Pirimiphos-methyl

Exposure related observations in humans: other data

Administrative data

Endpoint:

exposure-related observations in humans: other data

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1976

Report date:

1976

Materials and methods

Type of study / information:

56-day oral repeated dose toxicity study

Endpoint addressed:

repeated dose toxicity: oral

Principles of method if other than guideline:

A group of seven healthy human volunteers, consisting of three males and four females, was given orally a dose of 0.25 mg test substance/kg bw/day in capsule form for a period of 56 days. Two healthy female volunteers took a blank capsule over the same period. The effect of the administration on liver function, blood count and erythrocyte and plasma cholinesterase activity was evaluated.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Pirimiphos-methyl

EC Number:

249-528-5

EC Name:

Pirimiphos-methyl

Cas Number:

29232-93-7

Molecular formula:

C11H20N3O3PS

IUPAC Name:

O-2-(diethylamino)-6-methylpyrimidin-4-yl O,O-dimethyl phosphorothioate

Method

Ethical approval:

not specified

Details on study design:

Initially, eight healthy males and eight healthy females volunteered for the study. These were divided into two equal groups of four males and four females, one to be given capsules containing the substance and the other group to be given blank capsules, as a control. At the beginning of the trial, however, a number withdrew for various reasons, leaving only three males and six females. It was decided that two of the females should continue to act as controls. The nature of the trial was explained fully to each volunteer and each signed a form of consent. None had any known contact with organophosphates or carbamates before the trial, nor, apart from the given in dosing, during the trial. All were medically examined before the trial and care was taken to ensure that none had a history or past or present liver disease, alcoholism or were on potentially hepatotoxic drug regimes. The males were 22 to 27 years of age and weighed 62 to 82 kg, the females were 21 to 49 years of age and weighed 44 to 63 kg. The two control females were 20 and 30 years of age and weighed 44 and 46 kg.
Blood was taken twice by venepuncture at the antecubital fossa from each volunteer in the week before dosing began to determine plasma and erythrocyte cholinesterase activities which, together with the sample taken on day 1 of dosing schedule, provided mean pre-experimental baseline values. Plasma alanine amino-transferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase activities and full blood counts were determined on the second pre-dosing sample.
The test substance was given to the seven subjects at a dose of 0.25 mg/kg bw/day for a period of 56 days. The two controls were given a blank capsule each day for the same period. The capsules were taken at mid-morning each day and the blood samples were taken between 8.45 and 9.15 hours on days 7, 14, 21, 28, 35, 42, 49 and 56 after dosing began and also in the recovery period at days 7, 14, 21 and 28 after dosing had stopped, for the determination of plasma and erythrocyte cholinesterase activities. Liver function tests and full blood counts were carried out on day 56 of dosing and on day 28 of the recovery period.

Exposure assessment:

estimated

Details on exposure:

The doses were prepared by injecting the required amount of test substance into gelatin capsules by means of a graduated 100 µL Hamilton syringe. The capsules were heat sealed. The test substance was shown to be stable in contact with gelatin over a period of seven days by gas chromatographic analysis of the capsule content. The capsules for the controls were prepared by heat sealing the blank gelatin capsules using a pasteur pipette. All procedures were carried out under aseptic conditions in a fume cupboard.

Results and discussion

Results:

Blood counts and erythrocyte cholinesterase activity showed little change throughout the period of the trial. Slight changes in the levels of activity of gamma-glutamyl transpeptidase in the volunteers were also seen in the control subjects and values remained within normal limits. Such fluctuations probably represent the normal pattern of variation. Other plasma enzymes showed similar but less marked variations and again all results were within normal limits. Although other studies have shown apparent effects on the liver by long term low dose exposure to organophosphorus compounds (Grech 1965, Tocci et al. 1969), this was not demonstrated in the present investigation.
Plasma cholinesterase activity showed a greater degree of variation than other parameters. Examination of the data suggests a tendency for levels of activity in those receiving the test substance to fall slightly over the first 28 days of dosing, but this was not progressive and the values tended to rise slightly after day 28 and this was also seen in the recovery period. Individual values except for two subjects (F2 and F4) showed coefficients of variation between 5 and 10% which accords well with the controls (10.4 and 9.8%) and also observations on normal populations with a figure of 7.6% for the mean individual coefficient of variation for plasma cholinesterase.
Two of the females exposed to the substance (F2 and F4) showed decreases in plasma cholinesterase activity. At day 28 of treatment, the value for subject F2 had fallen to 77.5% of the pre-experimental mean and for subject F4 had fallen to 74.1%. Their respective coefficients of variation were 13.3 and 12.2%. At the end of the dosing period, plasma cholinesterase activity had risen to 83% and 87% of the pre-experimental values. The reductions in the plasma cholinesterase activity may represent a minimal response to the test substance, but there was no evidence of a progressive fall in activity over the period of dosing which may be the result of a compensatory increase in the rate of enzyme synthesis. Overall, the degree of depression was considered to be of dubious biological significance.
The overall results of the study confirmed the previous results indicating that repeated oral exposure to the substance at a dose of 0.25 mg/kg bw/day produced no adverse effects on the liver function, the plasma and erythrocyte cholinesterase activity, or the peripheral blood picture.

Applicant's summary and conclusion

Conclusions:

The overall results of the study confirmed that repeated oral exposure to the substance at a dose of 0.25 mg/kg bw/day over a period of 56 consecutive days produced no adverse effects on the liver function, the plasma and erythrocyte cholinesterase activity, or the peripheral blood picture in humans.

Executive summary:

In this study, the test substance was administered orally for a period of 56 days at a dose of 0.25 mg/kg bw/day to seven human volunteers, three males and four females. The doses were prepared by injecting the required amount of test substance into gelatin capsules by means of a graduated 100 µL Hamilton syringe. The capsules were heat sealed. The test substance was shown to be stable in contact with gelatin over a period of seven days by gas chromatographic analysis of the capsule content. Two further females were given blank gelatin capsules without test substance over the same period. In the week prior to dosing, two samples of blood were submitted by all human volunteers for pre-experimental cholinesterase activity assay. The volunteers then took a daily oral dose of 0.25 mg/kg bw/day for 56 days, or were given the blank gelatin capsule for the same period. The dose was taken orally by capsule at mid-morning each day. Blood samples were taken between 8.45 and 9.15 hours on days 7, 14, 21, 28, 35, 42, 49 and 56 after the commencement of administration. Blood samples were submitted 7, 14, 21 and 28 days after cessation of dosing. All samples were used to analyse the plasma and erythrocyte cholinesterase activities. Liver function tests and full blood counts were carried out on day 56 of dosing and on day 28 of the recovery period.
Two of the females exposed to the test substance showed decreases in plasma cholinesterase activity. At day 28 of treatment, the value had fallen to 77.5% and 74.1% of the pre-experimental mean. Their respective coefficients of variation were 13.3 and 12.2%. At the end of the dosing period, plasma cholinesterase activity had risen to 83% and 87% of the pre-experimental values. The reductions in the plasma cholinesterase activity may represent a minimal response to the test substance, but there was no evidence of a progressive fall in activity over the period of dosing which may be the result of a compensatory increase in the rate of enzyme synthesis. Overall, the degree of depression was considered to be of dubious biological significance and within the generally observed variation in normal subjects.
The overall results of the study confirmed the previous results indicating that repeated oral exposure to the substance at a dose of 0.25 mg/kg bw/day produced no adverse effects on the liver function, the plasma and erythrocyte cholinesterase activity, or the peripheral blood picture.