Bis(1-methyl-1-phenylethyl) peroxide

ビス(1-メチル-1-フェニルエチル)ペルオキシド

[CAS No. 80-43-3]

Dicumyl peroxide

ジクミルペルオキシド

Molecular formula: C₁₈H₂₂O₂　Molecular weight: 270.37

ABSTRACT

Bis(1-methyl-1-phenylethyl) peroxide was studied for oral toxicity in rats in a 28-day repeat dose toxicity test at doses of 0, 60, 200 and 600 mg/kg. No deaths were observed in any of the treatment groups in either sex. In the 200 and 600 mg/kg groups of both sexes, salivation was observed. In the 600 mg/kg group of both sexes, body weight gain was suppressed. These changes proved to be reversible after withdrawal. An increase in serum γ-GTP was observed in the 600 mg/kg group of both sexes. An increase in ALT was observed in the 600 mg/kg males.

Absolute and relative liver weights were increased in both sexes of the 600 mg/kg group and relative liver weights of were also increased in the 200 mg/kg group females. Absolute and relative thymus weights were decreased in both sexes in the 600 mg/kg group. Enlarged livers were grossly observed in the 600 mg/kg group females. Histopathologically, hypertrophy of hepatocytes was observed in the 200 and 600 mg/kg groups in both sexes. Degeneration of hepatocytes was observed in the 600 mg/kg group in both sexes. Mobilization of Kupffer cells was observed in the 600 mg/kg males. These changes proved reversible after withdrawal.

The NOEL for repeat dose toxicity is considered to be 60 mg/kg/day for both sexes.

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

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

SUMMARIZED DATA OF THE STUDIES

1. Single Dose Oral Toxicity ¹⁾

Purity	:	98.9 wt%
Test species/strain	:	Rat/Crj:CD(SD)
Test method	:	OECD Test Guideline 401
Route	:	Oral(gavage)
Doses	:	0, 2000 mg/kg
Number of animals/group	:	Males, 5; females, 5
Vehicle	:	Corn oil
GLP	:	Yes

　Test results:

No deaths occurred in either sex during the observation period. Abnormalities of general condition were not observed in any males or females during the observation period.

The LD₅₀ values were more than 2000 mg/kg for both sexes.

2. Repeat Dose Oral Toxicity ¹⁾

Purity	:	99.9 wt%
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), 60, 200, 600 mg/kg/day
Number of animals	:	Males, 5; females, 5
Vehicle	:	Corn oil
Administration period	:	Males and females, 28 days
Terminal kill	:	Males and females, days 29 and 43
GLP	:	Yes

　Test results:

No deaths were observed in any of the treatment groups in either sex. In both sexes of the 200 and 600 mg/kg groups, salivation was observed and in the 600 mg/kg group, body weight gain was suppressed. These changes proved reversible after withdrawal. An increase in serum γ-GTP was observed in both sexes in the 600 mg/kg group. Increased ALT was observed in the 600 mg/kg of males. Absolute and relative liver weights were increased in the 600 mg/kg group in both sexes and relative liver weights were increased in the 200 mg/kg females. Absolute and relative thymus weights were decreased in the 600 mg/kg group in both sexes. Enlarged livers were grossly observed in the 600 mg/kg group females. Histopathologically, hypertrophy of hepatocytes was observed in the 200 and 600 mg/kg groups in both sexes. Degeneration of hepatocytes was also observed in the 600 mg/kg groups in both sexes. Mobilization of Kupffer cells was observed in the 600 mg/kg males. These changes proved reversible after withdrawal.

The NOEL for repeat dose toxicity is considered to be 60 mg/kg/day for both sexes.

3. Genetic Toxicity

3-1. Bacterial test ²⁾

Purity	:	99.9 %
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, 313, 625, 1250, 2500, 5000 μg/plate(five strains) +S9 mix; 0, 313, 625, 1250, 2500, 5000 μg/plate(five strains)
S9	:	Rat liver, induced with phenobarbital and 5,6-benzoflavon
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 or E. coli WP2 uvrA strains, with or without S9 mix. Toxicity was not observed up to 5000 μg/plate in the five strains, 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	:	99.9 %
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, 0.00056, 0.0011, 0.0023 mg/mL +S9 mix(short-term treatment);0, 0.0094, 0.019, 0.038 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 structural chromosome aberrations nor polyploidy were manifested in any treatment system.

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), 582-2 Arahama, Shioshinden, Fukude-cho, Iwata-gun, Shizuoka, 437-1213, 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, 257-8523, Japan. Tel +81-463-82-4751　Fax +81-463-82-9627