4-methylpyrazole

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:

other: Human clinical study, published in peer reviewed literature.

Data source

Reference

Reference Type:

publication

Title:

Effects of 4-methylpyrazole, methanol/ethylene glycol antidote, in healthy humans

Author:

Jacobsen D.

Year:

1990

Bibliographic source:

J Emerg Med. 1990 Jul-Aug;8(4):455-61.

Materials and methods

Study type:

study with volunteers

Endpoint addressed:

repeated dose toxicity: oral

Principles of method if other than guideline:

A placebo-controlled, double blind, multiple dose, sequential, ascending-dose study had been performed to determine the tolerance of the test substance in 5 healthy male volunteers per dose. Along with each dose group there were two placebos. Oral loading doses were followed by supplemental doses every 12 h through 5 days, producing plasma levels in the therapeutic range. Blood and urine samples were taken for haematology and clinical chemistry evaluation. Furthermore, clinical signs were registered both by the test subjects as well as by the testing personnel.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

4-methylpyrazole

EC Number:

231-445-0

EC Name:

4-methylpyrazole

Cas Number:

7554-65-6

Molecular formula:

C4H6N2

IUPAC Name:

4-methyl-1H-pyrazole

Details on test material:

- Name of test material (as cited in study article): 4-methylpyrazole (4-MP)
- Purity: >99.5%

Method

Type of population:

general

Subjects:

Healthy males, within 15% of the normal weight range for their age (21-39 y), height, and frame size.

Ethical approval:

confirmed and informed consent free of coercion received

Route of exposure:

oral

Reason of exposure:

intentional

Exposure assessment:

measured

Details on exposure:

- Under double-blind conditions, subjects allowed into the study were divided into three groups. Each group randomly employed 5 subjects on the test substance and 2 on placebo.
- Group 1 received 10 mg/kg as loading dose, followed by supplemental doses of 3 mg/kg every 12 h up to 96 h.
- Group 2 received 15 mg/kg as loading dose, followed by supplemental doses of 5 mg/kg every 12 h up to 96 h.
- Group 3 received 10 mg/kg as loading dose, followed by supplemental doses of 5 mg/kg every 12 h up to 36 h, and then 10 mg/kg every 12 h up to 96 h.
- The total doses of the test substance were 34, 55, and 75 mg/kg in Groups 1, 2, and 3, respectively.
- The taste of the substance was disguised as a 0.5% (w/v) solution in a mixture of vegetable juice (V-8, Campbell Soup company), lime juice, and 6-8 drops of hot pepper sauce.
- After dosing the subjects fasted for an additional 2 h.

Examinations:

- The monitoring of side effects was done by self-report as well as observation by testing personnel at indicated times (0, 4, 8, 12, 24, 28, 32, 36, 48, 52, 56, 60, 72, 76, 80, 84, 96, 100, 104, 108, 120, 132, and 144 h after exposure). The subjects were asked to rate all side effects on a 1 to 3 schale, where 1 was mild, 2 moderate and 3 severe. At the end of the study, each subject filled out a fixed questionnaire on which they were asked about specific side effects.
- Venous blood was drawn from a permanently inserted teflon catheter after aspiration of the heparin dead-volume. This was done at 0, 4, 8, 10, 12, 24, 28, 32, 34, 36, 48, 52, 56, 58, 60, 72, 76, 80, 82, 84, 96, 100, 104, 106, 108, 120, 132, and 144 h after exposure.
- Urine was collected at 24 h prior to exposure, and 0, 4, 8, 12, 24, 28, 32, 36, 48, 52, 56, 60, 72, 76, 80, 84, 96, 100, 104, 108, 120, 132, and 144 h after exposure.
- The laboratory parameters that were monitored: complete blood count (including differential and platelets), as standard serum chemistry screen (electrolytes, liver enzymes, proteins, lipids, glucose, BUN, and creatinine), and a complete urinalysis.
- 4-MP was analyzed in plasma and urine by modification of an HPLC method.

Results and discussion

Clinical signs:

Subjects side effects were reported in 3 out of 6 placebos and in 7 out of 15 drug subjects. The side effects reported at various times in both groups were dizziness, lightheadedness, diarrhea, and headache. All effects were rated mild (grade 1) and were short in duration.

Results of examinations:

- There were nog significant changes in objective clinical parameters such as pulse rate, body temperature, or respiratory rate in any subject at any time during the study. A mild, sporadic, and transient elevation in the blood pressure was seen in 5 of the 15 drug subjects and in 3 of the 6 placebos. The blood pressure elevation was apparently not related to test substance administration.
- The values for several of the laboratory parameters were outside of the study reference range at some measurement time in 9 of the 15 drug subjects and in 1 of the 6 placebos. One or both serum transaminase values were elevated in 6 drug subjects, but elevations were mild and had returned to normal 1-2 weeks after completion of the study. Elevation of serum cholesterol or triglyceride levels and test substance administration occurred in 3/10 drug subjects but also in 1/4 placebos
- In groups 1 and 2, the mean plasma levels of the test substance remained in the 50 to 150 µM range for about 36 to 60 h. Then the levels decreased markedly so that the test substance was detectable for only 8 h after the last administration. In group 3 the plasma levels were 100 to 200 µM and were maintained throughout the 5 day treatment.