4-(1-Methyl-1-phenylethyl)phenol

4-(1-メチル-1-フェニルエチル)フェノール


[CAS No. 599-64-4]

p-(α,α-Dimethylbenzyl)phenol

p-(α,α-ジメチルベンジル)フェノール

Molecular formula: C15H16O　Molecular weight: 212.29

ABSTRACT

Single dose oral toxicity of 4-(1-methyl-1-phenylethyl)phenol dissolved in olive oil was investigated using Crj:CD(SD)IGS rats, at doses of 0, 1500, 2000 mg/kg and revealed an LD50 value of 2000 mg/kg or more for males and females.

In the 28-day repeat dose toxicity test, males and females given 1000 mg/kg showed soft feces. Two males and a female died on Day 26, and a male was killed in a moribund condition. Males given 1000 mg/kg had decreased body weight from Day 7. Males and females given 300 mg/kg or more had transiently decreased food consumption. On urinalysis, males and females given 300 mg/kg or more showed irregularly sized particles of a black substance, and increased water consumption, accompanied by decrease of specific gravity. Males and females given 300 mg/kg or more showed slight changes in coagulating factors, and hepatic and renal function parameters. These changes were reversible. Males and females given 1000 mg/kg demonstrated increased absolute and relative weights of liver and kidney. On histopathological examination, males and females given 1000 mg/kg showed hyperplasia of squamous cells in the stomach, dilatation of renal tubules, and proliferation of bile duct cells.

The NOELs are considered to be 100 mg/kg/day for males and females.

A reverse mutation test of 4-(1-methyl-1-phenylethyl)phenol in bacteria was carried out. This substance was not mutagenic in Salmonella typhimurium TA100, TA1535, TA98, TA1537 or Escherichia coli WP2 uvrA, with or without an exogenous metabolic activation system.

Genotoxicity of 4-(1-methyl-1-phenylethyl)phenol was studied by chromosomal aberration test using cultured Chinese hamster lung (CHL/IU) cells. 4-(1-Methyl-1-phenylethyl)phenol did not induce structural chromosomal aberrations and polyploidy any dose, with and without metabolic activation.

SUMMARIZED DATA OF THE STUDIES

1. Single Dose Oral Toxicity 1)

Purity:99.88 %
Test species/strain:Rat/Crj:CD(SD)IGS
Test method:OECD Test Guideline 401
　Route:Oral(gavage)
　Doses:0(vehicle), 1500, 2000 mg/kg
　Number of animals/group:Males, 5; Females, 5
　Vehicle:Olive oil
GLP:Yes

　Test results:

No deaths occurred in males and females given 1500 or 2000 mg/kg. Signs of acute toxicity like altered behavior, diarrhea, and soiled perianal and/or perigenital fur, were found from 30 minutes to 1 hour or 2 days in both sexes given 1500 mg/kg or more. Body weight gain was suppressed for 5 days in males and 1 day in females. Pathological lesions due to 4-(1-methyl-1-phenylethyl)phenol were not observed.

The LD50 value was estimated to be 2000 mg/kg or more for males and females.

2. Repeat Dose Oral Toxicity 1)

Purity:99.88 %
Test species/strain:Rat/Crj:CD(SD)IGS
Test method:Guideline for 28-Day Repeated Dose Toxicity Test in Mammalian Species (Chemical Substances Control Law of Japan)
　Route:Oral(gavage)
　Doses:0(vehicle), 100, 300, 1000 mg/kg/day
　Number of animals/group:Males and females, 14, 7, 7 and 14/group for the 0, 100, 300 and 1000 mg/kg, respectively
　Vehicle:Olive oil
　Administration period:Males and females, 28 days
　Terminal kill:Days 29 and 43
GLP:Yes

　Test results:

Males and females given 1000 mg/kg showed soft feces, and 2 males and a female died on Day 26. A male was killed in a moribund condition. Males given 1000 mg/kg had decreased body weights from Day 7, and males and females given 300 mg/kg or more demonstrated decreased transiently food consumption. On urinalysis, males and females given 300 mg/kg or more showed scattered particles of a black substance of irregular size. Increase in water consumption and urine volume were accompanied with reduction in the specific gravity. These changes were clear in male rats. 300 mg/kg or more caused slight changes in coagulating factors, hepatic function and renal function, which were reversible. Males and females given 1000 mg/kg exhibited increase in absolute and relative weights of the liver and kidney. On histopathological examination, males and females given 1000 mg/kg showed squamous cell hyperplasia in the fore stomach, dilatation of renal tubules, and proliferation of bile duct cells.

The NOELs are considered to be 100 mg/kg/day for males and females.

3. Genetic Toxicity

3-1. Bacterial test 2)

Purity:99.88 %
Test species/strains:Salmonella typhimurium TA100, TA1535, TA98, TA1537, Escherichia coli WP2 uvrA
Test method:Guidelines for Screening Mutagenicity Testing of Chemicals(Chemical Substances Control Law of Japan) and OECD Test Guideline 471
　Procedures:Pre-incubation method
　Solvent:Dimethyl sulfoxide
　Positive controls:-S9 mix; 2-(2-Furyl)-3-(5-nitro-2-furyl)acrylamide (TA100, TA98, WP2 uvrA), Sodium azide (TA1535) and 9-Aminoacridine (TA1537)
+S9 mix; 2-Aminoanthracene (five strains)
　Doses:-S9 mix; 0, 6.25, 12.5, 25.0, 50.0, 100, 200 μg/plate(five strains)
+S9 mix; 0, 6.25, 12.5, 25.0, 50.0, 100, 200 μg/plate(four TA strains)
+S9 mix;0, 12.5, 25.0, 50.0, 100, 200, 400 μg/plate(WP2 uvrA)
　S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
　Plates/test:3(1 for cytotoxicity test)
　Number of replicates:2(plus 1 cytotoxicity test)
GLP:Yes

　Test results:

This chemical did not induce gene mutations in S. typhimurium TA100, TA1535, TA98, TA1537 and E. coli WP2 uvrA strains, with or without S9 mix. Toxicity was observed at and above 100 μg/plate (five strains) without S9 mix and at and above 150 μg/plate (four TA strains) and at 200 μg/plate (WP2 uvrA) with S9 mix.

Genetic effects:
Salmonella typhimurium TA100, TA1535, TA98, TA1537
+?-
　Without metabolic activation:[ ][ ][*]
　With metabolic activation:[ ][ ][*]

Escherichia coli WP2 uvrA
+?-
　Without metabolic activation:[ ][ ][*]
　With metabolic activation:[ ][ ][*]

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

Purity:99.88 %
Type of cell used:Chinese hamster lung (CHL/IU) cells
Test method:Guidelines for Screening Mutagenicity Testing of Chemicals(Chemical Substances Control Law of Japan) and OECD Test Guideline 473
　Solvent:Dimethyl sulfoxide
　Positive controls:-S9 mix; Mitomycin C
+S9 mix; Cyclophosphamide
　Doses:-S9 mix(short-term treatment); 0, 0.0020, 0.0040, 0.0080 mg/mL
+S9 mix(short-term treatment); 0, 0.0075, 0.015, 0.030 mg/mL
-S9 mix(continuous treatment for 24 hr); 0, 0.0050, 0.010, 0.020 mg/mL
　S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
　Plates/test:2
GLP:Yes

　Test results:

Neither stuructural chromosome aberrations nor polyploidy were manifested in any treatment system.

Genotoxic effects:
clastogenicitypolyploidy
+?-+?-
　Without metabolic activation:[ ][ ][*][ ][ ][*]
　With metabolic activation:[ ][ ][*][ ][ ][*]

1)The tests were performed by the Safety Research Institute for Chemical Compounds Co., Ltd., 363-24, Shin-ei, Kiyota-ku, Sapporo, Hokkaido, 004-0839, Japan. Tel +81-11-885-5031 Fax +81-11-885-5313
2)The tests were performed by the Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano-shi, Kanagawa, 257-8523, Japan. Tel +81-463-82-4751 Fax +81-463-82-9627