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

Carcinogenicity

Description of key information

No carcinogenic effect after oral exposure for 99 weeks (rats)
No carcinogenic /tumour promotion effects after 30 weeks or dermal exposure following DMBA induction.
It is reasonably assumed that TGIC is not carcinogenic

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Dose descriptor:

NOAEL

4.36 mg/kg bw/day

Carcinogenicity: via dermal route

Endpoint conclusion

Dose descriptor:

NOAEL

200 mg/kg bw/day

Justification for classification or non-classification

Ther are no indications for any carcinogenic activity of TGIC in rodents or men.

On the other hand alpha-TGIC was shown to be anti-neoplastic in rodents. However, this activity was not found in Humans due to the rapid metabolism of TGIC by epoxide hydrolases in man.

Additional information

No peer-reviewed studies were found concerning the carcinogenicity of TGIC. However, the carcinogenic potential of TGIC was examined in a non peer reviewed study (CIT, 1999. Carcinogenicity study in male rats with TGIC (1,3,5-triglycidyl isocyanurate).

Miserey, Centre Internationale de Toxicologie). In this study TGIC was administered by dietary admixture to groups of 50 male rats at concentrations of approximately 0, 10, 30 and 100 ppm (corresponding to 0, 0.4, 1.3 and 4.4 mg/kg body weight/day) for up to 99 weeks or 300 ppm (13.6 mg/kg body weight/day) for 63 weeks. The animals in the 300 ppm group were killed at

week 63 due to the high level of mortality (the cause of death was possibly a histamine-related hypotension). TGIC did not show a carcinogenic potential at any dose level. At 300 ppm lower food consumption and a marked decrease in

body weight gain was recorded as well as poor clinical condition. Histopathological investigations (300 ppm) revealed a significantly higher incidence of mastocytosis, haemosiderosis and sinusal haemorrhage in the mesenteric lymph nodes and lymphoid depletion in the spleen and a high incidence of dilatation of some intestinal segments. In addition, a higher incidence

of hyposecretion and small tubulo-alveolar units in the prostate was found.

Hematological changes (week 52: a higher neutrophil count and monocyte count, lower lymphocyte count; week 63: lower total leukocyte count) were also noted. These findings were attributed to treatment. No indication of treatment-related non-neoplastic changes was seen in the 10, 30 and 100 ppm groups and the no observed adverse effect level (NOAEL) in the study was considered to be 100 ppm.

In a satellite study the subchronic toxicity of TGIC was evaluated over a 26-week treatment period. Groups of 10 male rats were given 0, 100 or 300 ppm (0, 5.8 or 16.7 mg/kg body weight/day) TGIC in the diet. No mortality or clinical signs considered as substance-related occurred during the treatment period, and no adverse effects were observed at 100 ppm. At 300 ppm, the

principal signs of toxicity were markedly lower body weight gain and food consumption. Other effects reported at this dose level were lymphoid depletion of spleen and thymus and hyposecretion of prostate and seminal vesicles, allcorrelating with lower organ weights (p>0.05). Furthermore, a higher weight of the mesenteric lymph nodes, associated with haemosiderosis, plasmocytosis, mastocytosis and sinusal haemorrhages, was seen. A slightly lower mean total leukocyte count was also found at 300 ppm. The anti-tumour properties of α- and ß-TGIC have been investigated in various transplantable mouse tumour systems. Both stereoisomers displayed a high therapeutic activity, but α-TGIC was superior to the ß-isomer in prolonging the lifespan of treated animals and in inducing long-term survival, probably due to a higher water solubility . In vitro studies measuring cells killed by the drug indicated that neoplastic cells were more susceptible to α-TGIC than non-neoplastic cells. α-TGIC has also been available as an experimental anti-neoplastic agent and was used in human clinical trials in the early 1980s. However, it has been suspected that some of the clinical trials were conducted with TGIC mixtures, rather than pure α-TGIC as reported .

Based on the findings in the male mouse carcinogenicity study and taking into account the dermal tumour promotionn study , and considering the studies performed earlier on alpha-TGIC (Henkels compound) on the tumour inhibition studies in rodents it is reasonable to assume that TGIC is not carcinogenic for rodents.

Despite the fact that TGIC is a direct acting mutagen in-vivo in rodents, no carcinogenic effects have been observed at significant exposure levels . As TGIC has been shown to be metabolized by epoxide hydrolases, a group of enzymes more concentrated in Humans than in rodents, it can be expected that TGIC is metabolized much faster in Humans than in rodents. This means, that TGIC is less mutagenic in Humans than in rodents, and has an even lower potential to cause carcinogenic effects at very high dose levels.

Carcinogenicity: via oral route (target organ): cardiovascular / hematological: lymph nodes

Carcinogenicity: via dermal route (target organ): other: skin