheimer disease patients. In this study, the volunteers were given a loading dose of 0.5 mg/kg/d for 2 weeks, followed by a maintenance dose of 0.2 mg/kg/d for 8 weeks. The 54th Committee meeting concluded that the maintenance dose had not significantly enhanced the inhibition of erythrocyte cholinesterase activity established in patients by the loading dose and concluded that the maintenance dose was the NOEL. Because the NOEL was derived from a human study, a safety factor of 10 was applied to the NOEL to derive the ADI. The 60th Committee re-examined the basis on which it had established the ADI and concluded that the dose previously identified as the NOEL was more appropriately considered a LOEL. Furthermore, the Committee recalled that a clear NOEL of 0.2 mg/kg/d for inhibition of erythrocyte cholinesterase activity was established in a 10-year study of toxicity in monkeys treated orally. If that study had been selected as the basis for setting the ADI, a safety factor of 100 would have been applied, resulting in an ADI of 0–2 μg/kg bw. The 60th Committee concluded that an ADI could be derived from the human study by applying an additional factor of 10 to this LOEL such that the amended ADI is 0–2 μg/kg bw. The present Committee concluded that deriving ADIs from studies in diseased human populations, where such data are available, likely represents a worst-case scenario for establishing ADIs. Available data indicate that the pharmacokinetics of trichlorfon were not appreciably different between the study population and healthy subjects. The present Committee confirmed the ADI of 0-2 µg/kg bw for trichlorfon previously established by the 60th Committee.

MRL Comment:

The MRLs recommended by the 60th Committee were not reconsidered and were maintained. MRLs (expressed as trichlorfon, in µg/kg tissue, µg/l milk): Muscle, liver, kidney, fat and milk (cattle): 50. At the fifty-fourth meeting, the Committee noted that the concentrations of residues were very low in muscle, liver, kidney and fat. These MRLs are for guidance only and are based on the limit of quantification of the analytical method.

Intake:

TMDI 75 µg/p/d (62% of ADI)

Meeting:

66

Report: 

Tox Monograph: 

Residues: 

Previous Years: