Glycerol trinitrate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1956 -1989

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Tests and tests's results were being analysed by the special group from the Colegium Medicusof of the Jagielonian University in Cracow. These results were accepted as grounds to the study, the state official standard for the highest allowed concentration of the nitroglycerine in air on posts of work in Poland

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Unnamed

Year:

1969

Reference 2

Reference Type:

publication

Title:

Unnamed

Year:

1968

Reference 3

Reference Type:

publication

Title:

Unnamed

Year:

1960

Reference 4

Reference Type:

publication

Title:

Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrates, nitroprusside and nitric oxide.

Author:

Ignarro l.J., and other

Year:

1981

Bibliographic source:

J Pharmacol Exp Ther September 1981 218:739-749

Reference 5

Reference Type:

publication

Title:

Occupational exposure to nitroglycerin and ethylene glycol dinitrate

Author:

C Hogstedt, R Ståhl

Year:

1978

Bibliographic source:

American Industrial Hygiene Association Journal, Volume 41, Issue 5 May 1980 , pages 367 - 372

Materials and methods

Objective of study:

toxicokinetics

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Glycerol trinitrate

EC Number:

200-240-8

EC Name:

Glycerol trinitrate

Cas Number:

55-63-0

Molecular formula:

C3H5N3O9 C3H5(NO3)3

IUPAC Name:

propane-1,2,3-triyl trinitrate

Constituent 2

Reference substance name:

propane-1,2,3 triyl trinitrate

IUPAC Name:

propane-1,2,3 triyl trinitrate

Details on test material:

- Name of test material (as cited in study report): NG, nitroglycerin
- Organic liquid substance
- Physical state: vapour
- Storage condition of test material: NG was stored at 15°C in glass bottles placed in metal flasks.

Test animals

Species:

human

Sex:

male/female

Administration / exposure

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on excretion:

The elimination of NG from organism is ensured mainly by kidneys and by the respiratory tract. Only metabolites are expelled from the organism. Although no toxicokinetic data are available now, on the basis of studies by Di Carlo and others it has been well ascertained that the elimination of metabolites in urine and air breathed out is rapid and similar as to the quantities. After 4 hours from a single intragastric administration, circa 20% of NG dose were found in urine in form of the above mentioned metabolites, and circa 20% of NG dose were found in the air breathed out in form of carbon dioxide.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study resultsThe lack of NG residues in excrements proves that the substance undergoes total metabolic transformation in the organism

Executive summary:

TOXICOKINETICS

 In industrial environments NG may be absorbed by human skin, mucosa, and respiratory tract.

The studies byGrossand others show that the rate of Nitroglycerin absorption trough the skin of rat’s side amounts to 0,85 mg/cm²/hour, which equals to the 1/12 of the limit value, as defined for EGDN.

Distribution and accumulation in organisms 

Di Carloand others have found, that the radioactivity levels in rats, after 30 minutes from the intragastric administration of radiocarbon-labeled NG, were respectively 6,4% in blood, 2,9% in urine, and 2,4 % in the air breathed out by them as carbon dioxide.

In rabbits and dogs, after the intravenous administration of NG in rate of 1 mg/kg, it was found that the parent compound’s concentration in blood plasma reaches its maximal level of 10 μg/ml during first 10 to 20 minutes after the administration, and then rapidly decreases. In parenchymatous organs this process is alike. The NG is fixed by plasma proteins in quantities up to 30% of the administrated dose. The concentration in erythrocytes is lower than in the plasma.

The toxicokinetic data show that NG does not accumulate in organisms.

Metabolism

The biotransformation of NG, which consist in progressive splitting of ester bonds, takes place in the presence of reduced glutathion(G-SH).HeppelandHilmoehave found in their experimentsin vitrothat NG enters in reaction with G-SH to form inorganic nitrite
(NO₂^-) and oxidized glutathione. This reaction seems to be catalyzed by an enzyme that is present in the soluble fraction of liver.According to the opinion by the above researchers, since the G-SH does not react spontaneously with inorganic nitrides, therefore it would be a reduction by G-SH before. In this manner electrons that are released when disulfide bonds are generated, may be easily attached by nitrate radicals, the latter finally transforming in NO₂^-ions.

In biotransformation process of NG 1,2-ethanediol dinitrate, 1,3-ethanediol dinitrate, 1-mononitrate, 2-mononitrate, as well as glycerol and other metabolites are created. The above metabolites are characterized by levels of biological activity that are significantly lower that those of parent compounds. According toNeelemanandKrantz, glycerol dinitrates are about 4 times less efficient in increasing the coronary circulation of blood, and about 8 times less efficient in decreasing arterial systolic pressure, in comparison with NG.

The lack of NG residues in excrements proves that the substance undergoes total metabolic transformation in the organism

Excretion

The elimination of NG from organism is ensured mainly by kidneys and by the respiratory tract. Only metabolites are expelled from the organism. Although no toxicokinetic data are available now, on the basis of studies byDi Carloand others it has been well ascertained that the elimination of metabolites in urine and air breathed out is rapid and similar as to the quantities. After 4 hours from a single intragastric administration, circa 20% of NG dose were found in urine in form of the above mentioned metabolites, and circa 20% of NG dose were found in the air breathed out in form of carbon dioxide.

Mechanism of the toxic action

The NG belongs to the group of compounds characterized by their spasmolytic action. The relaxing effect by this substance to the smooth muscles of blood vessels is caused by the creation of so-called S-nitrozothiols which are biologically active metabolic intermediaries. These intermediary substances are generated in non enzymatic manner, through the reaction of NO which is released from lipophile compounds of NG type, thiol chains that are free (cysteine, for instance), and those bond in smooth muscles of blood vessels. The S-nitrozothiols enable guanylyl cyclase, and increase the level of intracellular cyclic guanosine monophosphate (cGMP) that has a relaxing effect to the smooth muscles of blood vessels. The mechanism of this process is still unknown.

The spasmolytic effects of NG are manifested by several hemodynamic changes in the circulatory system caused by angiectasia of heart’s coronary vessels, coronary arteries, and bed of veins. These changes include several symptoms, such as increased blood flow in the coronary system, lower arterial systolic pressure, lower pulse pressure (amplitude of systolic-diastolic pressure of the pulse), lower stroke volume, and tachycardia, as a result of a reflex stimulation by the adrenergic system.

Cephalalgia, which is a characteristic sign for the NG toxicity, and similar to histaminic headache, is caused by angiectasia of intracranial blood vessels.

According toNeedlmanandJohnson, the tolerance to NG, which is typical for repeated exposures, is caused by the metabolism. Under multiple exposures active thiol groups of the nitroglycerin receptor may oxidize, and consequently reduce its sensibility for NG. This conclusion seems to be supported by the specificity of NG biotransformation mechanism itself (18), as well as by the lack of such a tolerance if previously 2-thiol chains have been added.