4.17 Phosmet (103)(T)

T- toxicological evaluation

TOXICOLOGY

Phosmet (O,O-dimethyl S-phthalimidomethyl phosphorodithioate) is an insecticide and acaricide that acts by inhibiting acetylcholinesterase activity. Phosmet was evaluated previously by the JMPR in 1978, 1979, 1994 and 1998. An ADI of 0-0.01 mg/kg bw was set in 1994. In 1998, an acute reference dose (RfD) of 0.02 mg/kg bw was set, based on a NOAEL of 2 mg/kg bw per day in a study of developmental toxicity in rabbits. By request of a WHO Member State and the European Union, the acute RfD for phosmet was reviewed by the present Meeting in 2003, instead of in 2004 as originally scheduled. A recent study in human volunteers and additional information on the study of developmental toxicity in rabbits were reviewed by the current Meeting.

In an acceptable^[17] double blind, randomized study, volunteers received a single dose of phosmet (96% pure) or placebo, in a capsule, with water. Six subjects receiving phosmet were paired with three subjects receiving placebo, for each dose group. Males received doses of 1, 2 or 4 mg/kg bw, with females receiving 2 mg/kg bw. A wide range of investigations, including assays for erythrocyte cholinesterase activity, were performed pre- and post-dosing (up to 168 h). There were no adverse findings in any dose groups. The pattern of clinical signs, results of investigations and cholinesterase activities were similar in groups receiving test substance and placebo. The Meeting noted that females had only been given a dose of 2 mg/kg bw and concluded that the overall NOAEL for both sexes was thus 2 mg/kg bw.

The Meeting considered the study in volunteers together with other data on the toxicity of phosmet. The Meeting paid particular attention to the data on fetotoxicity, from the study of developmental toxicity in rabbits, which had been used to derive the acute RfD in 1998. The skeletal effects (reduced ossification) seen at 5 mg/kg bw per day in this study were not reproduced at a dose of 15 mg/kg bw per day and were mostly within the contemporary historical control ranges for the test facility. The forepaw flexure observed in four (out of 132) fetuses receiving 5 mg/kg bw per day was not present in the contemporary historical control database, but there was no dose-response relationship, this finding being present in a single fetus (out of 118) receiving a dose of 15 mg/kg bw per day. Taking into account the absence of dose-response relationship and of historical control data, the Meeting concluded that there were no clear compound related effects at a dose of 5 mg/kg bw per day. The altered ossification observed at 15 mg/kg bw per day was seen in the presence of cholinergic signs and significantly reduced maternal bodyweight gain. The Meeting concluded that the fetal effects were unlikely to occur after a single dose that did not induce significant inhibition of acetylcholinesterase activity.

The Meeting established an acute RfD of 0.2 mg/kg bw on the basis of the NOAEL of 2 mg/kg bw (the highest dose tested) for inhibition of erythrocyte cholinesterase in male and female volunteers, and a safety factor of 10.

The Meeting recognized that it was possible that the acute RfD might be refined after a full evaluation of the complete database on phosmet.

An addendum to the toxicological monograph was prepared.

Dietary risk assessment

International estimated short-term intake (IESTI) for phosmet was calculated for the raw or processed commodities for which appropriate data on residues and consumption were available. The IESTI for the general population represented 0-90% of the acute RfD. The IESTI for children aged £6 years represented 0-230% of the acute RfD; the short-term intakes for apples and pears were 150% and 230% of the acute RfD, respectively. The information presented to the Meeting precluded the conclusion that the acute dietary intake for these commodities would be below the acute RfD.

The Meeting concluded that the short-term intake of residues of phosmet from uses that have been considered by the JMPR, with the exception of apples and pears, is unlikely to present a public health concern.