1,3,5-Tris(2-propenyl)isocyanuric acid

1,3,5-トリス(2-プロペニル)イソシアヌル酸


[CAS No. 1025-15-6]

1,3,5-Triallylisocyanurate

トリアリルイソシアヌル酸

Molecular formula: C12H15N3O3　Molecular weight: 249.27

ABSTRACT

A single dose oral toxicity test of 1,3,5-tris(2-propenyl)isocyanuric acid in rats revealed LD50 values of 707 mg/kg for males and 812 mg/kg for females. The animals that died showed hypoactivity, gait disturbance, tremors and convulsions. Necropsy of these animals revealed erosions or ulcers in the forestomach.

1,3,5-Tris(2-propenyl)isocyanuric acid was studied for oral toxicity in rats in a 28-day repeat dose toxicity test at doses of 0, 5, 15 and 50 mg/kg.

Suppressed body weight gain was observed in males and females of the 50 mg/kg group. Decreased food consumption was observed in males of the 50 mg/kg group. Blood chemistry examination revealed increase in ASAT, ALAT and LDH, and decrease in inorganic phosphorus in males of the 50 mg/kg group, increase in AlP in females of the 50 mg/kg group, and increase in total cholesterol and phospholipid in males and females of the 50 mg/kg group. Pathological examination revealed increase in liver weight in males and females of the 50 mg/kg group and dark red discoloration of the liver in males of the 50 mg/kg group, and histopathological examination revealed hypertrophy of centrilobular hepatocytes in males of the 5 and 15 mg/kg groups and in males and females of the 50 mg/kg group. In addition, single cell necrosis of hepatocytes was observed in males of the 50 mg/kg group, vacuolation of centrilobular hepatocytes in males of the 5 and 50 mg/kg groups, bile thrombi and pericholangitis in males and females of the 50 mg/kg group, and hypertrophy of bile duct cells in males of the 50 mg/kg group.

The NOEL is considered to be lower than 5 mg/kg/day for males and 15 mg/kg/day for females.

Genotoxicity of 1,3,5-tris(2-propenyl)isocyanuric acid was studied by a reverse mutation test in bacteria. This substance was not mutagenic in Salmonella typhimurium TA100, TA98, TA1535, TA1537 or Escherichia coli WP2 uvrA, with or without an exogenous metabolic activation system.

Genotoxicity of 1,3,5-tris(2-propenyl)isocyanuric acid was studied by chromosomal aberration test in cultured Chinese hamster lung (CHL/IU) cells. 1,3,5-Tris(2-propenyl)isocyanuric acid did not induce structural chromosomal aberrations or polyploidy under the present test conditions.

SUMMARIZED DATA FROM THE STUDIES

1. Single Dose Oral Toxicity 1)

Purity:99.12 %
Test species/strain:Rat/Crj:CD(SD)IGS
Test method:OECD Test Guideline 401
　Route:Oral (Gavage)
　Dosage:0 (Vehicle), 250, 500, 1000 mg/kg
　Number of animals/group:Males, 5; females, 5
　Vehicle:Olive oil
GLP:Yes

　Test results:

Deaths occurred in males and females given 1000 mg/kg. In the animals that died, decrease in spontaneous movement, abnormal gait, tremors, clonic convulsions, hypothermia, mydriasis and smudging in the peri-genitourinary area were observed from the day following administration or from day 2 after administration, and body weights decreased until death. Necropsy of animals that died revealed malnutrition, small thymi and spleens, small mesenteric lymph nodes, white foci in the forestomach and dark red foci in the glandular stomach. The white foci in the forestomach were observed on the fundal end and indicative of histopathological erosion or ulceration in the mucosa and thickening of mucosal epithelium of the forestomach. The animals that survived until termination showed suppressed body weight gain on the day following administration or until day 2 after administration, but no abnormalities in general conditions. Necropsy revealed white foci in the forestomach in females at 500 and 1000 mg/kg, similarly to those in the animals that died.

LD50: Male, 707 mg/kg; female, 812 mg/kg

2. Repeat Dose Oral Toxicity 1)

Purity:99.12 %
Test species/strain:Rat/Crj:CD(SD)IGS
Test method:Guideline for 28-Day Repeated Dose Toxicity Test in Mammalian Species (Chemical Substances Control Law of Japan)
　Route:Oral (Gavage)
　Dosage:0 (Vehicle), 5, 15, 50 mg/kg/day
　Number of animals/group:Males, 6; females, 6
　Vehicle:Olive oil
　Administration period:Males and females, 28 days
　Terminal killing:Days 29 or 43
GLP:Yes

　Test results:

No test article-related effects were observed in clinical signs or hematological examination. Suppressed body weight gain was observed in males and females of the 50 mg/kg group. Decreased food consumption was observed in males of the 50 mg/kg group from day 21 to day 28 of administration. Blood chemistry examination revealed increase in ASAT, ALAT and LDH, and decrease in inorganic phosphorus in males of the 50 mg/kg group, increase in AlP in females of the 50 mg/kg group, and increase in total cholesterol and phospholipid in males and females of the 50 mg/kg group. Pathological examination revealed increases in liver weight in males and females of the 50 mg/kg group, and dark red discoloration of the liver in males of the 50 mg/kg group, and histopathological examination revealed hypertrophy of centrilobular hepatocytes in males of the 5 and 15 mg/kg groups and in males and females of the 50 mg/kg group. In addition, single cell necrosis of hepatocytes was observed in males of the 50 mg/kg group, vacuolation of centrilobular hepatocytes in males of the 5 and 50 mg/kg groups, bile thrombi and pericholangitis in males and females of the 50 mg/kg group, and hypertrophy of bile duct cells in males in the 50 mg/kg group.

After the recovery period, the changes observed in body weight, food consumption, urinalysis, blood chemistry examination, necropsy as well as single cell necrosis and vacuolation of centrilobular hepatocytes were no longer observed. For the change in organ weight, hypertrophy of centrilobular hepatocytes, bile thrombus, pericholangitis and hypertrophy of bile duct cells, the frequency and degree were reduced, and eosinophilic inclusion bodies and microgranulomas, which reflect restoration, were observed in the centrilobular region. Therefore, reversibility of the changes was suggested.

The NOEL is considered to be lower than 5 mg/kg/day for males and 15 mg/kg/day for females.

3. Genetic Toxicity

3-1. Bacterial test 2)

Purity:99.12 %
Test species/strains:Salmonella typhimurium TA100, TA1535, TA98, TA1537, Escherichia coli WP2 uvrA
Test method:Guidelines for Screening Mutagenicity Testing of Chemicals (Chemical Substances Control Law of Japan)and OECD Test Guideline 471
　Procedures:Pre-incubation method
　Solvent:Dimethyl sulfoxide
　Positive controls:-S9 mix; 2-(2-Furyl)-3-(5-nitro-2-furyl)acrylamide (TA100, TA98, WP2 uvrA), Sodium azide (TA1535) and 9-Amino-acridine (TA1537)
+S9 mix; 2-Aminoanthracene (five strains)
　Dosage:-S9 mix; 0, 156, 313, 625, 1250, 2500, 5000 μg/plate (five strains)
+S9 mix; 0, 156, 313, 625, 1250, 2500, 5000 μg/plate (TA100, TA1535, TA98, TA1537)
+S9 mix; 0, 313, 625, 1250, 2500, 5000 μg/plate (WP2 uvrA)
　S9:Rat liver, induced with phenobarbital and 5,6-benzoflavon
　Plates/test:3 (1 for the cytotoxicity test)
　Number of replicates:2 (plus 1 cytotoxicity test)
GLP:Yes

　Test results:

This chemical did not induce gene mutations in S. typhimurium TA100, TA98, TA1535, TA1537 or E. coli WP2 uvrA strains with or without S9 mix. Growth inhibition was observed at and above 2500 μg/plate in all strains without S9 mix and four S. typhimurium strains with S9 mix.

Genetic effects:
Salmonella typhimurium TA100, TA98, TA1535, TA1537
+?-
Without metabolic activation:[ ][ ][*]
With metabolic activation:[ ][ ][*]

Escherichia coli WP2 uvrA
+?-
Without metabolic activation:[ ][ ][*]
With metabolic activation:[ ][ ][*]

3-2. Non-bacterial in vitro test (chromosomal aberration test) 2)

Purity:99.12 %
Type of cell used:Chinese hamster lung (CHL/IU) cells
Test method:Guidelines for Screening Mutagenicity Testing of Chemicals (Chemical Substances Control Law of Japan) and OECD Test Guideline 473
Solvent:Dimethyl sulfoxide
　Positive controls:-S9 mix; Mitomycin C
+S9 mix; Cyclophosphamide
　Dosage:-S9 mix (short-term treatment); 0, 0.63, 1.3, 2.5 mg/mL
+S9 mix (short-term treatment); 0, 0.63, 1.3, 2.5 mg/mL
-S9 mix (continuous treatment); 0, 0.25, 0.50, 1.0 mg/mL
+S9 mix (short-term treatment); 0, 1.5, 2.0, 2.5 mg/mL
　S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
　Plates/test:2
GLP:Yes

　Test results:

The incidence of cells with structural chromosomal aberrations and polyploidy was not biologically significant at any dose in all test systems, although statistically significant increase of cells with structural aberrations was observed at 1.3 mg/mL and 2.5 mg/mL after short-term treatment without S9 mix.

Genotoxic effects:
clastogenicitypolyploidy
+?-+?-
Without metabolic activation:[ ][ ][*][ ][ ][*]
With metabolic activation:[ ][ ][*][ ][ ][*]

1)The tests were performed by Bozo Research Center Inc, 1284, Kamado, Gotemba-shi, Shizuoka, 412-0039, Japan. Tel +81-550-82-2000 Fax +81-550-82-2379
2)The tests were performed by the Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano-shi, Kanagawa, 257-8523, Japan. Tel +81-463-82-4751 Fax +81-463-82-9627