6-tert-Butyl-2,4-xylenol

6-tert-ブチル-2,4-キシレノール

CAS No. 1879-09-0

6-tert-Butyl-2,4-dimethylphenol

6-tert-ブチル-2,4-ジメチルフェノール

Molecular formula: C12H18O Molecular weight: 178.30

ABSTRACT

With regard to repeat dose toxicity, two female rats given 150 mg/kg died at the end of the gestation period (one of them during delivery). Body weight gain of females given 150 mg/kg was lower than that of the control during the gestation period. Hematological examination showed decreases of hematocrit, hemoglobin and red blood cells, and increases of reticulocytes and a slight tendency for anemia in male rats given 150 mg/kg. Blood chemical examination revealed decreases in levels of GOT and increases in γ-GTP in males given 30 and 150 mg/kg. Liver and kidney weights was showed increases or a tendency for increase in the male rats given 30 mg/kg or more and in the females given 150 mg/kg. As gross findings, enlargement of the liver was observed in males given 30 and 150 mg/kg, and enlargement of the liver and kidneys was observed in females given 150 mg/kg. Histopathological examination revealed swelling of liver cells in the centrilobular zone in males and females of the 150 mg/kg group, and degeneration of liver cells, necrosis of centrilobular hepatocytes and single cell necrosis in the females of the same group. NOELs for repeat dose toxicity are considered to be 6 mg/kg/day in males and 30 mg/kg/day in females of the group. In terms of reproductive/developmental toxicity, one female given 150 mg/kg died during the delivery. With three females in the same all pups died treatment group during the lactation period. NOELs for reproductive performance of males and for that of females and pup development are considered to be 150 mg/kg/day and 30 mg/kg/day, respectively.

6-tert-Butyl-2,4-xylenol 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, in the absence or presence of an exogenous metabolic activation system.

SUMMARIZED DATA FROM THE STUDIES

1. Single Dose Oral Toxicity1)

Purity	:	98.5%
Test species/strain	:	Rats/Crj:CD (SD)
Test method	:	OECD Test Guideline 401
Route	:	Oral (gavage)
Doses	:	Males: 0, 819, 1024, 1280, 1600, 2000 mg/kg Females: 0, 655, 819, 1024, 1280, 1600 mg/kg
Number of animals	:	Males, 5; females, 5/group
Vehicle	:	Corn oil
GLP	:	Yes
Test results	:	LD50: males, 910 mg/kg; females, 972 mg/kg

2. Repeat Dose and Reproductive/Developmental Toxicity1)

Purity	:	98.5%
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), 6, 30, 150 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 killing	:	Males, day 45 Females, day 4 of laction
GLP	:	Yes

　Test results:

<Repeat dose toxicity>

There were no clinical abnormal signs attributable to the administration of the test substance. However, two female animals given 150 mg/kg died at the end of gestation period (one of them during the delivery). The body weight gain of females given 150 mg/kg was lower than that of the controls during the gestation period. However, body weights of males and food consumption of both males and females did not demonstrate any effects attributable to the administration of test substance.

Hematological examination revealed decreases in hematocrit, hemoglobin and red blood cells, increases in reticulocytes and a slight tendency for anemia in males given 150 mg/kg. Blood clinical examination revealed decreases in GOT and increases in γ-GTP in the 30 and 150 mg/kg males.

Liver and kidney weights showed increases or a tendency for increase in males given 30 mg/kg or more and females given 150 mg/kg. At necropsy enlargement of the liver in males given 30 and 150 mg/kg, and of the liver and kidneys in females given 150 mg/kg was noted.

Histopathological examination revealed swelling of centrilobular hepatocytes in males given 150 mg/kg and swelling and necrosis of centrilobular hepatocytes, and single cell necrosis in females given 150 mg/kg. The dead females and females with pups which all died showed increased incidences of parakeratosis of the tongue, esophageal swelling and necrosis of centrilobular hepatocytes, as well as a variety of degenerative charges, single cell necrosis and mitosis in the liver. Degeneration and protein cast in the proximal tubules and PAS positive granules deposited in the renal papilla, were observed in the kidneys of females given 150 mg/kg. NOELs for repeat dose toxicity are considered to be 6 mg/kg/day for males and 30 mg/kg/day for females.

<Reproductive and Developmental toxicity>

The compound showed no effects on mating, fertility and estrous cycle. One female given 150 mg/kg died during delivery and another at the end of the gestation period. In addition with three females of the same treatment group all pups died during the lactation period. A tendency for decrease in the viability index of the pups at Day 4 after birth was also observed in this group. NOELs for reproductive performance of males and for that of females and pup development are considered to be 150 mg/kg/day and 30 mg/kg/day, respectively.

3. Genetic Toxicity

3-1 Bacterial test2)

Purity	:	98.5%
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, 6.25, 12.5, 2550, 100 and 200 μg/plate on -S9 Mix and 0, 12.5, 25, 50, l00, 200 and 400 (6.25 - 200 in TA1537) on +S9 Mix Rat liver. induced with phenobarbital and 5,6-benzoflavone,
Plates/test	:	3
Number of replicates	:	2
GLP	:	Yes

　Test results:

Minimum concentration of test substance at which toxicity was observed:

Toxicity was observed at concentrations of 200 μg/plate (100 μg/plate for TA100 and TA1537) with out an -S9 Mix and 400 μg/plate (200 μg/plate for TA100 and TA1537) with a n +S9 Mix.

　Genetic effects :

S. typhimurium TA100, TA1535, TA 98, TA1537

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

E. Coli WP2 uvrA

without metabolic activation:	[ ]	[ ]	[*]
with metabolic activation:	[ ]	[ ]	[*]

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

Purity	:	98.5 %
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, 0.008, 0.017, 0.033 mg/ml -S9 (short-term treatment): 0, 0.008, 0.017, 0.033 mg/ml +S9 (short-term treatment): 0, 0.014, 0.028, 0.056 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 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