3,5-Dimethylaniline

3,5-ジメチルアニリン


[CAS No. 108-69-0]

3,5-Xylidine

3,5-キシリジン

Molecular formula: C8H11N Molecular weight: 121.20

ABSTRACT

3,5-Dimethylaniline was studied for oral toxicity in rats in a 28-day repeat dose toxicity test at doses of 0, 10, 60 and 360 mg/kg.

Cyanosis, blanching, salivation, exophthalmos and staggering gait were observed in males and/or females of the 360 mg/kg group, along with decreased body weight gain and food consumption. Urinalysis showed increase in urine volume, increases in sodium, potassium and chloride excretion, and decreases in osmotic pressure and specific gravity in males and females of the 360 mg/kg group. Hematological examination showed increases in methemoglobin and reticulocytes, and decreases in erythrocytes, hemoglobin and hematocrit in males and females of the 60 mg/kg and 360 mg/kg groups. Further, increase in leukocytes in males and females of the 360 mg/kg group, increase in segmented neutrophils in males of the 360 mg/kg group, and shortening of activated partial thromboplastin time in females of the 360 mg/kg group were detected. Blood chemical examination showed increases in total bilirubin, GOT, GPT, phospholipids and inorganic phosphorus in males and females of the 360 mg/kg group. Further, decreases in potassium and chloride in males of the 360 mg/kg group, and increases in total cholesterol and calcium in females of the 360 mg/kg group were detected. Spleen weights were increased in males and females of the 60 mg/kg and 360 mg/kg groups, and the thyroid, liver and kidney weights in both sexes of the 360 mg/kg group. In addition, the testis weights were increased in the 360 mg/kg group. Histopathologically, hemosiderin deposits in the liver and spleen, and extramedullary hematopoiesis of the spleen were apparent in males and females of the 60 mg/kg and 360 mg/kg groups. Hemosiderin deposits in the kidney and extramedullary hematopoiesis in the liver were also observed in males and females of the 360 mg/kg group. Hypertrophy of hepatocytes and follicular cells in the thyroid was noted in males of the 60 mg/kg group and males and females of the 360 mg/kg group. In the kidney, papillary necrosis was observed in males and females of the 360 mg/kg group, and hyaline droplets in the tubular epithelium in males of the 360 mg/kg group. In the recovery test, papillary necrosis in the kidney, and hemosiderin deposit in the liver, spleen and kidney persisted in males and females of the 360mg/kg group. However, the other changes observed during the administration period demonstrated recovery. The NOEL is considered to be 10 mg/kg/day for males and females.

3,5-Dimethylaniline induced structural chromosomal aberrations in CHL/IU cells at the highest concentration (900μg/ml) after a 6 hr short-term treatment with and without exogenous metabolic activation. Polyploidy was not induced under the conditions of the present study.

SUMMARIZED DATA FROM THE STUDIES

1. Repeat Dose Toxicity１）

Purity:99.9%
Test species/strain:Rat/Crj:CD (SD)
Test method:Guidelines for 28-day Repeat Dose Toxicity Testing of Chemicals (Japan)
　Route:Oral (gavage)
　Dosage:0 (vehicle), 10, 60, 360 mg/kg/day
　Number of animals:Males, 6 and 12 (0, 360 mg/kg)
Females, 6 and 12 (0, 360 mg/kg)
　Vehicle:Corn oil
　Administration period:Males and females, 28 days
　Terminal kill:Days 29 or 43
GLP:Yes

　Test results:

Cyanosis, blanching, salivation, exophthalmos and staggering gait were observed in males and/or females of the 360 mg/kg group, along with decreased body weight gain and food consumption. Urinalysis showed increase in urine volume, and sodium, potassium and chloride excretion, and decreased osmotic pressure and specific gravity in males and females of the 360 mg/kg group. Hematological examination showed increases in methemoglobin and reticulocytes, and decreases in erythrocytes, hemoglobin and hematocrit in males and females of the 60 mg/kg and 360 mg/kg groups. Further, increase in leukocytes in males and females of the 360 mg/kg group, increase in segmented neutrophils in males of the 360 mg/kg group, and shortening of activated partial thromboplastin time in females of the 360 mg/kg group were detected. Blood chemical examination showed increases in total bilirubin, GOT, GPT, phospholipids and inorganic phosphorus in males and females of the 360 mg/kg group. Further, decreases in potassium and chloride in males of the 360 mg/kg group, and increases in total cholesterol and calcium in females of the 360 mg/kg group were detected. Spleen weights were increased in males and females of the 60 mg/kg and 360 mg/kg groups, and the thyroid, liver and kidney weights were increased in males and females of the 360 mg/kg group. In addition, the testis weights were increased in the 360 mg/kg group. Histopathologically, hemosiderin deposits in the liver and spleen, and extramedullary hematopoiesis of the spleen were noted in males and females of the 60 mg/kg and 360 mg/kg groups. Hemosiderin deposits in the kidney and extramedullary hematopoiesis in the liver were also observed in males and females of the 360mg/kg group. Hypertrophy of hepatocytes and follicular cells in the thyroid was apparent in males of the 60 mg/kg group and males and females of the 360 mg/kg group. In the kidneys, papillary necrosis was observed in males and females of the 360 mg/kg group, and hyaline droplets in the tubular epithelium in males of the 360 mg/kg group. In the recovery test, renal papillary necrosis and hemosiderin deposits in the liver, spleen and kidney persisted in males and females of the 360mg/kg group. However the other changes observed during the administration period demonstrated recovery.

The NOEL is considered to be 10 mg/kg/day for males and females.

2. Genetic Toxicity

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

Purity:99.9 %
Type of cell used:Chinese hamster CHL/IU cells
Test method:OECD Guidelines No. 473 and Guidelines for Screening Mutagenicity Testing of Chemicals (Japan)
　Solvent:DMSO
　Positive controls:-S9 mix, Mitomycin C +S9 mix, Benzo[a]pyrene
　Doses:-S9 mix (24 hr continuous treatment): 0, 75, 150, 300, 600μg/ml
-S9 mix (48 hr continuous treatment): 0, 75, 150, 300, 600μg/ml
-S9 mix (6 hr short-term treatment): 0, 113, 225, 450, 900μg/ml
+S9 mix (6 hr short-term treatment): 0, 113, 225, 450, 900μg/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.
At the highest concentration (900μg/ml) after 6 hr short-term treatment with and without exogenous metabolic activation, 22.5 and 12.0% cells demonstrated structural chromosomal aberrations including gaps.

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

1)The tests were performed by Safety Assessment Laboratory, Panapharm Laboratories Co., Ltd. 1285 Kurisaki-machi, Uto-shi, Kumamoto, 869-04, Japan Tel +81-964-23-5111 Fax +81-964-23-2282
2)The tests were performed by the Mitsubishi Chemical Safety Institute Ltd., 14 Sunayama, Hasaki-machi, Kashima-gun, Ibaraki, 314-02, Japan. Tel +81-479-46-2871 Fax +81-479-46-2874