o-Dichlorobenzene

o-ジクロロベンゼン


[CAS No. 95-50-1]

1,2-Dichlorobenzene

1,2-ジクロロベンゼン

Molecular formula: C6H4Cl2 Molecular weight: 147.00

ABSTRACT

A single dose oral toxicity test of o-dichlorobenzene revealed LD50 values of about 2000 mg/kg for males and 2000 mg/kg or more for females.

o-Dichlorobenzene was studied for oral toxicity in rats in a 28-day repeat dose toxicity test at doses of 0, 20, 100 and 500 mg/kg. No deaths were observed in either sex. Repeated administration of the test substance caused centrilobular hypertrophy of hepatocytes in the animals of both sexes at 100 mg/kg and more. Besides, in the male animals given 100 mg/kg and more, and in the female animals of the 500 mg/kg group, single cell necrosis in the centrilobular zone was observed. In the male animals given 100 mg/kg or more, the frequency and degree of intracytoplasmic eosinophilic inclusion bodies in proximal renal tubules were significantly increased and this change was thought to be due to the test substance administered. Thus, the NOEL for the 28-day repeat dose oral toxicity test of o-dichlorobenzene is considered to be 20 mg/kg/day for males and females.

Reverse mutation assays using microorganisms (Salmonella typhimurium, Escherichia coli) were conducted to assess the potential of o-dichlorobenzene to induce gene mutations.

o-Dichlorobenzene 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 o-dichlorobenzene to induce chromosomal aberrations.

o-Dichlorobenzene induced chromosomal aberrations in cultured cells under the conditions of this study.

SUMMARIZED DATA FROM THE STUDIES

1. Single Dose Oral Toxicity 1)

Purity:99.7 %
Test species/strains:Rat/Crj:CD(SD)IGS
Test method:OECD Test Guideline 401
　Route:Oral (gavage)
　Doses:Males, 0(vehicle), 500, 1000, 2000 mg/kg
Females, 2000 mg/kg
　Number of animals/group:Males, 5; females, 5
　Vehicle:Corn oil
GLP:Yes

　Test results:

Deaths occurred of male rats given 2000 mg/kg. Clinical signs of decrease in locomotor activity, adoption of a prone position, tremors, irregular respiration and salivation were observed. Body weights of the treated animals were dose dependently lower than those of the control group. At autopsy, pale discoloration of the liver and accumulation of dark colored fluid in the urinary bladder were observed in dead animals. Histopathologically, the liver showed degeneration and/or necrosis of hepatocytes accentuated in the centrilobular area in dead animals and centrilobular hypertrophy of hepatocytes in a survivors.
The LD50 values were estimated to be about 2000 mg/kg for males and 2000 mg/kg or more for females.

2. Repeat Dose Toxicity 1)

Purity:99.7 %
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)
　Doses:0(vehicle), 20, 100, 500 mg/kg/day
　Number of animals/group:Males, 10; females, 10(0, 500 mg/kg)
Males, 5; females, 5(20, 100 mg/kg)
　Vehicle:Corn oil
　Administration period:Males and females, 28 days
　Terminal kill:Males and females, on days 29 and 43
GLP:Yes

　Test results:

In the repeat dose study, no deaths were observed in either sex. In the initial administration period, food consumption was decreased in the animals of both sexes in the 500 mg/kg group and the body weights were less than those in the control group from the 4th day of administration to the end of the recovery period. The decrease in body weight of male animals was significant up to the 4th day of the recovery period. In blood chemistry, total cholesterol concentration and γ-GTP activity tended to be increased or significantly increased in the animals of both sexes in the 500 mg/kg group. The liver and kidney absolute weights, or the weights of these organs relative to the body weight were increased in male animals given 100 mg/kg and more and in the female animals given 500 mg/kg. On autopsy at the end of administration period, large and dark colored livers were found mainly in the high dose group. On histopathological examination, centrilobular hypertrophy of the hepatocytes was found in the animals of both sexes given 100 mg/kg and more, and the degree of this change tended to be dose-dependent. Additionally, single cell necrosis in the centrilobular zone was frequently observed in animals of both sexes in the 500 mg/kg group and in male animals given 100 mg/kg. The frequency and degree of intracytoplasmic eosinophilic inclusion bodies found in the proximal renal tubules were significantly increased in the male animals given 100 mg/kg and more. At the end of recovery period, however, such morphological changes observed at the end of administration tended to be attenuated or abolished.
Thus, the NOEL for the 28-day repeat dose toxicity is considered to be 20 mg/kg/day for males and females.

3. Genetic Toxicity

3-1. Bacterial test 2)

Purity:99.7 %
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:DMSO
　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; 0, 2.44, 4.88, 9.77, 19.5, 39.1, 78.1 μg/plate(TA100)
-S9 mix; 0, 9.77, 19.5, 39.1, 78.1, 156, 313 μg/plate(TA1535, WP2 uvrA, TA98, TA1537)
+S9 mix; 0, 9.77, 19.5, 39.1, 78.1, 156, 313 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 increase in revertant colonies was observed in the test with either the non-activation method (-S9)or activation (+S9).

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:99.7 %
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:DMSO
　Positive controls:-S9 mix; Mitomycin C
+S9 mix; Cyclophosphamide
　Doses:-S9 mix(short-term treatment); 0, 80.0, 130, 180, 230 μg/mL
+S9 mix(short-term treatment); 0, 130, 180, 230, 280 μg/mL
+S9 mix(short-term treatment, confirmative test); 0, 230, 240, 250, 260, 270 μg/mL
　S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
　Plates/test:2
GLP:Yes

　Test results:

Slight increase in chromosomal aberrations was observed in the test with the short-term treatment (+S9).

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

1)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
2)The tests were performed by the Biosafety Research Center, Foods, Drugs and Pesticides(An-pyo Center), 582-2 Shioshinden, Fukude-cho, Iwata-gun, Shizuoka, 437-1213, Japan. Tel +81-538-58-1266 Fax +81-538-58-1393