ABSTRACT

In the repeat dose study, all dosed male and female rats revealed transiently increased salivation after every dosing of the test compound. Body weight gain and food consumption of the 1000 mg/kg males significantly decreased when compared to the controls. Clinical chemistry showed decreased glucose and potassium levels and increased sodium, GPT and γ-GTP levels in 1000 mg/kg males, and increased GPT and GOT levels in the 1000 mg/kg females. The histopathological examination revealed diffuse hyperplasia of mucous epithelium in the forestomach in all the 1000 mg/kg males and females and one 300 mg/kg male, and papillary necrosis in the kidneys in a few males and females that received 300 mg/kg or more. Eosinophilic debris in the papillary interstitium was also noted in these rats. A 14-day recovery test indicated recovery from these compound-related alterations except for papillary necrosis of the kidney. The NOEL is considered to be 100 mg/kg/day both for both males and females.

4-(1-Methyl propyl)phenol was not mutagenic in Salmonella typhimurium TA100, TA98, TA1535, TA1537 and Escherichia coli WP2 uvrA. Neither structural nor numerical chromosomal aberrations were induced in CHL/IU cells up to the concentration going 50% cell growth inhibition, in the absence or presence of an exogenous metabolic activation system.

SUMMARIZED DATA FROM THE STUDIES

1. Repeat Dose Toxicity 1)

Purity	:	> 66%
Test species/strain	:	Rat/Crj:CD (SD)
Test method	:	Guidelines for 28-Day Repeat Dose Toxicity Testing of Chemicals (Japan)
Route	:	Oral (gavage)
Dosage	:	0 (vehicle), 100, 300, 1000 mg/kg/day
Number of animals	:	100 and 300 mg/kg groups, 5 males and 5 females; 0 and 1000 mg/kg groups, 10 males and 10 females
Vehicle	:	Sesame Oil
Administration period	:	Males and females, 28 days
Terminal kill	:	5 males and 5 females/group, 29 days; 5 males and 5 females each in the 0 and 1000 mg/kg group, 44 days
GLP	:	Yes

　Test results:

<Repeat dose toxicity>

All males and females revealed transient salivation after every dosing of the test compound at any dose. Further, sporadic abnormal respiratory sounds, coarse respiration and/or mouth breathing were other notable signs in several males and females receiving 1000 mg/kg. The 1000 mg/kg group included one male and one female that died, probably due to intubation errors. Mean body weight gain of 1000 mg/kg males significantly decreased throughout the study. The mean food consumption of 1000 mg/kg males was also lowered during the 1st week. Blood chemical examination at the termination of the dosing period showed compound related alterations including decreases in glucose and potassium levels and increases in sodium, GPT and γ-GTP levels in 1000 mg/kg males, and increases in GPT and GOT levels in 1000 mg/kg females. At the end of the 14-day recovery period, a decrease in glucose and an increase in sodium levels were noted in 1000 mg/kg males, and an increase in BUN level in 1000 mg/kg females. Necropsy at the termination of the dosing period revealed compound-related histopathological lesions, which were diffuse hyperplasia of mucous epithelium of the forestomach in all the 1000 mg/kg males and females and one 300 mg/kg male, and papillary necrosis in the kidneys in a few males and females that received 300 mg/kg or more. Eosinophilic debris in the papillary interstitium was also noted in these males and females. At the termination of the recovery period, altered cell debris in the papillary interstitium and slight hyperplasia of the forestomach mucous epithelium were only evident in one 1000 mg/kg male and one 1000 mg/kg female, respectively.

The NOEL is considered to be 100 mg/kg/day for both males and females in terms of general toxicological effects.

2. Genetic Toxicity

2-1Bacterial test 1)

Purity	:	66%
Test species/strains	:	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, AF-2 (TA100, WP2, TA98), sodium azide (TA1535) and 9-aminoacridine (TA1537) +S9, 2-aminoanthracene (all strains)
Dosage	:	without metabolic activation; 0, 6.25, 12.5, 25, 50, 100, 200 μg/plate metabolic activation method 0, 12.5, 25, 50, 100, 200 μg/plate
S-9	:	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 a concentration of 200 μg/plate without metabolic activation, and 400 μg/plate with metabolic activation.

Genetic effects:
S. typhimurium TA100, TA1535, TA 98, TA1537

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

E. coli WP2 uvrA

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

2-2. Non-bacterial in vitro test (chromosomal aberration test) 1)

Purity	:	66%
Type of cell used	:	Chinese hamster CHL/IU cells
Test method	:	Guidelines for Screening Mutagenicity Testing of Chemicals (Japan)
Solvent	:	DMSO
Positive controls	:	-S9, Mitomycin C +S9, Cyclophosphamide
Dosage	:	-S9 (continuous treatment): 0, 0.012, 0.025, 0.049 mg/ml -S9 (short-term treatment): 0, 0.012, 0.025, 0.049 mg/ml +S9 (short-term treatment): 0, 0.017, 0.034, 0.067 mg/ml
S-9	:	Rat liver, induced with phenobarbital and 5,6-benzoflavone
Plates/test	:	2
GLP	:	Yes

　Test results:

Lowest concentration producing cytogenetic effects in vitro:

without metabolic activation (continuous treatment ): > 0.049 mg/ml

without metabolic activation (short-term treatment): > 0.049 mg/ml

with metabolic activation (short-term treatment): > 0.067 mg/ml

Genotoxic effects:

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

1)	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