2,3-Dimethylaniline

2,3-ジメチルアニリン


[CAS No. 87-59-2]

2,3-Dimethylbenzenamine/2,3-Xylidine

2,3-ジメチルベンゼナミン/2,3-キシリジン

Molecular formula: C8H11N Molecular weight: 121.20

ABSTRACT

2,3-Dimethylaniline was studied for oral toxicity in rats in a 28-day repeat dose toxicity test at doses of 0, 12, 60 and 300 mg/kg.

Hematological and blood chemical changes associated with methemoglobinemia were noted in both sexes given 60 and 300 mg/kg. The spleen weight increased and gross enlargement was observed in both sexes given 300 mg/kg. Histopathologically, heavy deposits of hemosiderin in red pulp in females given 12 mg/kg and both sexes given 60 and 300 mg/kg, increased extramedullary hematopoiesis in both sexes given 300 mg/kg and congestion in males given 300 mg/kg were noted. Kidney weights were increased in both sexes given 300 mg/kg and histopathologically, papillary necrosis, dilatation of renal tubules and cellular infiltration in cortical interstitium in both sexes given 300 mg/kg, basophilia of renal tubules, mineralization of inner medulla and a high incidence of eosinophilic bodies in tubular epithelium in males given 300 mg/kg, and hyaline casts in males given 60 mg/kg and females given 300 mg/kg were observed. Liver weights were increased in females given 60 mg/kg and in both sexes receiving 300 mg/kg and histopathologically, hypertrophy of the centrilobular hepatocytes, bile duct proliferation, deposits of hemosiderin in Kupffer cells and extramedullary hematopoiesis were noted in both sexes given 300 mg/kg. In the bone marrow, increased hematopoiesis was evident in both sexes given 60 and 300 mg/kg. Almost all changes, except for those in the kidney, disappeared or were diminished after a 14-day recovery period. The NOEL is considered to be 12 mg/kg/day for males and less than 12 mg/kg/day for females.

2,3-Dimethylaniline was mutagenic in Salmonella typhimurium TA100, with an exogeneous metabolic activation system.

Genotoxicity of 2,3-dimethylaniline was studied by chromosomal aberration test in cultured Chinese hamster lung (CHL/IU) cells.

Structural chromosomal aberrations were induced at 0.60 mg/ml (high concentration) in the short-term treatment with an exogenous metabolic activation system. Polyploidy was not induced in any treatment groups.

SUMMARIZED DATA FROM THE STUDIES

1. Repeat Dose Toxicity １）

Purity:99.7 %
Test species/strain:Rat/Crj:CD (SD)
Test method:Guidelines for 28-Day Repeat Dose Toxicity Testing of Chemicals (Japan)
　Route:Oral (gavage)
　Doses:0 (vehicle), 12, 60, 300 mg/kg/day
　Number of animals:Males, 6; females, 6/group
　Vehicle:Olive oil
　Administration period:Males and females, 28 days
　Terminal kill:Days 29 or 43
GLP:Yes

　Test results:

A temporary decrease in food consumption was noted in males given 300 mg/kg during the early period of administration.

On urinalysis, decreases in pH and specific gravity and increases in bilirubin, occult blood, RBC and WBC in urinary sediment, water intake and urine volume in both sexes given 300 mg/kg, an increase in small round epithelial cells in urinary sediment in males given 300 mg/kg and an increase in urinary protein in females given 300 mg/kg were observed. Hematological and blood chemical changes associated with methemoglobinemia were noted in both sexes given 60 and 300 mg/kg. Spleen weights were increased and gross enlargement was evident in both sexes given 300 mg/kg and histopathologically, heavy deposits of hemosiderin in red pulp in females given 12 mg/kg and both sexes given 60 and 300 mg/kg, increased extramedullary hematopoiesis in both sexes given 300 mg/kg and congestion in males given 300 mg/kg were noted. Kidney weights were increased in both sexes given 300 mg/kg and histopathologically, papillary necrosis, dilatation of renal tubules and cellular infiltration in cortical interstitium in both sexes given 300 mg/kg, basophilia of renal tubules, mineralization of inner medulla and a high incidence of eosinophilic bodies in males given 300 mg/kg and hyaline casts in males given 60 mg/kg and females given 300 mg/kg were noted. Liver weights were increased in females given 60 mg/kg and both sexes given 300 mg/kg and histopathologically, hypertrophy of centrilobular hepatocytes, bile duct proliferation, deposits of hemosiderin in Kupffer cells and extramedullary hematopoiesis were apparent in both sexes given 300 mg/kg. In the bone marrow, increased hematopoiesis was noted in both sexes given 60 and 300 mg/kg. Almost all changes, except for those in the kidney, disappeared or were diminished after a 14-day recovery period. The NOEL is considered to be 12 mg/kg/day for males and less than 12 mg/kg/day for females.

2. Genetic Toxicity

2-1. Bacterial test２）

Purity:99.7 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 the 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, 78.1, 156, 313, 625, 1250, 2500 μg/plate (TA1537)
　0, 156 - 5000 μg/plate (TA100, TA1535, TA98, WP2)
+S9 mix;
　0, 78.1 - 2500 μg/plate (TA100)
　0, 156 - 5000 μg/plate (TA1535, TA98, TA1537, WP2)
　S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
　Plates/test:3
　Number of replicates:2
GLP:Yes

　Test results:

This chemical induced mutations in S. typhimurium TA100 with an S9 mix. Toxicity was observed at 1250 μg/plate (TA1537), 2500 μg/plate (TA100, TA1535, TA98), 5000 μg/plate (WP2) without an S9 mix, and at 1250 μg/plate (TA100), 2500 μg/plate (TA1537), 5000 μg/plate (TA1535, TA98, WP2) with an S9 mix.

Genetic effects:
Salmonella typhimurium TA100
+?-
Without metabolic activation:[ ][ ][*]
With metabolic activation:[*][ ][ ]

Salmonella typhimurium 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:99.7%
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, 0.10, 0.20, 0.40 mg/ml
-S9 mix (short-term treatment): 0, 0.15, 0.30, 0.60 mg/ml
+S9 mix (short-term treatment): 0, 0.15, 0.30, 0.60 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.
In the short-term treatment with exogenous metabolic activation, structural chromosomal aberrations (19.6%, including gap) were induced at 0.60 mg/ml (high concentration), though the cell numbers observed were low because of the strong cytotoxicity. Polyploidy was not induced in any treatment group.

Lowest concentration producing cytogenetic effects in vitro:
With metabolic activation (short-term treatment): 0.60 mg/ml (clastogenicity)

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

1)The tests were performed by Bozo Research Center Inc, 1284, Kamado, Gotemba-shi, Shizuoka, 412, Japan. Tel +81-550-82-2000 Fax +81-550-82-2379
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