4-Aminophenol

4-アミノフェノール

[CAS No. 123-30-8]

p-Aminophenol

p-アミノフェノール

Molecular formula: C6H7NO Molecular weight: 109.14

ABSTRACT

4-Aminophenol was studied for oral toxicity in rats in a 28-day repeat dose toxicity test at doses of 0, 4, 20, 100 and 500 mg/kg.

One male given 500 mg/kg died with renal necrosis on day 4 of the administration period. Decreased locomotor activity, body weight gain and food consumption and increased water intake were observed in the 500 mg/kg group. Hematological and blood chemical examinations revealed decreases in erythrocyte count, Ht and Hb and increases in reticulocyte count, MCH and albumin in the 500 mg/kg group. Dark brown urine and increases in specific gravity and epithelial cells were observed in the 100 and 500 mg/kg groups. The relative liver and spleen weights were increased in the 500 mg/kg group and the kidney weights in the 100 and 500 mg/kg groups. Histopathological examination revealed increases in extramedullary hematopoiesis and hemosiderin deposition in the spleen and basophilic renal tubules in the 100 and 500 mg/kg groups.

The NOEL for the repeat dose toxicity is considered to be 20 mg/kg/day for both sexes.

4-Aminophenol was not mutagenic in Salmonella typhimurium TA100, TA1535, TA98, TA1537 and Escherichia coli WP2 uvrA, with or without an exogenous metabolic activation system.

Genotoxicity of 4-aminophenol was studied by chromosomal aberration test in cultured Chinese hamster lung (CHL/IU) cells. Structural chromosomal aberrations were induced at 0.0025, 0.0050 and 0.010 mg/ml (all concentrations) with continuous treatment, and at 0.013 and 0.025 mg/ml (low and high concentrations) with short-term treatment, without an exogenous metabolic activation system. Polyploidy was not induced in any treatment group.

SUMMARIZED DATA FROM THE STUDIES

1. Repeat Dose Toxicity１）

Purity	:	99.0%
Test species/strain	:	Rat/Crj:CD (SD)
Test method	:	Guidelines for 28-Day Repeat Dose Toxicity Testing for Chemicals (Japan)
Route	:	Oral (gavage)
Dosage	:	0 (vehicle), 4, 20, 100, 500 mg/kg/day
Number of animals	:	Males, 6; females, 6/group
Vehicle	:	0.5% Sodium Carboxymethyl Cellulose solution
Administration period	:	Males and females, 28 days
Terminal kill	:	Days 29 or 43
GLP	:	Yes

　Test results:

One male given 500 mg/kg died on day 4 of the administration period. This death may have been caused by renal necrosis based on the microscopic findings. Decreased locomotor activity was observed in one other male given 500 mg/kg. Body weights and food consumption were decreased in males given 500 mg/kg. Water intake was increased in both sexes given 500 mg/kg. Hematological examination revealed a decrease in erythrocyte count in both sexes given 500 mg/kg; decreases in Ht and Hb and an increase in reticulocyte count in females given 500 mg/kg; and an increase in MCH in males given 500 mg/kg. Blood chemical examinations revealed an increase in albumin in males given 500 mg/kg. Dark brown urine was observed in both sexes receiving 100 and 500 mg/kg. Urinalysis revealed an increase in specific gravity in females given 500 mg/kg and an increase in epithelial cells in females given 100 mg/kg and in both sexes given 500 mg/kg. The absolute and relative liver weights were increased in both sexes, and the spleen relative weights in females given 500 mg/kg. Histopathologically, extramedullary hematopoiesis was noted in both sexes and hemosiderin deposition in females given 500 mg/kg. The kidney absolute and relative weights were increased in females given 100 mg/kg and in both sexes given 500 mg/kg and histopathologically, basophilic renal tubules were noted in both sexes given 100 and 500 mg/kg. These changes disappeared or tended to recover during the recovery period.

The NOEL for the repeat dose toxicity is considered to be 20 mg/kg/day for both sexes.

2. Genetic Toxicity

2-1. Bacterial test２）

Purity	:	99.0 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 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, 62.5, 125, 250, 500, 1000, 2000 μg/plate (TA100, TA1535, TA1537) 0, 156 - 5000 μg/plate (TA98) 0, 313 - 5000 μg/plate (WP2) +S9 mix; 0, 156 - 5000 μg/plate (TA100, TA1535, TA1537) 0, 313 - 5000 μg/plate (TA98, WP2)
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 mutations in the S. typhimurium and E. coli strains. Toxicity was observed at 1000 μg/plate (TA100, TA1535, TA1537), 2500 μg/plate (TA98), 5000 μg/plate (WP2) without an S9 mix, and 5000 μg/plate (TA100, TA1535, TA1537) with an S9 mix. Toxicity was not observed in the other cases.

Genetic effects:
Salmonella typhimurium TA100, 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	:	99.0 wt%
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, 0.0025, 0.0050, 0.010 mg/ml -S9 mix (short-term treatment):0, 0.013, 0.025 mg/ml +S9 mix (short-term treatment):0, 0.28, 0.55, 1.1 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.

With continuous treatment, structural chromosomal aberrations (4.0 - 50.0 %, including gap) were induced at 0.0025, 0.0050 and 0.010 mg/ml (all concentrations). With short-term treatment without an exogenous metabolic activation system, structural chromosomal aberrations (4.0 and 9.0 %, including gap) were induced at 0.013 and 0.025 mg/ml (low and high concentrations). With short-term treatment with the metabolic activation system, structural chromosomal aberrations (5.5 and 6.5%, including gap) were significantly increased at 0.28 and 1.1 mg/ml (low and high concentrations), respectively. However a trend test showed no dose-dependency. Polyploidy was not induced in any treatment group.

Lowest concentration producing cytogenetic effects in vitro:

Without metabolic activation (continuous treatment): 0.0025 mg/ml (clastogenicity)

Without metabolic activation (short-term treatment): 0.013 mg/ml (clastogenicity)

With metabolic activation (short-term treatment): 0.28 mg/ml (clastogenicity)

Genotoxic effects:

	clastogenicity			polyploidy
	+	?	-	+	?	-
Without metabolic activation:	[*]	[ ]	[ ]	[ ]	[ ]	[*]
With metabolic activation:	[ ]	[*]	[ ]	[ ]	[ ]	[*]

1) 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
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

1)	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
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