1-Aminoanthraquinone

1-アミノアントラキノン

CAS No. 82-45-1

1-Amino-9,10-anthracenedione

1-アミノ-9,10-アントラセンジオン

Molecular formula: C14H9NO2 Molecular weight: 223.24

ABSTRACT

With regard to repeat dose toxicity, in the compound-treated females, deterioration of general condition was observed, with some females becoming moribund in the 200 mg/kg group and 2 females dying in the 1000 mg/kg group.

In males the erythrocyte count, hemoglobin, hematocrit and mean corpuscular hemoglobin were decreased, and the reticulocyte count was increased in the 200 mg/kg and 1000 mg/kg groups. In females, the reticulocyte ratio, mean corpuscular hemoglobin and leukocyte count were increased in the 1000 mg/kg group. In addition, activated partial thromboplastin time tended to be prolonged dose-dependently. At necropsy, in males of the 200 mg/kg or more groups, the spleen showed dark discoloration, and in the 1000 mg/kg group swelling of the spleen was observed. In females, thymic atrophy, splenic atrophy, adrenal swelling, renal discoloration and hepatic dark discoloration were observed in all of the treatment groups. Liver and spleen weights were increased in males of the 200 mg/kg or more groups, and spleen weights were increased in females of the 1000 mg/kg group.

In the histopathological findings, formation of the eosinophilic bodies was increased in the kidneys in males of the all treatment groups. In the spleen remarkable changes were pigmentation and extramedullary hematopoiesis in the 200 and 1000 mg/kg groups. In females of the 1000 mg/kg group, necrosis and regeneration in the cortical renal tubules were increased, as well as tubular regeneration in the renal medulla. Increase in pigmentation of Kupffer cells was found in the liver in the 1000 mg/kg group.

With regard to the reproductive/developmental toxicity, in some females of all the treatment groups, nursing behavior disappeared. Viability of pups on day 4 after birth was decreased in the 1000 mg/kg group. In conclusion, NOELs for toxicity in parental animals in both sex are suggested to be less than 40 mg/kg/day, and NOELs for reproductive/developmental toxicity in males to be 1000 mg/kg/day and in females to be less than 40 mg/kg/day.

1-Aminoanthraquinone was not mutagenic in Salmonella typhimurium TA100, TA98, TA1535, TA1537 and Escherichia coli WP2 uvrA.

Neither structural chromosomal aberrations nor polyploidy were induced in CHL/IU cells up to the concentration giving 50% cell growth inhibition or the limit concentration of 10 mM, in the absence or presence of an exogenous metabolic activation system.

SUMMARIZED DATA FROM THE STUDIES

1. Repeat Dose and Reproductive/Developmental Toxicity1)

Purity	:	98.7 wt%
Test species/strain	:	Rat/Crj:CD (Sprague-Dawley)
Test method	:	OECD Combined Repeat Dose and Reproductive/Developmental Toxicity Screening Test
Route	:	Oral (gavage)
Doses	:	0 (Vehicle), 40, 200, 1000 mg/kg/day
Number of animals	:	Males, 13/group; Females, 13/group
Vehicle	:	Corn oil
Administration period	:	Males, 42 days Females, from 14 days prior to mating to Day 3 of lactation
Terminal killing	:	Males, Day 43 Females, Day 4 of lactation of lactation
GLP	:	Yes

　Test results:

<Repeat dose toxicity>

In the treated animals, deterioration of general condition was observed as a toxic effect of the compound: females were debilitated showing bloody staining around the vagina, stained hair coat, labored respiration, decreased activity, blephaloptosis and pallor, and they did not show nursing behavior. Some recovered to normal after pups died. However, in the 200 mg/kg group some animals became moribund and in the 1000 mg/kg 2 animals died. There was no toxicity in terms of loss of general condition in males and nonpregnant animals.

There were no toxic effects evident from body weight and food consumption values in animals of either sex in any compound treatment group .

In males, the erythrocyte count, hemoglobin, hematocrit and mean corpuscular hemoglobin were decreased, and the reticulocyte count was increased in the groups treated with 200 mg/kg or 1000 mg/kg. In addition, the mean corpuscular volume and mean corpuscular hemoglobin were significantly increased in the 1000 mg/kg group. Furthermore, the platelet count, was also increased in the 1000 mg/kg group. In the differential leukocyte count, lobulated leukocytes and lymphocytes were significantly decreased in the 200 mg/kg group. However these changes were slight, and in the 40 mg/kg group there were no toxic changes evident on hematological examination. In the groups treated with 200 mg/kg or more, the chloride level was dose-dependently and significantly decreased. The potassium level was also decreased in the 1000 mg/kg group. In dams with surviving offspring all groups including the control tended to be anemic when necropsied on day 4 postpartum. In the 1000 mg/kg group the reticulocyte ratio, mean corpuscula r hemoglobin and leukocyte count were significantly increased. In the dams where pups died and in sacrificed animals moribund changes were similar to those with surviving offspring. However, no reticulocytes were found in sacrificed animals in a moribund condition in the 1000 mg/kg group. Clotting time did not change significantly. However, activated partial thromboplastin time tended to be prolonged dose-dependently, and the prolongation was marked in moribund animals.

t necropsy, the spleen showed dark discoloration in most animals in the groups treated with 200 mg/kg or more, and in the 1000 mg/kg group swelling of the spleen was also observed. In females, thymic atrophy, splenic atrophy and dark discoloration, adrenal swelling, renal discoloration and hepatic dark discoloration were observed in all the treated groups.

The liver weight relative to body weight, and absolute and relative spleen weights were significantly increased in males of the groups treated with 200 mg/kg or more. In females, a dose-dependent increase in the spleen weight was observed in nursing dams sacrificed on day 4 postpartum, and in the 1000 mg/kg group the relative spleen weight was significantly increased.

On histopathological examination, males of all compound-treated groups, formation of the eosinophilic bodies was found to be significantly increased in the kidney as compared with the control group. In the spleen, remarkable changes were pigmentation and extramedullary hematopoiesis, and congestion was also observed in the red pulp in the groups treated with 200 mg/kg or more. In females, necrosis and regeneration in the cortical renal tubules were significantly increased as compared with the controls. Tubular regeneration was also increased in the renal medulla in the 1000 mg/kg group. In the spleen, pigmentation and extramedullary hematopoiesis were significantly increased in the groups treated with 200 mg/kg or more, and a significant increase in pigmentation of kupffer cells was shown in the liver in the 1000 mg/kg group. The NOELs for repeat dose toxicity in parent animals in both sex are suggested to be less than 40 mg/kg/day.

<Reproductive and developmental toxicity>

There were no significant differences between the controls and each of the compound treatment groups in the mating rate and the duration from cohabitation to successful mating. Neither implantation nor pregnancy rates were significantly different between the control and compound treatment groups. No abnormal deliveries related to the compound administration were observed in any of the groups. In some of the animals treated with compound, nursing behavior disappeared, and in the 1000 mg/kg group only 5 of 13 dams continued nursing until day postpartum. There were no significant differences in numbers of corpora lutea and implants, and implantation rate, parturition rate and duration of pregnancy between the control and compound treatment groups.

Viability on day 0 after birth in the compound treatment groups did not differ from that in the control group. However, viability on day 4 after birth in the 1000 mg/kg group was decreased. There were no significant differences in pup weight between groups. No external and visceral abnormalities were found. The NOELs for reproductive/developmental toxicity in males are suggested to be 1000 mg/kg/day and that in females to be less than 40 mg/kg/day.

2. Genetic Toxicity

2-1. Bacterial test1)

Purity	:	98.7%
Test species/strain	:	S.typhimurium TA100, TA1535, TA98, TA1537 E. coli WP2 uvrA
Test method	:	Guidelines for Screening Mutagenicity Testing of Chemicals (Japan)
Procedures	:	Plate incorporation method
Solvent	:	DMSO
Positive controls	:	-S9 Mix, AF-2 (TA100, WP2, TA98) sodium azide (TA1535) and 9-aminoacridine (TA1537) +S9 Mix, 2-aminoanthracene (all strains)
Doses	:	0, 312.5, 625, 1250, 2500, 5000 μg/plate
S-9	:	Rat liver, induced with phenobarbital and 5,6-benzoflavone
Plates/test	:	3
Number of replicates	:	2
GLP	:	Yes

　Test results:

No toxicity was observed up to a concentration of 5000 μg/plate with or without metabolic activation.

　Genetic effects :

S. typhimurium TA100, TA1535, TA 98

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

S. typhimurium TA1537

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

E. coli WP2 uvrA

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

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

Purity	:	98.7%
Type of cell used	:	Chinese hamster lung (CHL/IU) cells
Test method	:	Guidelines for Screening Mutagenicity Testing of Chemicals (Japan)
Solvent	:	0.5% Carboxymethylcellulose sodium solution
Positive controls	:	-S9, Mitomycin C +S9, Cyclophosphamide
Doses	:	-S9 (continuous treatment): 0, 0.3, 0.7, 1.3 mg/ml -S9 (short-term treatment): 0, 0.6, 1.1, 2.2 mg/ml +S9 (short-term treatment): 0, 0.6, 1.1, 2.2 mg/ml
S-9	:	Rat liver, induced with phenobarbital and 5,6-benzoflavone
Plates/test	:	2
GLP	:	Yes

　Test results:

Cytogenetic effects were not seen under the conditions of this experiment.

　Genotoxic effects:

	clastogenicity			polyploidy
	+	?	-	+	?	-
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, Japan. Tel +81-463-82-4751 Fax +81-463-82-9627