1,3,5-tris(oxiranylmethyl)-1,3,5-triazine-2,4,6(1H,3H,5H)-trione

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
Non-guideline target-oriented studies have been conducted to investigate the influence of epoxide hydrolase and other enzymes on teh hydrolysis end detoxification of TGIC, on the DNA-binding potential of TGIC, and in clinical trials to elucidate the potential anti-tumour activity of TGIC in Humans.
Epoxide hydrolase is the key enzyme to hydrolyse TGIC in many organs of the animal and human body. It forms the respective triols which are glucuronidated and ectretes. Degradation / hydrolysis of TGIC also occurs in the stomach due tolow pH of 1-3, conditions the alkylation potential is rapidly eliminated by acid treatment of TGIC, thus, the mutagenic potential is dependent on the intact TGIC-molecule (hydrolysis products are inactive).
Human clinical studies (Phase-1) have shown that the anti-tumour activity found in mice was lacking in Humans. this is due to the very short half-life of TGIC in the Human body (t/2 < 2minutes).
Together with othe repeated dose studies, the follwing toxico-kinetic picture of TGIC can be drawn:
TGIC is rapidly absorbed from the lung , and the gastro-intestinal tract, but slowly and to a small extent from skin.
In the stomach it is hydrolyzed by acid and in the organism by epoxide hydrolases.
The serum half-life of teh substance is <2 minutes , then ot is present to a large extent as a triol cyanurate, which is rapidly excreted.
After oral exposure, the maximum blood levels are reached after 2-4 hours with a rapid decline afterwards.
Due to the short serum half-life, no organ defects are found after acute exposure. Only after repeated exposure, ematological effects and effects on the lymph nodes, spleen and thymus are found. The same is true for effects in spermatogonial cells which appear only after repeated exposure.
Based on its half-lief in the organisms and based on teh logPow (0.8) no bio-accumulation is expected.

Additional information

The basis for the toxico-kinetic assessment are repeated-dosestudies in dogs, mice and Humans, as well as studies on the hydrolysis of TGIC via acidic pH or epoxide hadrolases.

The most important available human data are from clinical trials with triglycidyl isocyanurate (intravenous

administration), which indicate that TGIC (specifically alpha TGIC, called Teroxirone) has a mean half-life in the blood of approximately 1 min and a mean total body clearance of 5.7 litres/min. Less than 1% of the administered dose was

recovered unchanged in urine within 24 h. In an oral (gavage) study in mice, at least 17% of the administered dose was absorbed within 24 h, with blood analysis indicating that the absorption of TGIC administered in aqueous solution was twice that of TGIC in sesame oil. TGIC was distributed to the liver, stomach, and testes (the only tissues studied). Blood plasma analysis indicated that TGIC was metabolized by hydrolysis to the diol diepoxide, the bis-diol epoxide, and the fully hydrolysed tris-diol, with no free TGIC detected 8 h after treatment.

In oral (gavage) and intravenous studies with [14C]TGIC in rabbits, the radioactivity recovered in urine within 24 h was approximately 30% and 60–70%, respectively. In the intravenous study, the half-life of TGIC in the blood was <5 min.

In in vitro studies, rapid hydrolysis of triglycidyl isocyanurate involving the enzyme epoxide hydrolase was observed in mouse liver preparations. Hydrolysis was also observed in rat liver preparations but not in rat lung preparations. Microsomal epoxide hydrolase activity with triglycidyl isocyanurate as substrate measured in two human livers obtained from kidney donors was found to

be greater than the activity in rat liver.