1,4-Dimethyl-2-(1-phenylethyl)benzene

1,4-ジメチル-2-(1-フェニルエチル)ベンゼン


[CAS No. 6165-51-1]

2-(1-Phenylethyl)-p-xylene

2-(1-フェニルエチル)-p-キシレン

Molecular formula: C16H18　Molecular weight: 210.31

ABSTRACT

1,4-Dimethyl-2-(1-phenylethyl)benzene, was studied for oral toxicity in rats in a single dose toxicity test at doses of 0, 500, 1000 and 2000 mg/kg for both sexes.

As an result, deaths occurred of one male and two females in the 2000 mg/kg group.

1,4-Dimethyl-2-(1-phenylethyl)benzene was studied for oral toxicity in Crj:CD(SD)IGS rats in an OECD combined repeated dose and reproductive/developmental toxicity screening test at doses of 0, 12.5, 50 and 200 mg/kg/day.

With regard to repeated dose toxicity, depression of body weight gain was observed in both sexes of the 200 mg/kg group, and a tendency toward decrease in food consumption was observed in males of the 100 mg/kg group. Urinalysis showed increase in urine volume, decreases in osmotic pressure and specific gravity, and increase in crystals in males of the 200 mg/kg group. Hematological examination showed shortening of prothrombin time in males of the 50 mg/kg and more groups. Blood chemical examination showed increase in total cholesterol in males of the 50 mg/kg and more groups, increase in γ-GTP and decrease in chlorine in males of the 200 mg/kg group, and increase in glucose in females of the 200 mg/kg group. Liver weights were increased in males of the 50 mg/kg and more groups and females of the 200 mg/kg group, and histopathological examination of the liver revealed centrilobular hypertrophy of hepatocytes. Furthermore, decrease in the incidence of periportal fatty change of the hepatocytes was also found in males of the 200 mg/kg group. Adrenal weights were decreased in males at 12.5 mg/kg or more, and histopathological examination of the adrenal revealed atrophy of the zona fasciculata. Furthermore, increase in incidence of hypertrophy of the zona glomerulosa was also found in males of the 200 mg/kg group. The NOELs for repeated dose toxicity are considered to be less than 12.5 mg/kg/day for males and 50 mg/kg/day for females.

In terms of reproductive/developmental toxicity, there were no effects related to the test substance on reproductive performance of parents or development of the next generation. The NOEL is considered to be 200 mg/kg/day for reproductive performance of parents and for development of offspring.

Genotoxicity of 1,4-dimethyl-2-(1-phylethyl)benzene was studied by a reverse mutation test in bacteria and by a chromosomal aberration test in cultured Chinese hamster lung (CHL/IU) cells.

1,4-Dimethyl-2-(1-phylethyl)benzene was not mutagenic in Salmonella typhimurium TA100, TA1535, TA98, TA1537 and Escherichia coli WP2uvrA, with or without an exogenous metabolic activation system.

1,4-Dimethyl-2-(1-phylethyl)benzene did not induce chromosomal aberrations in CHL/IU cells, with or without an exogenous metabolic activation system.

SUMMARIZED DATA FROM THE STUDIES

1. Single Dose Oral Toxicity 1)

Purity:99.0 mass%
Test species/strain:Rat/Crj:CD(SD)IGS
Test method:OECD Test Guideline 401
　Route:Oral (gavage)
　Dosage:0 (vehicle), 500, 1000, 2000 mg/kg
　Number of animals/group:Males, 5; females, 5
　Vehicle:Olive Oil
GLP:Yes

　Test results:

Deaths occurred in both sexes of the 2000 mg/kg group. Treatment-related clinical signs were noted as follows: periproctal soiling, hypoactivity, bradypnea and adoption of a prone or lateral position. Depression or inhibition of body weight gain was observed in both sexes of the 2000 mg/kg group, and inhibition in both sexes of the 1000 mg/kg group. In the dead male animal, light gray spots on the kidneys were noted macroscopically, and granular casts, proteinaceous casts and retention of blood in uriniferous tubules were noted histopathologically, along with hyaline droplets in the proximal uriniferous tubules. Dark red spots on the thymus were also observed macroscopically, and hemorrhage and cortex lymphocyte necrosis histopathologically. In addition, retention of dark red urine in the urinary bladder was observed macroscopically. However, there were no histopathological changes in the urinary bladder. In the dead female animals, dark red coloration in the lung was noted macroscopically, and edema was noted histopathologically. In the surviving animals, there were no changes at necropsy or histopathological examination.

2. Repeated Dose and Reproductive/Developmental Toxicity 1)

Purity:99.0 mass%
Test species/strain:Rat/Crj:CD(SD)IGS
Test method:OECD Test Guideline 42
　Route:Oral (gavage)
　Dosage:0 (vehicle), 12.5, 50, 200 mg/kg/day
　Number of animals/group:Males, 12; females, 12
　Vehicle:Olive oil
　Administration period:Males, 49 days
Females, from 14 days before mating to day 3 of lactation
　Terminal killing:Males, day 50
Females, day 4 of lactation
GLP:Yes

　Test results:

<Repeated dose toxicity>

No effects related to the test article were apparent on clinical observation. Depression of body weight gain was observed in both sexes of the 200 mg/kg group, and a tendency toword decrease in food consumption was observed in males of the 100 mg/kg group. Urinalysis showed increase in urine volume, decreases in osmotic pressure and specific gravity, and increase in crystals in males of the 200 mg/kg group. Hematological examination revealed shortening of the prothrombin time in males of the 50 mg/kg or more groups. Blood chemical examination showed increase in total cholesterol in males of the 50 mg/kg or more groups, increase in γ-GTP and decrease in chlorine in males of the 200 mg/kg group, and increase in glucose in females of the 200 mg/kg group. Liver weights were increased in males of the 50 mg/kg or more groups and females of the 200 mg/kg group, and histopathological examination of the liver revealed centrilobular hypertrophy of the hepatocytes. Furthermore, decrease in incidence of periportal fatty change of hepatocytes was also found in males of the 200 mg/kg group. Adrenal weights were decreased in males given 12.5 mg/kg or more, and histopathological examination of the adrenals revealed atrophy of the zona fasciculata. Furthermore, increase in the incidence of hypertrophy of the zona glomerulosa was also found in males of the 200 mg/kg group. The NOELs for repeated dose toxicity are considered to be less than 12.5 mg/kg/day for males and 50 mg/kg/day for females.

<Reproductive and developmental toxicity>

Regarding reproductive performance, no effects related to the test substance were observed in terms of the estrous cycle, numbers of corpora lutea and implantations, the copulation index or fertility indices for males or females. Examination at delivery and during the lactation period, demonstrated no effects related to the test article on gestational days, numbers of litter and live newborn, gestation index, stillborn index, birth index, sex ratio, body weight of offspring at birth and at day 4 after birth, or viability index on day 4. No external anomalies were evident. The NOEL is considered to be 200 mg/kg/day for reproductive performance of parents and for development of offspring.

3. Genetic Toxicity

3-1. Bacterial test 2)

Purity:99.0 %
Test species/strain: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, WP2uvrA), Sodium azide(TA1535) and 9-Aminoacridine (TA1537)
+S9 mix; 2-Aminoanthracene (all strains)
　Dosage:-S9 mix; 0, 156, 313, 625, 1250, 2500, 5000 μg/plate
+S9 mix; 0, 156, 313, 625, 1250, 2500, 5000 μg/plate
　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 gene mutations in the S. typhimurium and E. coli strains. Toxicity was not observed in any strain, with or without 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:99.0 %
Type of cell used:Chinese hamster lung (CHL) 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; 1-Methyl-3-nitro-1-nitrosoguanidine
+S9 mix; 3,4-Benzo[a]pyrene
　Dosage:-S9 mix (6 hr short-term treatment); 0, 15.6, 31.3, 62.5, 125, 250, 500 μg/mL
+S9 mix (6 hr short-term treatment); 0, 65.6, 131, 263, 525, 1050, 2100 μg/mL
-S9 mix (24 hr continuous treatment); 0, 7.81, 15.6, 31.3, 62.5, 125 μg/mL
　S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
　Plates/test:2
GLP:Yes

　Test results:

With the 6 hr short-term treatment, chromosomal aberrations were not induced, with or without S9 mix. Moreover, chromosomal aberrations were not induced after the 24 hr continuous treatment without S9 mix.

Cytotoxicity was observed at 125 μg/mL after 24 hr continuous treatment without S9 mix.

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

1)The tests were performed by the Safety Assessment Laboratory, Panapharm Laboratories Co., Ltd., 1285 Kurisaki-machi, Uto-shi, Kumamoto, 869-0425, Japan. Tel +81-964-23-5111 Fax +81-964-23-2282
2)The tests were performed by the Research Institute for Animal Science in Biochemistry and Toxicology, 3-7-11 Hashimotodai, Sagamihara-shi, Kanagawa, 229-1132, Japan. Tel +81-42-762-2775 Fax +81-42-762-7979