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sensitivity with that of laboratory animal species. In this placebo-controlled study in healthy volunteers,
40 males and 10 females were given capsules containing azinphos-methyl at a dose of 0.25, 0.5,
0.75, or 1 mg/kg bw for males and 0.25, 0.5, or 0.75 mg/kg bw for females, according to the dosing
schedule described in Table 17. Selection of doses was based on a study of neurotoxicity in rats given
repeated doses, in which a NOAEL of 1 mg/kg bw was observed (Sheets & Hamilton, 1995), and a
study in humans given repeated doses, in which the NOAEL was 0.29 mg/kg bw (Rider et al., 1971).
Azinphos methyl was administered in capsules.
The mean age and weight of the male subjects was 32.7 ± 9.3 years and 75.52 ± 8.36 kg
respectively, and the mean female age and weight were 31.0 ± 4.6 years and 63.83 ± 6.71 kg respectively.
All subjects were selected from a panel of volunteers who were screened less than 3 weeks
before study initiation. For inclusion in the study, all volunteers met the following criteria: age 18−50
years; with no clinically relevant physiological findings; no clinically relevant serum or blood findings
(including cholinesterase activity); normal electrocardiogram (ECG); normal arterial pressure
and heart rate; body weight between 50 and 100 kg; and within ± 15% of ideal body weight; able to
communicate well with the investigator and to comply with the requirements of the entire study; and
provision of written informed consent to participate. The study protocol was reviewed and approved
by an independent research ethical committee.
Before the start of the study, a screening examination was performed which consisted of the
following: medical history; complete physical examination and vital signs (pulse rate, respiratory
rate and blood pressure); ECG recording; haematology, clinical chemistry, plasma and erythrocyte
cholinesterase activity and urine analysis; hepatitis B, C and human immunodeficiency virus (HIV)
status; drug screening; pregnancy status (females). Subjects could be withdrawn from the study in
any of the following events: serious adverse effects; major violations to the protocol; withdrawal of
consent; termination of the study by the sponsor. The study showed that azinphos-methyl was well
tolerated at all doses. No clinical relevant reductions in plasma or erythrocyte cholinesterase values
occurred. The NOAEL for azinphos-methyl when administered as a single oral dose was 1.0 mg/kg
bw for males and 0.75 mg/kg bw for females (McFarlane & Freestone, 1999a).
Two male subjects each received 16 mg of azinphos-methyl orally each day for 30 days (body
weight not stated, but assuming a 70 kg bw the administered dose would be 0.23 mg/kg bw per day).
The daily urinary output of azinphos-methyl-related compounds, estimated by a method that converted
them to anthranilic acid, was determined before, during and after cessation of treatment. The
amount of anthranilic acid excreted in the urine was increased on the day after the start of treatment
and remained at a high level during treatment with azinphos-methyl; it returned to a normal level
Table 17. Dosing schedule for a study in humans given capsules containing azinphos-methyl
Group
No. of subjects
Dose (mg/kg bw)
0 0.25 0.5 0.75 1.0
Session 1; males 1 1 0 0 0
Session 2; males 2 6 1 0 0
Session 3; males 3 0 6 1 0
Session 4; males 3 0 0 6 0
Session 5; females 3 0 0 7 0
Session 6; males 3 0 0 0 7
From McFarlane & Freestone (1999a)
AZINPHOS-METHYL 139–172 JMPR 2007