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

Endpoint summary

Description of key information

28 days oral NOAEL (male rat): 15 mg/kg bw/day
28 days oral LOAEL (male rat): 50 mg/kg bw/day
28 days oral NOAEL (female rat): ≥50 mg/kg bw/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

15 mg/kg bw/day

Study duration:

subacute

Species:

rat

Additional information

In a GLP guideline study according to OECD guideline 407 rats (6 per sex and dose) were administered triallyl isocyanurate via gavage at concentrations of 5, 15 and 50 mg/kg bw/day for 28 days (2003-0756-FGT). An additional satellite group of 12 rats (6 per sex and dose) in the control, mid and high dose group for observation of reversibility, persistence or delayed occurrence of toxic effects were included for 14 days post treatment.

All animals survived to the end of the study and no test substance related effects were observed in clinical signs. Suppressed body weight gain was observed in males and females of the 50 mg/kg bw/day group. Decreased food consumption was noted in males of the 50 mg/kg group from day 21 to day 28 of administration. Haematological examination did not show any substance-related differences between control and treated animals. Acidification of urine was observed in males of the 50 mg/kg bw/day dose group at the end of the exposure period. Blood chemistry examination revealed increase in ASAT, ALAT and LDH, and decrease in inorganic phosphorus in males of the 50 mg/kg bw/day group, increase in AlP in females of the high dose group, and increase in total cholesterol and phospholipid in males and females of the 50 mg/kg bw/day group. Pathological examinations in animals sacrificed on day 29 revealed increases in liver weight in males and females of the 50 mg/kg bw/day group, and dark red discoloration of the liver in males of the high dose group. Hypertrophy of central hepatocytes in males of the 5 and 15 mg/kg bw/day groups and in males and females of the 50 mg/kg bw/day group were found at histopathological examination of livers. In addition, single cell necrosis of hepatocytes was observed in males of the 50 mg/kg bw/day group, vacuolation of central hepatocytes in males of the 5 and 50 mg/kg bw/day groups, bile thrombi and pericholangitis in males and females of the 50 mg/kg bw/day group, and hypertrophy of bile duct cells in males in the 50 mg/kg bw/day group.
During recovery period a significant body weight gain increase was observed in male and female rats, which received 50 mg/kg bw/day for 28 days. Thus, after the recovery period, the changes observed in body weight were no longer observed. In addition 15 days after the end of treatment there were no longer any differences between control and treated animals regardingfood consumption, urinalysis, blood chemistry parameters and necropsy. A significant increase in relative liver weight in females of the high dose group was still present after the recovery period. However this increase was to a less extent compared to the degree after the end of the treatment period. In females of the high dose group no longer any liver effect was noted after recovery period at histopathology. In addition single cell necrosis and vacuolation of central hepatocytes were no longer observed in male rats. For the change in hypertrophy of central hepatocytes, bile thrombus, pericholangitis and hypertrophy of bile duct cells the frequency or degree was reduced. Hypertrophy of central hepatocytes, pericholangitis and hypertrophy in bile ductal cell was found each in 3 males of the 50 mg/kg bw/day group. Bile thrombus was noted in 5 males of the high dose group. Eosinophilic inclusion bodies, seen in 2 males of the 15 mg/kg bw/day and in 4 males of 50 mg/kg bw/day group and microgranulomas, which reflect restoration, were found in the central region. Thus, based on these findings after recovery period of 14 days reversibility of the changes was suggested.

 

The NOAEL is considered to be 15 mg/kg bw/day for males based on the significant histopathological changes in the liver still present after recovery period in the 50 mg/kg bw/day group. A NOAEL of ≥50 mg/kg bw/day is applied for females due to no adverse effects observed after recovery period. The liver was identified as target organ.

 

 

The applied test concentrations in the 28-day study were based on the results of a pre-study in rats, in which concentrations of 17, 50, 150 and 450 mg triallyl isocyanurate/kg bw/day were administered for 14 days. Two males of the 150 mg/kg bw/day dose group died and five deaths occurred in females and males of the 450 mg/kg bw/day group. In the 50 mg/kg bw/day group increased liver weight was observed in both sexes. In males of the 50 mg/kg bw/day group, higher ASAT, ALAT and cholesterol values were determined. In females of the 50 mg/kg bw/day group, lower haematocrit values, higher ALAT and higher cholesterol values were found.

 

 

In another subacute study similar to OECD guideline 407 rats (10 per sex and dose) received triallyl isocyanurate by oral gavage administration in concentrations of 1, 10 and 100 mg/kg bw/day (Komsta et al., 1989). Biochemical and haematological parameters as well as histopathological changes were evaluated after 14 days of dosing. In the high dose group 3 males and 2 females were killed for human reasons after 10 or 11 doses. Significantly suppressed body weight in males and females of the 100 mg/kg bw/day group was observed. No clinical signs, no changes in haematological parameters and no induction of liver mixed function oxidases were noted in any of the dose groups. Affected clinical parameters in the high dose group were decreased alkaline phosphatase, decreased glucose, potassium, calcium, inorganic phosphorus and uric acid levels as well as increased bilirubin and sorbitol dehydrogenase activity. Pathology revealed spleen, lymph nodes, thymus and kidney as the targt organs. Increased liver and kidney weights and decreased spleen weights were oberved in males receiving 100 mg triallyl isocyanurate/kg bw/day. All males and one female of the high dose group had smaller spleens and occasionally dark liver and kidneys. The spleen in the animals sacrificed before study termination were also smaller in size and the kidneys in one of the males were darker. Moderate to severe thymic atrophy was observed, which was more prominent in male animals. Males also revealed moderate to severe atrophy of the mesenteric lymph nodes and mild to moderate renal tubular degenerative changes. Follicular and mantle zone atrophy was observed in the spleen and was more prominent in male animals.

Since toxic effects were restricted to the high dose group animals, the NOAEL was determined to be 10 mg/kg bw/day for males and females, respectively. However in general, the changes induced by triallyl isocyanurate were in general more severe in males than in females.

 

 

In a not-reliable publication by Bidnenko (1969) rats (6 per dose) were administered daily triallyl isocyanurate at 1/5, 1/10 and 1/20 of the LD50 (corresponding to approx. 35, 70 and 140 mg/kg bw/day) for three months. The author reported death of 5 of 6 animals applied 1/5 of the LD50 and decreased body weight in the treated rats. No further information was provided.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

The available data on repeated oral toxicity of the test substance meet the criteria for classification as "STOT RE 2, H373" according to Regulation (EC) 1272/2008 and as "Xn (R48/22)" according to Directive 67/548/EEC.