With regard to repeat dose toxicity, one female rat given 200 mg/kg died during delivery. Body weight gain of females given 200 mg/kg was lower than that of controls during the gestation period. Hematological examination showed decreases of red blood cells in males given 8 mg/kg or more, as well as decreases of hematocrit and hemoglobin, increases of reticulocytes, and slight anemia in males given 40 and 200 mg/kg. Blood chemical examination revealed increases in total protein, albumin and g-GTP and decreases in creatinine in males given 40 and 200 mg/kg. Increases in total bilirubin and A/G ratio were also observed in males given 200 mg/kg. Absolute and relative weights of the liver and kidneys showed increases or a tendency for increase in both sexes given 200 mg/kg. As gross findings, enlargement of the liver was observed in both sexes given 200 mg/kg and enlargement of the kidneys in males given 200 mg/kg. Histopathological examination revealed swelling and single cell necrosis of liver cells in both sexes given 200 mg/kg. Moreover, mitosis of livers cells were observed in the liver of males given 200 mg/kg. The slight increase in the incidence of hyaline droplets of the renal tubules in males and basophilic change of the renal tubules in females, both given 200 mg/kg, were also noted in a few females given 8 mg/kg or more, and necrosis of the renal tubules was observed in a few females given 40 and 200 mg/kg. NOELs for repeat dose toxicity are considered to be less than 8 mg/kg/day for both sexes. In terms of reproductive/developmental toxicity, one female given 200 mg/kg died during delivery. All pups were stillborn in two females and all pups died during the lactation period in three females of the treated group given 200 mg/kg. In the same group the number of live pups born was decreased and the live birth index, viability index of the pups at Day 4 after birth and delivery demonstrated tendencies for index decrease. NOELs for reproductive performance of males and females, and pup development are considered to be 200 mg/kg/day for males and 40 mg/kg/day for females.

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

1. Repeat Dose and Reproductive/Developmental Toxicity1)

Purity	:	98.0%
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), 8, 40, 200 mg/kg/day
Number of animals	:	Males,12; females, 12/group
Vehicle	:	Corn oil
Administration period	:	Males, 45 days Females, from 14 days before mating to day 3 of laction
Terminal kill	:	Males, day 45 Females, day 4 of laction
GLP	:	Yes

　Test results:

<Repeat dose toxicity>
There were no abnormal clinical signs attributable to the administration of the test substance, although, one female rat given 200 mg/kg died during delivery. The body weight gain of females given 200 mg/kg was lower than that of the controls during the gestation period.

Hematological examination revealed decreases in red blood cells in males given 8 mg/kg or more, decreases in hematocrit and hemoglobin, increases in reticulocytes, and slight anemia in males given 40 and 200 mg/kg. Blood clinical examination revealed increases in total protein, albumin and γ-GTP and decreases in creatinine in males given 40 and 200 mg/kg. Total bilirubin and the A/G ratio were increased in males given 200 mg/kg.

Absolute and relative liver and kidney weights showed increase or a tendency for increase in both sexes given 200 mg/kg .

Necropsy revealed enlargement of the liver in both sexes given 200 mg/kg, and enlargement of the kidneys in males given 200 mg/kg. Other treatment-related gross findings included atrophy of the thymus and enlargement of the adrenal glands in treated females.

Histopathological examination revealed swelling and single cell necrosis of liver cells in both sexes given 200 mg/kg. Moreover, mitosis of liver cells were observed in males given 200 mg/kg. The slight increase in the incidence of hyaline droplets of the renal tubules in males and basophilic change of the renal tubules in females, both given 200 mg/kg, were also noted in a few females given 8 mg/kg or more, and necrosis of the renal tubules was observed in a few females given 40 and 200 mg/kg. A variety of lesions including a moderate degree of pigment deposit on in the spleen, atrophy of the thymus, swelling of the liver cells, ulcer action in the stomach, duodenum and large intestine, single liver cell necrosis and fibrosis of the renal tubular epithelium, were observed in females that delivered all stillborn pups and in females where pups all died, in the group given 200 mg/kg. Counting of numbers of spermatogenic cells at stage VIII in the testes from control males and males given 200 mg/kg revealed no treatment-related effects. NOELs for repeat dose toxicity are considered to be less than 8 mg/kg/day for both sexes.

<Reproductive and Developmental Toxicity>
The compound showed no effects on mating, fertility or the estrous cycle. One female given 150 mg/kg died during delivery. All pups were stillborn with two females and all pups died during the lactation period with three females given 200 mg/kg. In addition the number of live pups born decreased, and the number of stillbirth pups tended to increase. The live birth index, viability index of pups at Day 4 after birth and delivery index were decreased or showed a tendency for decrease in the same group, suggesting functional disturbances in delivery or lactation caused by the test substance. NOELs for reproductive performance of males and that of females and for pups development are considered to be 200 mg/kg/day and 40 mg/kg/day, respectively.

2. Genetic Toxicity

Purity	:	99.6%
Type of cell used	:	Chinese hamster lung (CHL/IU) cells
Test method	:	Guidelines for Screening Mutagenicity Testing of Chemicals (Japan)
Solvent	:	Dimethyl sulfoxide
Positive controls	:	-S9, Mitomycin C +S9, Cyclophosphamide
Doses	:	-S9 (continuous treatment): 0, 0.04, 0.07, 0.14 mg/ml -S9 (short-term treatment): 0, 0.04, 0.07, 0.14 mg/ml +S9 (short-term treatment): 0, 0.04, 0.07, 0.14 mg/ml
S-9	:	Rat liver, induced with phenobarbital and 5,6-benzoflavone
Plates/test	:	2
GLP	:	Yes

　Test results:

Cytogenetic effect 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 Biosafety Research Center, Foods, Drugs and Pesticides (An-pyo Center), Japan, 582-2 Shioshinden Arahama, Fukude-cho, Iwata-gun, Shizuoka, 437-12, Japan. Tel 81-538-58-1266 Fax 81-538-58-1393
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