Methomyl

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:

direct observations: clinical cases, poisoning incidents and other

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:

1998

Report date:

1998

Materials and methods

Study type:

study with volunteers

Endpoint addressed:

neurotoxicity

Test guideline

Qualifier:

no guideline followed

GLP compliance:

yes

Remarks:

followed GCP

Test material

Test material information

Constituent 1

Reference substance name:

Methomyl

EC Number:

240-815-0

EC Name:

Methomyl

Cas Number:

16752-77-5

Molecular formula:

C5H10N2O2S

IUPAC Name:

(E)-[1-(methylsulfanyl)ethylidene]amino N-methylcarbamate

Test material form:

solid: crystalline

Specific details on test material used for the study:

Lannate SP
Lot #: T101397-00
Purity: 89%

Method

Type of population:

other: volunteers

Subjects:

- Number of subjects exposed: 19
- Sex: Male
- Age: 18-40 years
- Demographic information: There were no major differences noted in mean age, height, and weight of the subjects between each dose group. All subjects were white males except for one Asian. All were non-smokers or previous smokers. Two of the subjects were non-drinkers, and the remaining 17 reported they were in the habit of consuming moderate amounts of alcohol.

Ethical approval:

other: Ethically accepted

Route of exposure:

oral

Reason of exposure:

intentional

Exposure assessment:

measured

Details on exposure:

A test substance formulation, and its matching placebo (the formulation's inert ingredient, hydrated silica), were each administered as a capsule at doses of 0, 0.1, 0.2, or 0.3 mg/kg body weight. The treatment duration was a single dose administration with two nights observation and one follow-up visit 7 (± 2)days post dose.

Results and discussion

Outcome of incidence:

The only compound-related effects observed in the study were statistically significant depressions in RBC and plasma cholinesterase activity, a single occurrence of a mild headache, and quantitatively increased salivation. Increased salivation was subtle, as this increase was not clinically observed but was only detected by measuring the weight of secretion over a 5 min period.

Applicant's summary and conclusion

Conclusions:

NOAEL (humans, oral): 0.1 mg/kg body weight

Executive summary:

A single oral dose of the test substance was given to 19 healthy male volunteers, ages 18 - 40 years, to determine the no adverse effect level. A test substance formulation, and its matching placebo (the formulation's inert ingredient, hydrated silica), were each administered as a capsule at doses of 0, 0.1, 0.2, or 0.3 mg/kg body weight. The treatment duration was a single dose administration with two nights observation and one follow-up visit 7 (± 2)days post dose.

No deaths or adverse events requiring treatment with atropine were observed during the study . There were no treatment related effects on ECG, heart rate, pulse, blood pressure, respiratory rate, body temperature, hematology parameters, clinical chemistry parameters (excluding cholinesterase activities), urinalysis, or pupillometry.

The only compound-related effects observed in the study were statistically significant depressions in RBC and plasma cholinesterase activity, a single occurrence of a mild headache, and quantitatively increased salivation. Increased salivation was subtle, as this increase was not clinically observed but was only detected by measuring the weight of secretion over a 5 min period.

This study was designed and conducted as a double blinded ascending dose escalation clinical trial at planned doses of 0.1, 0.3, 0.5, 0.75, 1.0, and 1.5 mg/kg body weight to be administered over eight dosing sessions. On the first day of dosing, only two subjects were dosed. One received a placebo capsule and the other received the lowest dose, 0.1 mg/kg body weight. The second session consisted of a total of 6 individuals: one placebo, four individuals at 0.1 mg/kg body weight dose, and one individual at the next lead dose of 0.3 mg/kg body weight. This same dosing schedule of a total of 6 individuals per session consisting of one placebo, four of the last higher dose, and one individual at the next escalating dose was to be repeated for each subsequent dosing session if the red blood cell (RBC) cholinesterase (ChE) activities did not exceed 40% inhibition and no adverse clinical event occurred. If either of these occurred, the next escalating or lead dose was not administered and the study was terminated. Safety data evaluated during the study included physical examination, vital signs, oral temperature, 12 lead ECG, and continuous ECG monitoring. Pupillary size (pupillometry) and saliva collection were measured as sensitive indicators for cholinergic responses. Plasma and RBC cholinesterase activities were measured at multiple timepoints to monitor inhibition and return to baseline levels.

Neither the clinical staff nor the volunteers knew who received the placebo or the treatment doses. All volunteers were informed of the nature of the risks of the study and informed consent was obtained. All volunteers were screened prior to acceptance into the study. Each subject was allowed to eat breakfast on the day of dosing, and 5 min after completion of breakfast, the individual was given a capsule followed by 150 ml of water. Five or six subjects were treated each session (with the exception of the first session) and were staggered about 5 min apart from each other. Each subject's electrocardiogram (ECG) was monitored continuously from -30 min through +3 h post dosing, and 12 lead ECGs were recorded at screening; -30 min; +30 min; and +1, +2, , and +24 h. Vital signs (blood pressure, heart rate, clinical signs) were taken at screening; -16 h, - 30 min, and +1, +2, +3, +4, +8, and +24 h. RBC and plasma cholinesterase samples were collected and immediately frozen at -16 h, -30 min, every 15 min for the first 2 h after dosing, and then hourly through 8 h, at 24 h, and again one week later, The size of the right pupil of each subject was measured (initial), as a high intensity light flash was given (minimum) and just after the light flash (recovery) at -16 h, -30 min, and +1, +2, +3, +4, +8, and +24 h and recorded as pupillometry data. The quantity of saliva secreted within a 5 min period was measured at -16 h, -30 min, and +1, +2, +3, +4, +8 and +24 hours.

Two subjects of 5 who received the 0.3 mg/kg of the test substance demonstrated a greater than 40 % inhibition of RBC cholinesterase activity, criteria set by the protocol to halt dose escalation. No further dosing at 0.3 mg/kg or above occurred. The study protocol was amended to add a dose level of 0.2 mg/kg. One subject of 5 demonstrated greater than 40 % inhibition of RBC ChE at the 0.2 mg/kg level. Of the 3 subjects, dosed at 0.2 or 0.3 mg/kg, who demonstrated a greater than 40% decrease from baseline in RBC ChE. only one subject (0.3 mg/kg dose) had any clinical signs (a mild headache which occurred about 1 h after the maximum depression of RBC cholinesterase and resolved within 1 h without treatment.) The other 2 subjects did not report any clinical signs of cholinesterase inhibition. Thus the 0.3 mg/kg dose was considered a minimal adverse effect level based on the occurrence of a mild headache correlated with depression of RBC cholinesterase.

The 0.1 mg/kg group did not have any statistically significant decreases in either plasma or RBC cholinesterase inhibition; any decrease in pupillary size; any quantitative increase in saliva secretion; or compound-related effects on ECGs, vital signs, body temperature, hematology, clinical chemistry, urine, or clinical signs at any timepoint.

The 0.2 mg/kg group did not have any statistically significant decreases in pupillary size nor any compound-related effects on ECGs, vital signs, body temperature, hematology, clinical chemistry, urine, or clinical signs at any timepoint There was also no statistically significant increase in salivary secretion when no outliers were excluded. A statistically significant increase in salivary secretion, when outliers were excluded, was noted when compared to placebo using quantitative measures (weight secreted over 5 min) at 3 h. Statistically significant RBC and plasma cholinesterase activities were observed beginning at 45 min post dosing and up to and including the 2 h timepoint. Both cholinesterase activities returned to baseline level within 6 h post dosing. One individual in the 0.2 mg/kg group had at least a 40% inhibition of RBC cholinesterase, without adverse clinical signs. This dose was considered to be the minimal effect level demonstrating a minimal increase in salivation.

The 0.3 mg/kg group did not have any statistically significant decreases in pupillary size nor any compound-related effects on ECGs, vital signs, body temperature, hematology, clinical chemistry, or urine. A statistically significant increase in salivary secretion, when outliers were excluded, was noted when compared to placebo using quantitative procedures (weight secreted over 5 min at 1 h). Statistically significant reductions in RBC and plasma cholinesterase activities were observed beginning at 15 min post dosing and up to and including the 4 h timepoint. Both cholinesterase activities returned to baseline levels within 6 h post dosing. Two individuals in the 0.3 mg/kg group had at least a 40% inhibition of RBC cholinesterase and one individual reported a headache approximately 1 h after the maximum point of his RBC cholinesterase inhibition. This dose was considered to be the minimal adverse effect level.

Under the conditions of this study and based on the absence of any clinical signs of cholinergic stimulation, changes in ECG analysis, pulse or respiratory rate, body temperature or any statistically significant increases in salivation, pupillary responses, hematology, clinical chemistry, or RBC or plasma ChE activities, the no-observed- adverse-effect level (NOAEL) of the test substance for humans after a single oral dose is 0.1 mg/kg body weight.