3a,4,7,7a-Tetrahydro-1H-indene

3a,4,7,7a-テトラヒドロ-1H-インデン

[CAS No. 3048-65-5]

3a, 4, 7, 7a-Tetrahydroindene

3a, 4, 7, 7a-テトラヒドロインデン

Molecular formula: C9H12 Molecular weight: 120.21

ABSTRACT

As a part of OECD high production volume chemicals program, an oral combined repeat dose and reproductive/development toxicity screening test of 3a,4,7,7a-tetrahydro-1H-indene was carried out in male and female rats. The test compound was administered at doses of 67, 200 and 600 mg/kg/day to males for 46 days before, during and after the mating period, and to females before and during the mating period, during the gestation period, and until day 3 of lactation.

In the repeat dose toxicity test, body weight gain was suppressed in males and females given 200 and 600 mg/kg. Hematological examination revealed slight decreases in red blood cell counts, hematocrit values and hemoglobin concentrations in males given 600 mg/kg. Absolute liver weights were increased or tended to increase and relative liver weights were increased in males given 600 mg/kg and females given 200 mg/kg and more. Absolute weights of the right and left kidneys were increased or tended to be increased and relative kidney weights were increased in males given 67 mg/kg and more and in females given 600 mg/kg. Histopathological examination revealed slight hypertrophy of centrilobular hepatocytes in males and females given 600 mg/kg, increased incidences of hyaline droplets and eosinophilic bodies of the proximal tubular epithelium in males given 67 mg/kg and more, and slight regeneration of renal tubular epithelium in males given 200 and 600 mg/kg. On the basis of these findings, NOELs for repeat dose toxicity were considered to be less than 67 mg/kg/day for males, and 67 mg/kg/day for females, respectively.

With regard to reproductive ability, no effects were detected in males. Gestation length was prolonged, and number of corpora lutea and implantation sites decreased in females given 600 mg/kg. Numbers of pups born and those born alive were decreased in the 600 mg/kg group. On the basis of these findings, NOELs for reproductive/developmental toxicity were considered to be 600 mg/kg/day for males and 200 mg/kg/day for females and for offspring, respectively.

3a,4,7,7a-Tetrahydro-1H-indene was not mutagenic in Salmonella typhimurium TA100, TA1535, TA98, TA1537 and Escherichia coli WP2 uvrA, with or without an exogeneous metabolic activation system.

Genotoxicity of 3a,4,7,7a-tetrahydro-1H-indene was studied by chromosomal aberration test in cultured Chinese hamster lung (CHL/IU) cells. Structural chromosomal aberrations were induced at 0.10 mg/ml (high concentration) with short-term treatment and an exogenous metabolic activation system. Polyploidy was not induced in any treatment group.

SUMMARIZED DATA FROM THE STUDIES

1. Repeat Dose and Reproductive/Developmental Toxicity１）

Purity	:	99.0%
Test species/strain	:	Rat/Crj:CD (SD)
Test method	:	OECD Combined Repeat Dose and Reproductive/Developmental Toxicity Screening Test
Route	:	Oral (gavage)
Dosage	:	0 (vehicle), 67, 200 and 600 mg/kg/day
Number of animals	:	Males, 5; females, 5/group
Vehicle	:	Olive oil
Administration period	:	Males, 46 days Females, from 14 days before mating to day 3 of lactation
Terminal kill	:	Males, day 47 Females, day 4 of lactation
GLP	:	Yes

　Test results:

Body weight gain was suppressed in males and females given 200 and 600 mg/kg. Hematological examination revealed slight decreases in red blood cell counts, hematocrit values and hemoglobin concentrations in males given 600 mg/kg. Absolute liver weights were increased or tended to be increased and relative liver weights were increased in males given 600 mg/kg and females given 200 mg/kg and more. Absolute weights of the right and left kidneys were increased or tended to be increased and relative kidney weights were increased in males given 67 mg/kg and more and in females given 600 mg/kg. Histopathological examination revealed slight hypertrophy of centrilobular hepatocytes in males and females given 600 mg/kg, and increased incidences of hyaline droplets and eosinophilic bodies of the proximal tubular epithelium in males given 67 mg/kg and more, and a slight regeneration of renal tubular epithelium in males given 200 and 600 mg/kg. The NOELs for repeated dose toxicity were considered to be less than 67 mg/kg/day for males, and 67 mg/kg/day for females, respectively.

No effects were detected in males. Gestation length was prolonged, and numbers of corpora lutea and implantation sites were decreased in females given 600 mg/kg. Numbers of pups born and those born alive were decreased in the 600 mg/kg group. The NOELs for reproductive/developmental toxicity were considered to be 600 mg/kg/day for males and 200 mg/kg/day for females and for offspring, respectively.

2. Genetic Toxicity

2-1. Bacterial test２）

Purity	:	99.0 wt%
Test species/strains	:	Salmonella typhimurium, TA100, TA1535, TA98, TA1537, Escherichia coli WP2 uvrA
Test method	:	Guidelines for Screening Mutagenicity Testing of Chemicals (Japan) and OECD Guideline No. 471 and 472
Procedures	:	Pre-incubation method
Solvent	:	DMSO
Positive controls	:	-S9 mix, 2-(2-Furyl)-3-(5-nitro-2-furyl) acrylamide (TA100, TA98, WP2), Sodium azide (TA1535) and 9-Aminoacridine (TA1537) +S9 mix, 2-Aminoanthracene (five strains)
Doses	:	-S9 mix; 0, 3.91, 7.81, 15.6, 31.3, 62.5, 125 μg/plate (TA1535, TA1537) 0, 7.81 - 250 μg/plate (TA100, TA98, WP2) +S9 mix; 0, 7.81 - 250 μg/plate (TA1535, TA1537) 0, 15.6 - 500 μg/plate (TA100, TA98, WP2)
S9	:	Rat liver, induced with phenobarbital and 5,6-benzoflavone
Plates/test	:	3
Number of replicates	:	2
GLP	:	Yes

　Test results:

This chemical did not induce mutations in the S. typhimurium and E. coli strains. Toxicity was observed at 62.5 μg/plate (TA1535, TA1537), 125 μg/plate (TA100, TA98, WP2) without an S9 mix, and at 125 μg/plate (TA1535), 150 μg/plate (TA1537), 250 μg/plate (TA100, TA98, WP2) with an 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: [ ] [ ] [*]

2-2. 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 (Japan) and OECD Guideline No. 473
Solvent	:	Dimethylsulfoxide
Positive controls	:	-S9 mix, Mitomycin C +S9 mix, Cyclophosphamide
Doses	:	-S9 mix (continuous treatment):0, 0.013, 0.025, 0.050 mg/ml -S9 mix (short-term treatment):0, 0.013, 0.025, 0.050 mg/ml +S9 mix (short-term treatment):0, 0.025, 0.050, 0.10 mg/ml
S-9	:	Rat liver, induced with phenobarbital and 5,6-benzoflavone
Plates/test	:	2
GLP	:	Yes

　Test results:

Cytogenetic effects were seen as follows.

With the short-term treatment and an exogenous metabolic activation, structural chromosomal aberrations (14.5%, including gap) were induced at 0.10 mg/ml (high concentration). Polyploidy was not induced in any treatment group.

Lowest concentration producing cytogenetic effects in vitro:

With metabolic activation (short-term treatment)

:0.10 mg/ml (clastogenicity)

Genotoxic effects:

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

1) The tests were performed by the Safety Research Institute for Chemical Compounds Co., Ltd., 363-24, Shin-ei, Kiyota-ku, Sapporo, Hokkaido, 004, Japan. Tel +81-11-885-5031 Fax +81-11-885-5313

2) The tests were performed by the Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano-shi, Kanagawa, 257, Japan. Tel +81-463-82-4751 Fax +81-463-82-9627

1)	The tests were performed by the Safety Research Institute for Chemical Compounds Co., Ltd., 363-24, Shin-ei, Kiyota-ku, Sapporo, Hokkaido, 004, Japan. Tel +81-11-885-5031 Fax +81-11-885-5313
2)	The tests were performed by the Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano-shi, Kanagawa, 257, Japan. Tel +81-463-82-4751 Fax +81-463-82-9627