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

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The lowest-observed-adverse-effect level (LOAEL) for cholinesterase inhibition in erythrocytes
in repeat-dose studies was 10 ppm (equivalent to 1 mg/kg bw per day) in a 92-day dietary study in rats.
The highest NOAEL in the database was 5 ppm (equivalent to 0.5 mg/kg bw per day) in the 92-day
study in rats.
In a study of acute toxicity in male volunteers given ascending doses of diazinon, cholinesterase
activity was not inhibited in erythrocytes at 0.21 mg/kg bw, the second highest dose tested. The
highest dose was ignored, as the group comprised a single volunteer. Repeat-dose studies in male
volunteers given diazinon for 28–37 days showed that, while there was some inhibition of plasma
cholinesterase activity at the highest tested dose of 0.03 mg/kg bw per day, no inhibition of erythrocyte
cholinesterase activity was observed.
Toxicological evaluation
The Meeting identified inhibition of cholinesterase activity as the most sensitive endpoint
observed after single or repeated doses of diazinon in all species. The LOAEL for reduced
cholinesterase activity in erythrocytes was 1 mg/kg bw per day and the NOAEL was 0.5 mg/kg bw
per day. In considering the NOAEL and LOAEL identified in all repeat-dose studies, the Meeting
concluded that all species appeared to be equally sensitive and the extent of cholinesterase inhibition
was not dependent on duration of dosing, once steady-state had been achieved within 4 weeks. After
considering all previously evaluated data and the new studies, the Meeting established an ADI of
0–0.005 mg/kg bw based on the highest NOAEL of 0.5 mg/kg bw per day for inhibition of erythrocyte
cholinesterase activity in a 92-day repeat-dose study in rats, and with a safety factor of 100.
Levels relevant to risk assessment
Species Study Effect NOAEL LOAEL
Rat
Acute
neurotoxicity b
Time course of
cholinesterase
inhibition after a single
dose b
Behavioural changes
and cholinesterase
inhibition in
erythrocytes
Cholinesterase
inhibition in
erythrocytes and
brain
Human Acute toxicity c No inhibition of
cholinesterase
activity
Rat
Dog
3-month studies of
toxicity a
98–99 week study of
toxicity a
1-year study of
toxicity a
Cholinesterase
inhibition in
erythrocytes and
brain
Cholinesterase
inhibition in
erythrocytes c
Cholinesterase
inhibition in
erythrocytes and
brain
Cholinesterase
inhibition in
erythrocytes and
brain
2.5 mg/kg bw 150 mg/kg bw
2.5 mg/kg bw 25 mg/kg bw
0.21 mg/kg bw —
5 ppm, equal to
0.4 mg/kg bw per day
5 ppm, equivalent to
0.5 mg/kg bw per day
1.5 ppm, equal to
0.07 mg/kg bw per day
0.5 ppm, equal to
0.02 mg/kg bw per day
250 ppm, equal to
19 mg/kg bw per day
10 ppm, equivalent to
1 mg/kg bw per day
125 ppm, equal to
6 mg/kg bw per day
150 ppm, equal to
4.5 mg/kg bw per day
DIAZINON X-X JMPR 2006