Dicyclopentylsilanediol

ジシクロペンチルシランジオール


[CAS No. ―――]

Molecular formula: C10H30O2Si Molecular weight: 200.35

ABSTRACT

The single oral dose LD50 value of dicyclopentylsilanediol was found to be above 2000 mg/kg for both sexes.

Dicyclopentylsilanediol was studied for oral toxicity in rats in a 90-day repeat dose toxicity test at 0, 40, 200 and 1000 mg/kg. Ataxic gait and salivation were observed in the 200 and 1000 mg/kg groups, and decrease in locomotor activity was observed in the 1000 mg/kg group. Body weight was decreased in the 1000 mg/kg group. Blood chemical examination revealed an increase in total cholesterol in the 200 and 1000 mg/kg groups and a decrease in triglyceride in the 1000 mg/kg group. Liver weight was increased in the 200 and 1000 mg/kg groups, and enlargement and dark brownish color of the liver were observed in the 1000 mg/kg group. Hypertrophy of hepatocytes was observed in the 200 and 1000 mg/kg groups. In the thyroid, hypertrophy of the follicular cell was observed in the 1000 mg/kg group. In the kidneys, increase in the appearance of hyaline droplets in the proximal tubular epithelium was observed in males of the 1000 mg/kg group. These changes disappeared or diminished after withdrawal.

The NOEL is considered to be 40 mg/kg/day for both sexes.

A reverse mutation test of dicyclopentylsilanediol in bacteria was carried out. This substance was not mutagenic in Salmonella typhimurium TA100, TA1535, TA98, TA1537 and Escherichia coli WP2 uvrA, with or without an exogenous metabolic activation system.

Genotoxicity of dicyclopentylsilanediol was studied by chromosomal aberration test using cultured Chinese hamster lung (CHL/IU) cells. Dicyclopentylsilanediol did not induce structural chromosomal aberrations or polyploidy at any dose, with and without metabolic activation.

SUMMARIZED DATA FROM THE STUDIES

1. Single Dose Toxicity 1)

Purity:>99 %
Test species/strains:Rat/Crj:CD(SD)IGS
Test method:OECD Test Guideline 401
　Route:Oral (gavage)
　Dosage:0(vehicle), 500, 1000, 2000 mg/kg
　Number of animals/group:Males, 5; females, 5
　Vehicle:0.5 % CMC-Na aqueous solution mixed with 0.1 % Tween 80
GLP:Yes

　Test results:

One female of the 2000 mg/kg group died. Clinical signs observed were as follows: ataxic gait, decrease in locomotor activity, abnormal gait, crouching, a prone, lateral or supine position, hypothermia, and bradypnea. No changes attributable to the administration of dicyclopentylsilanediol were observed in the body weight or necropsy findings.
The LD50 value was estimated to be above 2000 mg/kg for both sexes.

2. Repeat Dose Toxicity 1)

Purity:>99 %
Test species/strain:Rat/Crj:CD(SD)IGS
Test method:OECD Test Guideline 408
　Route:Oral (gavage)
　Dosage:0(vehicle), 40, 200, 1000 mg/kg/day
　Number of animals/group:Males, 10; females, 10
　Vehicle:0.5 % CMC-Na aqueous solution mixed with 0.1 % Tween 80
　Administration period:Males and females, 90 days
　Sacrifice:Days 91 and 119
GLP:Yes

　Test results:

Transient ataxic gait and transient salivation were observed in both sexes of the 200 and 1000 mg/kg groups, and decrease in locomotor activity was observed in both sexes of the 1000 mg/kg group. Body weight was decreased in females of the 1000 mg/kg group. Blood chemical examination revealed an increase in total cholesterol in females of the 200 and 1000 mg/kg groups, and a decrease in triglyceride in males of the 1000 mg/kg group. Organ weight measurement revealed increases in absolute and/or relative weights of the liver in males of the 200 mg/kg group and in both sexes of the 1000 mg/kg group, and in absolute weight of the kidneys in males of 1000 mg/kg group. Necropsy revealed enlargement and dark brownish color of the liver in females of the 1000 mg/kg group. Histopathological examination revealed centrilobular hypertrophy of hepatocytes in females of the 200 mg/kg group and in both sexes of the 1000 mg/kg group, diffuse hypertrophy of follicular cells of the thyroid in both sexes, and increase in appearance of hyaline droplets in the proximal tubular epithelium in males of the 1000 mg/kg group. These changes disappeared or diminished after withdrawal.
The NOEL is considered to be 40 mg/kg/day for both sexes.

3. Genetic Toxicity

3-1. Bacterial test 2)

Purity:Above 99%
Test species/strains:Salmonella typhimurium TA100, TA1535, TA98, TA1537, Escherichia coli WP2 uvrA
Test method:uidelines 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-Aminoacridine (TA1537)
+S9 mix; 2-Aminoanthracene (five strains)
　Doses:-S9 mix; 0, 39.1, 78.1, 156, 313, 625, 1250 μg/plate(four TA strains)
-S9 mix; 0, 78.1, 156, 313, 625, 1250, 2500 μg/plate(WP2 uvrA)
+S9 mix; 0, 156, 313, 625, 1250, 2500, 5000 μg/plate(TA100, TA98)
+S9 mix; 0, 78.1, 156, 313, 625, 1250, 2500 μg/plate(TA1535, TA1537)
+S9 mix; 0, 313, 625, 1250, 2500, 5000 μg/plate(WP2 uvrA)
　S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
　Plates/test:3(1 for cytotoxicity test)
　Number of replicates:2(plus 1 cytotoxicity test)
GLP:Yes

　Test results:

This chemical did not induce gene mutations in S. typhimurium and E. coli WP2 uvrA strains with or without S9 mix. Toxicity was observed at and above 625 μg/plate (TA1535, TA1537) and at and above 1250 μg/plate (TA100, TA98, WP2 uvrA) without S9 mix and at and above 1250 μg/plate (TA100, TA1535, TA1537), at and above 2500 μg/plate (TA98) and at 5000 μg/plate (WP2 uvrA) with S9 mix.

Genetic effects:
Salmonella typhimurium TA100, TA1535, TA98, 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:Over 99 %
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:0.5 % Carboxymethylcellulose sodium
　Positive controls:S9 mix; Mitomycin C
+S9 mix; Cyclophosphamide
　Doses:-S9 mix(short-term treatment); 0, 0.075, 0.15, 0.30 mg/mL
+S9 mix(short-term treatment); 0, 0.10, 0.20, 0.40 mg/mL
-S9 mix(continuous treatment for 24 hr); 0, 0.050, 0.10, 0.20 mg/mL
　S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
　Plates/test:2
GLP:Yes

　Test results:

Neither stuructural chromosome aberrations nor polyploidy were manifested in any treatment system.

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

1)The tests were performed by the Kashima Laboratory, Mitsubishi Chemical Safety Institute Ltd., 14 Sunayama, Hasaki-machi, Kashima-gun, Ibaraki, 314-0255, Japan. Tel +81-479-46-2871 Fax +81-479-46-2874
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