1,2,3-Trimethylbenzene

1,2,3-トリメチルベンゼン

[CAS No. 526-73-8]

Molecular formula: C9H12 Molecular weight: 120.20

ABSTRACT

With regard to repeat dose toxicity, increased salivation was evident in both sexes of the 1000 mg/kg group, along with suppression of body weight gain in 1000 mg/kg group females. Blood coagulation examination revealed prolonged APTT or PT in treated males and females of all groups. Absolute and relative liver weights were increased in both sexes of the 1000 mg/kg group, kidney weights were increased in males given 300 mg/kg or more, and thymus weights were decreased in females receiving 300 mg/kg or more. Histopathological examination revealed hepatocellular swelling in both sexes given 1000 mg/kg and in males of 300 mg/kg groups. Hyaline droplets and eosinophilic bodies in proximal tubules were observed in males of the 300 and 1000 mg/kg group and in 1000 mg/kg males, respectively. The NOEL for repeat dose toxicity is considered to be less than 100 mg/kg for both sexes.

Additional toxicity testing at doses of 0, 3, 10, 30 mg, did not reveal any substance related changes in terms of blood coagulation examination. Therefore, the NOEL for the repeat dose toxicity is considered to be 30 mg/kg/day for both sexes.

1,2,3-Trimethylbenzene was not mutagenic to Salmonella typhimurium, TA100, TA1535, TA98, TA1537 and Escherichia coli WP2 uvrA, with or without an exogeneous metabolic activation system.

1,2,3-Trimethylbenzene slightly increased incidences of structural chromosomal aberrations with an exogeneous metabolic activation system.

SUMMARIZED DATA FROM THE STUDIES

1. Repeat Dose Toxicity 1)

Purity	:	99.8%
Test species/strain	:	Rat/Crj:CD (SD)
Test method	:	Guidelines for 28-day Repeated Dose Toxicity Testing of Chemicals (Japan)
Route	:	Oral
Doses	:	0 (vehicle), 100, 300, 1000mg/kg/day
Number of animals/group	:	Males, 5 ; females, 5
Administration period	:	Males and females, 28 days
Terminal kill	:	Males and females, days 29 or 43
GLP	:	Yes

　 Test results:

Increased salivation was evident in both sexes of the 1000 mg/kg group, along with suppression of body weight gain in 1000 mg/kg females. Hematological examination revealed prolonged activated partial thromboplastin times in both sexes of all treatment groups, prolonged prothrombin times in all treated groups of males and in females receiving 300 mg/kg, and elevated fibrinogen levels in 1000 mg/kg males. Absolute and relative liver weights were increased in both sexes of the 1000 mg/kg group, kidney weights were increased in males given 300 mg/kg or more, and thymus weights were decreased in females given 300 mg/kg or more. Histopathological examination revealed hepatocellular swelling in both sexes receiving 1000 mg/kg and in 300 mg/kg males, hyaline droplets in 300 and 1000 mg/kg males, and eosinophilic bodies in the proximal tubules in 1000 mg/kg males.

The NOEL for repeat dose toxicity is seemed to be less than 100 mg/kg for both sexes.

2. Repeat Dose Toxicity (Additional test) 1)

Purity	:	99.8%
Test species/strain	:	Rat/Crj:CD (SD)
Test method	:	Guidelines for 28-day Repeated Dose Toxicity Testing of Chemicals (Japan)
Route	:	Oral
Doses	:	0 (vehicle), 3, 10, 30 mg/kg/day
Vehicle	:	Corn oil
Number of animals/group	:	Males, 5 ; females, 5
Administration period	:	Males and females, 28 days
Terminal kill	:	Males and females, days 29
GLP	:	Yes

　 Test results:

No test substance related changes were noted in terms of blood coagulation examination.

The NOEL for the repeat dose toxicity is considered to be 30 mg/kg/day for both sexes.

3. Genetic Toxicity

3-1. Bacterial test 1)

Purity	:	90.8%
Test species/strains	:	Salmonella typhimurium TA100, TA1535, TA98, TA1537, E. coli WP2 uvrA
Test methods	:	Guidelines for Screening Mutagenicity Testing of Chemicals (Japan)
Procedures	:	Pre-incubation method
Solvent	:	DMSO
Positive controls	:	-S9 mix AF-2 (TA100, TA98 and WP2 uvrA) Sodium azide (TA1535) 9-Aminoacridine (TA1537) +S9 mix 2-Aminoanthracene (all strains)
Doses	:	-S9 mix (all strains) 1.42, 2.84, 5.68, 11.4, 22.7, 45.4 μg/plate +S9 mix (TA100, TA1535 and TA1537) 1.42, 2.84, 5.68, 11.4, 22.7, 45.4 μg/plate +S9 mix (TA98 and WP2 uvrA) 5.68, 11.4, 22.7, 45.4, 90.8, 182 μg/plate
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 gene mutations in the S. typhimurium and E. coli strains.

Genetic effects:

S.typhimurium TA100, TA1535, TA98 and TA1537

	+	?	-
without metabolic activation:	[ ]	[ ]	[*]
with metabolic activation:	[ ]	[ ]	[*]

E. coli WP2 uvrA

	+	?	-
without metabolic activation	[ ]	[ ]	[*]
with metabolic activation	[ ]	[ ]	[*]

3-2. Non-bacterial in vitro test (chromosomal aberration test) 1)

Purity	:	90.8%
Type of cell used	:	Chinese hamster lung (CHL) cells
Test method	:	Guidelines for Screening Mutagenicity Testing of Chemicals (Japan)
Solvent	:	DMSO
Positive controls	:	long-term treatment; Mitomycin C (24 h and 48 h) short-term treatment; Cyclophosphamide (+S9 and -S9 mix)
Doses	:	long-term treatment; 90.0, 180, 360 μg/ml (24 h) long-term treatment; 60.0, 120, 240 μg/ml (48 h) short-term treatment; 120, 240, 480, 960 μg/ml (+S9 mix) short-term treatment; 120, 240, 480 μg/ml (-S9 mix)
S-9	:	Rat liver, induced with phenobarbital and 5,6-benzoflavone
Plates/test	:	2
GLP	:	Yes

　 Test results:

This chemical slightly increased incidences of structural chromosomal aberrations with an exogeneous metabolic activation system. Clear reproducibility was obtained the confirmation study.

Genotoxic effects:

	clastogenicity			polyploidy
	+	?	-	+	?	-
without metabolic activation:	[ ]	[ ]	[*]	[ ]	[ ]	[*]
with metabolic activation:	[ ]	[*]	[ ]	[ ]	[ ]	[*]

1) The tests were performed by the Biosafety Research Center, Foods, Drugs and Pesticides (An-pyo Center), Japan, 582-2 Shioshinden Arahama, Fukude-cho, Iwata-gun, Shizuoka, 437-12, Japan. Tel +81-538-58-1266 Fax +81-538-58-1393