3-Methoxybenzenamine

3-メトキシベンゼナミン


CAS No. 536-90-3

m-Methoxyaniline / m-Anisidine

m−メトキシアニリン/m−アニシジン

3-Methoxybenzenamine was studied for oral toxicity in rats in a single dose toxicity study at doses of 200, 300, 500, 800,1300 and 2000 mg/kg and in an OECD combined repeat dose and reproductive/developmental toxicity screening test at doses of 0, 2.4, 12, 60 and 300 mg/kg/day. 3-Methoxybenzenamine was also tested for mutagenicity with assays for reverse mutation in bacteria, chromosomal aberrations in cultured Chinese hamster (CHL) cells and induction of micronuclei in mice.

The single dose oral toxicity revealed the LD50s of 526 mg/kg when administerd in corn oil and above 300 mg/kg in both sexes with distilled water as the vehicle.

For repeat dose toxicity, 3-methoxybenzenamine caused changes such as salivation, brown urine, hemorrhage from the vagina, lowering of body weight gain, decrease in food consumption and splenomegaly in the 300 mg/kg/day males and females. The males at doses of 60 mg/kg or more showed hemolytic anemia, significant increases in blood total bilirubin, inorganic phosphorus and Na, decreases in total protein, glucose and Ca, and congestion and decreased cellularity of B-cell areas evident on histopathological examination of spleens. Extramedullary hematopoiesis and brown pigmentation were observed in the 2.4 mg/kg or higher and the 12 mg/kg or higher dose groups, respectively. These findings suggest that 3-Methoxybenzenamine affects the hematopoietic system, and hepatic and renal functions. NOEL for repeat dose toxicity was less than 2.4 mg/kg/day in males and females. For reproductive/developmental toxicity, all dams in the 300 mg/kg group failed to deliver pups. Their copulation and fertility, however, were not affected. Since necropsy of these dams revealed neonatal death in the early pregnancy period, the test chemical is suggested to have lethal effects on the fetus or neonates. NOELs for reproductive performance were 300 mg/kg/day in males and 60 mg/kg/day in females. The NOEL for offspring development was 60mg/kg/day.

3-Methoxybenzenamine was mutagenic for S. typhimurium, TA98 with metabolic activation, and not mutagenic for TA100, TA97 and TA102 with or without exogenous metabolic activation up to 5000 μg/plate. This chemical induced chromosomal aberrations in CHL cells without exogenous metabolic activation. Polyploidy was not evident under the assay conditions. The test chemical also induced micronucleated polychromatic erythrocytes in male BDF1 mouse bone marrow 72 h after treatment at a dose of 800 mg/kg.

3-Methoxybenzenamine[536-90-3]

1. Single Dose Oral Toxicity 1)

Purity:> 98%
Test species/strain:Rat/Crj:CD (SD)
Test method:OECD Guideline 401
 Doses:200, 300, 500, 800, 1300, 2000 mg/kg (in corn oil)
200, 300 mg/kg (in distilled water)
 Number of animals:Male, 5; Female, 5/group
GLP:Yes
Test results:LD50: LD50: Male and Female, 526 mg/kg in corn oil
Male and Female, 300 mg/kg or more in distilled water

2. Repeat Dose and Reproductive/Developmental Toxicity 1)

Purity:> 98 %
Test species/strain:Rat/Crj:CD (SD)
Test method:OECD Combined Repeat Dose and Reproductive/Developmental Toxicity Screening Test
 Route:Oral (gavage)
 Doses:0 (vehicle), 2.4, 12, 60, 300 mg/kg/day
 Number of animals:Male,12; Female,12
 Vehicle:Corn oil
 Administration period:Male, 50 days
Female, from 14 days before mating to day 3 of lactation
 Terminal kill:Male, day 51
Female, day 4 of lactation
GLP:Yes

 Test results:

<Repeat dose toxicity>
The test substance caused changes such as salivation, brown urine, hemorrhage from the vagina, lowering of body weights, decrease in food consumption, and splenomegaly on necropsy in the 300 mg/kg/day males and females. The males dosed with 60 mg/kg/day or more showed hemolytic anemia, significant increases in serum total bilirubin, inorganic phosphorus and Na, decreases in total protein, glucose and Ca, and congestion and decreased cellularity of B-cell areas evident on the histopathological examination of the spleens. Extramedullary hematopoiesis and brown pigmentation were respectively observed in groups receiving 2.4 mg/kg/day or more and the 12mg/kg/day or more. These findings suggest that the test substance affects the hematopoietic system, hepatic and renal functions.

NOEL: < 2.4 mg/kg/day

<Reproductive and developmental toxicity>
All dams in the 300mg/kg group failed deliver pups. Their copulation and fertility, however, were not affected. Since necropsy of these dams revealed neonatal death in the early pregnancy period, the test chemical is suggested to have lethal effects on the fetus or neonates.

NOEL for P generation: Male 300 mg/kg/day, Female 60 mg/kg/day
NOEL for F1 generation: 60 mg/kg/day

3. Genetic Toxicity

3-1 Bacterial test 2)

Purity:99 %
Test species/strains:S. typhimurium TA100, TA98, TA102, TA97
Test method:Maron & Ames (1983)
 Procedure:Preincubation assay
 Solvent:DMSO
 Positive controls:-S9, AF-2 (TA100, TA98) ICR-191 (TA97) Mitomycin C (TA102)
+S9, 2-Aminoanthracene (all strains)
 Doses:0, 25, 50, 100, 250, 500, 1000, 2500, 5000 μg/plate
 S-9:Mouse liver, induced with KC-400 (equivalent to PCB)
 Plates/test:2
 Number of replicates:Tests for TA98 with and without metabolic activation were repeated twice. Others were performed once.
 Test results:
Minimum concentration of test substance at which toxicity to bacteria was observed: No toxicity was observed up to a concentration of 5000 μg/plate with or without metabolic activation.

Genotoxic effects:
TA100, TA102, TA97

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

TA 98
+?-
with metabolic activation:[*][ ][ ]
without metabolic activation:[ ][ ][*]

3-2 Non-bacterial in vitro test (Chromosomal aberration) 2)

Purity:99 %
Type of cell used:Chinese hamster CHL cells
Test method:Guidelines for Screening Mutagenicity Testing of Chemicals (Japan)
 Solvent:DMSO
 Doses:-S9: 0, 0.25, 0.5, 0.75 mg/ml
+S9:0, 0.0313, 0.0625, 0.125 mg/ml
 S-9:Mouse, induced with PCB
 Plates/test:1

 Test results:
Chromosomal aberrations were induced by continuous treatment for 24 or 48 h with 3-methoxybenzenamine at a concentration of 0.5 mg/ml or more without exogenous metabolic activation. Polyploidy was not induced under the assay conditions.

Lowest concentration producing cytogenetic effects in vitro:
with metabolic activation: > 0.125 mg/ml
without metabolic activation: 0.5 mg/ml

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

3-3 Non-bacterial in vivo test (Micronucleus test) 3)

Purity:> 98 %
Test species/strain:Mouse/Crj:BDF1
Test method:Guidelines for Mutagenicity Testing of Chemicals (Japan)
 Doses:Male: 0, 200, 400, 800 mg/kg
Female: 0, 150, 300, 600 mg/kg
 Solvent:Olive oil
GLP:Yes

 Test results:
800 mg/kg of 3-methoxybenzenamine significantly increased micronucleated polychromatic erythrocytes in male mice 72 h after treatment. The result suggests that 3-methoxybenzenamine may induce micronuclei in bone marrow cells of male mouse, but exerts no inhibition effect on growth of the cells.

Lowest concentration producing toxicity: 800 mg/kg/day

Genotoxic effects:
+?-
Micronucleus test:[*][ ][ ]

1)The tests were performed by Nihon Bioresearch Inc., Hashima Laboratory, 6-104 Majima, Fukuju-cho, Hashima, Gifu, 501-62, Japan. Tel 81-583-92-6222 Fax 81-583-92-1284
2)The tests were performed by the Biological Safety Research Center, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158, Japan. Tel 81-3-3700-1141 Fax 81-3-3700-2348
3)The test was 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