Pesticide residues in food — 2006: Toxicological ... - ipcs inchem

DIAZINON (addendum)
First draft prepared by
U. Mueller 1 and R. Solecki 2
1
Offi ce of Chemical Safety, Therapeutic Goods Administration, Canberra, Australian Capital
Territory, Australia; and
2
Safety of Substances and Preparations, Coordination and Overall Assessment, Federal Institute
for Risk Assessment, Berlin, Germany
Explanation ...................................................................................................... 293
1. Toxicological studies .......................................................................... 294
1.1 Acute toxicity ............................................................................. 294
(a) Results of studies of acute toxicity ...................................... 294
(b) Time-course of acute inhibition of cholinesterase activity ..... 294
1.2 Short-term studies of toxicity ..................................................... 298
1.3 Long-term studies of toxicity ..................................................... 306
2. Observations in humans ..................................................................... 307
Comments ........................................................................................................ 310
References ........................................................................................................ 312
Explanation
Diazinon is the International Organization of Standardization (ISO) approved name for
the contact organothiophosphate insecticide, O,O-diethyl O-2-isopropyl-6-methylpyrimidin-4-
yl phosphorothioate (International Union of Pure and Applied Chemistry, IUPAC). Diazoxon, the
biologically active metabolite of diazinon, inhibits the activity of cholinesterase.
Diazinon has been reviewed by the Joint FAO/WHO Meeting on Pesticide Residues (JMPR)
on several occasions since the first evaluation in 1963. In 1966, an acceptable daily intake (ADI)
of 0–0.002 mg/kg bw per day was established based on a no-observed-effect level (NOEL) of
0.02 mg/kg bw per day for inhibition of plasma cholinesterase activity in a 37–43-day study in
humans. In 2001, the Meeting established an acute reference dose (ARfD) for diazinon. Although
a new study of acute toxicity in humans was submitted, the ARfD of 0.03 mg/kg bw was based
on a no-observed-adverse-effect level (NOAEL) of 2.5 mg/kg bw observed in a study of acute
neurotoxicity in rats.
The present Meeting re-considered the ADI and ARfD for diazinon because the existing ADI was
based on a study in men only, while a second study in male volunteers was not considered suitable as
the basis for an ARfD in 2001. As inhibition of cholinesterase activity is the most sensitive toxicological
end-point for diazinon, all previously-considered studies that reported cholinesterase activity and five
additional studies were reviewed by the present Meeting. The new data included the final report of the
preliminary study of acute toxicity in humans that was considered by the JMPR in 2001, another repeatdose
study in humans, a short-term study of toxicity in rats and two published studies.
Unpublished studies in laboratory animals complied with good laboratory practice (GLP) and
with the relevant Organisation for Economic Co-operation and Development (OECD) test guidelines.
Studies in humans were conducted in accordance with principles such as those expressed in the
DIAZINON X-X JMPR 2006