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

1,3,5-トリス(2-ヒドロキシエチル)-1,3,5-トリアジン-2,4,6-(1H,3H,5H)-トリオン

[CAS No. 839-90-7]

1,3,5-Tris(2-hydroxyethyl) isocyanurate

1,3,5-トリス(2-ヒドロキシエチル)イソシアヌラート

Molecular formula: C₉H₁₅N₃O₆ Molecular weight: 261.23

ABSTRACT

1,3,5-Tris(2-hydroxyethyl)-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione was studied for oral toxicity in rats of both sexes in a single dose toxicity test at doses of 0, 500, 1000 and 2000 mg/kg. The LD₅₀ value was estimated to be higher than 2000 mg/kg for both sexes.

1,3,5-Tris(2-hydroxyethyl)-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione was studied for oral toxicity in rats in an OECD combined repeat dose and reproductive/developmental toxicity screening test at doses of 0, 30, 100, 300 and 1000 mg/kg/day (12 animals of each sex per group).

Regarding the males, no changes caused by the substance were noted for general signs, body weight, food consumption, urinalysis, hematological examination, blood chemical analysis, necropsy, organ weights, or histopathological examination.

Regarding the females, no changes caused by the substance were noted for general signs, body weight, food consumption, necropsy, or organ weights. On histopathological examination, extramedullary hematopoiesis in the liver was noted in the 1000 mg/kg group.

The NOELs for repeat dose toxicity are considered to be 1000 mg/kg/day for males, and 300 mg/kg/day for females.

Regarding reproductive/developmental toxicity, no changes caused by the substance were noted in the copulation index, gestation length, delivery conditions, nursing conditions, fertility index, number of corpora lutea, implantation rate, or gestation index.

The NOELs for reproductive performance are considered to be 1000 mg/kg/day for both sexes. Regarding the pups, no changes caused by the substance were noted in terms of the numbers of pups, stillbirths, and live pups born, sex ratio, delivery index, birth index, live birth index, viability index, or body weight.

The NOEL for pup development is considered to be 1000 mg/kg/day.

Reverse mutation assays using microorganisms (Salmonella typhimurium, Escherichia coli) were conducted to assess the potential of 1,3,5-tris(2-hydroxyethyl)-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione to induce gene mutations.

1,3,5-Tris(2-hydroxyethyl)-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione did not induce gene mutations in bacteria under the conditions of this study.

In vitro chromosomal aberration tests using cultured cells (CHL/IU) were conducted to assess the potential of 1,3,5-tris(2-hydroxyethyl)-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione to induce chromosomal aberrations.

1,3,5-Tris(2-hydroxyethyl)-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione did not induce chromosomal aberrations in cultured cells under the conditions of this study.

SUMMARIZED DATA FROM THE STUDIES

1. Single Dose Toxicity ¹⁾

Purity	:	99.0 %
Test species/strains	:	Rat/Crj:CD(SD)IGS
Test method	:	OECD Test Guideline 401
Route	:	Oral (gavage)
Doses	:	0(vehicle), 500, 1000, 2000 mg/kg
Number of animals/group	:	Males, 5; females, 5
Vehicle	:	Water for injection
GLP	:	Yes

　Test results:

No deaths occurred in either sex in the treated groups.

The LD₅₀ value was estimated to be higher than 2000 mg/kg for both sexes.

2. Repeat Dose and Reproductive/developmental Toxicity ¹⁾

Purity	:	99.0 %
Test species/strains	:	Rat/Crj:CD(SD)IGS
Test method	:	OECD Test Guideline 422
Route	:	Oral (gavage)
Doses	:	0(vehicle), 30, 100, 300, 1000 mg/kg/day
Number of animals/group	:	Males, 12; females, 12
Vehicle	:	Water for injection
Administration period	:	Males, 49 days Females, from 14 days before mating to day 3 of lactation
Terminal kill	:	Males, day 50 Females, day 4 of lactation
GLP	:	Yes

　Test results:

<Repeat dose toxicity>

In the females, no changes caused by the substance were noted regarding general signs, body weight, food consumption, necropsy, or organ weights. On histopathological examination, extramedullary hematopoiesis in the liver was noted in the 1000 mg/kg group.

The NOELs for repeat dose toxicity are considered to be 1000 mg/kg/day for males, and 300 mg/kg/day for females.

<Reproductive and Developmental Toxicity>

The NOELs for reproductive performance are considered to be 1000 mg/kg/day for both sexes.

Regarding the pups, no changes caused by the substance were noted in terms of the numbers of pups, stillbirths, and live pups born, sex ratio, delivery index, birth index, live birth index, viability index, or body weight.

The NOEL for pup development is considered to be 1000 mg/kg/day.

3. Genetic Toxicity

3-1. Bacterial test ²⁾

Purity	:	99.0 %
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	:	Water for injection
Positive controls	:	-S9 mix; 2-(2-Furyl)-3-(5-nitro-2-furyl)acrylamide (TA100, TA98 and WP2 uvrA), Sodium azide (TA1535) and 9-Aminoacridine hydrochloride (TA1537) +S9 mix; 2-Aminoanthracene (all strains)
Doses	:	-S9 mix; 156, 313, 625, 1250, 2500, 5000 μg/plate(all strains) +S9 mix; 156, 313, 625, 1250, 2500, 5000 μg/plate(all strains)
S9	:	Rat liver, induced with phenobarbital and 5,6-benzoflavone
Plates/test	:	3
Number of replicates	:	2
GLP	:	Yes

　Test results:

No increases in revertant colonies were observed in the test with either the non-activation method (-S9) or activation (+S9).

Genetic effects:
Salmonella typhimurium TA100, TA1535, TA98 and 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	:	99.0 %
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	:	Physiological saline
Positive controls	:	-S9 mix; Mitomycin C +S9 mix; Cyclophosphamide
Doses	:	-S9 mix(short-term treatment); 0, 653, 1306, 2612 μg/mL +S9 mix(short-term treatment); 0, 653, 1306, 2612 μg/mL -S9 mix(continuous treatment 24 hr); 0, 653, 1306, 2612 μg/mL S9 : Rat liver, induced with phenobarbital and 5,6-benzoflavone
S9	:	Rat liver, induced with phenobarbital and 5,6-benzoflavone
Plates/test	:	2
GLP	:	Yes

　Test results:

No increases in chromosomal aberrations were observed in the test with either the short-term treatment (-S9 and +S9) or continuous treatment.

Genotoxic effects:

	clastogenicity			polyploidy
	+	?	-	+	?	-
Without metabolic activation:	[ ]	[ ]	[*]	[ ]	[ ]	[*]
With metabolic activation:	[ ]	[ ]	[*]	[ ]	[ ]	[*]