o-sec-Butylphenol

o-sec-ブチルフェノール


[CAS No. 89-72-5]

2-(1-Methylpropyl)phenol

2-(1-メチルプロピル)フェノール

Molecular formula: C10H14O Molecular weight: 150.22

ABSTRACT

Single oral dose LD50 values of o-sec-butylphenol were between 500 and 1000 mg/kg in both sexes. Pathological lesions were observed in the stomach and lung.

An OECD combined repeat dose and reproductive/developmental toxicity screening test was performed in rats for o-sec-butylphenol. With regard to repeat dose toxicity, no animals died in any groups. Salivation after dosing, decrease in activity and incomplete eyelid opening were observed in males and females of the 300 mg/kg group. In addition, an ataxic gait was observed in females of the same group. An increase in relative liver weight was observed in males and females, and hypertrophy of the centrilobular hepatocytes in males of the 300 mg/kg group. Concentration of total cholesterol was also increased in males given 300 mg/kg. No adverse effects were detected on food consumption and body weight change in males and females of the 300 mg/kg group. In the 60 mg/kg group, decrease in locomotor activity was observed in a few males early in the administration period. The NOELs for repeat dose toxicity are considered to be 12 mg/kg/day in males and 60 mg/kg/day in females.

Regarding reproductive and developmental toxicity, no adverse effects were observed on copulation, fertility, maintenance of pregnancy, delivery, and lactation. In addition, o-sec-butylphenol did not affect the viability of neonates, sex ratio, body weight changes, and morphological appearance of pups. NOELs for reproductive and developmental toxicity are considered to be 300 mg/kg/day in males, females and pups.

o-sec-Butylphenol was not mutagenic in Salmonella typhimurium TA100, TA1535, TA98, TA1537 and Escherichia coli WP2 uvrA, with or without an exogenous metabolic activation system.

o-sec-Butylphenol induced structural chromosomal aberrations in CHL cells, with or without an exogenous metabolic activation system.

SUMMARIZED DATA FROM THE STUDIES

1. Single Dose Oral Toxicity 1)

Purity:99.15 %
Test species/strain:Rat/Crj:CD(SD)
Test method:OECD Test Guideline 401
 Route:Oral (gavege)
 Doses:0, 250, 500, 1000, 2000 mg/kg
 Number of animals/group:Males, 5; females, 5
 Vehicle:Corn oil
GLP:Yes

 Test results:

Deaths of both sexes occurred in the groups given 1000 mg/kg and more. Adoption of a prone, lateral or crouching position and/or hypoactivity were observed in almost all of the animals administered o-sec-butylphenol. Bradypnea, respiratory murmur, tachypnea and salivation were observed in a few animals. Decrease in body weight gain was noted in survivoing females in the groups of 1000 mg/kg or more. There was no abnormality in body weight gain in male survivors. Pathological lesions due to o-sec-butylphenol were observed in the digestive organs and respiratory system.

The LD50 values were between 500 and 1000 mg/kg in both sexes.

2. Repeat Dose and Reproductive/Developmental Toxicity 1)

Purity:99.15 %
Test species/strain:Rat/Crj:CD(IGS)
Test method:OECD Combined Repeat Dose and Reproductive/Developmental Toxicity Screening Test
 Route:Oral (gavage)
 Doses:0 (vehicle), 12, 60, 300 mg/kg/day
 Number of animals/group:Males, 13; females, 13
 Vehicle:Corn oil
 Administration period:Males, 42 days
Females, from 14 days prior to mating to day 3 of lactation
 Terminal killing:Males, day 43
Females, day 4 of lactation
GLP:Yes

 Test results:

<Repeated dose toxicity>

No animals died in any groups. Salivation after dosing, decrease in activity (decreased locomotor activity, adoption of a prone or lateral position, leaning) and incomplete eyelid opening were observed in males and females of the 300 mg/kg group. In addition, ataxic gait was observed in females of the same group. An increase in relative liver weight was observed in males and females of the 300 mg/kg group. On histopathological examination of the liver, hypertrophy of the centrilobular hepatocytes was observed in males of the 300 mg/kg group, whereas this change was not observed in females of the same group. The total cholesterol concentration was increased in the males of the 300 mg/kg group. No adverse effects were detected in terms of food consumption and body weight change in males and females of the 300 mg/kg group. The hematological examination of males revealed no adverse effects of o-sec-butylphenol. In the 60 mg/kg group, decrease in locomotor activity was observed in few males in the early administration period, but not in females. No adverse effects of o-sec-butylphenol at the dose level of 12 mg/kg were found.

The no observed effect dose levels (NOELs) for repeat dose toxicity are considered to be 12 mg/kg/day in males and 60 mg/kg/day in females.

<Reproductive and developmental toxicity>

No adverse effects were observed on copulation, fertility, maintenance of pregnancy, delivery, and lactation. In addition, o-sec-butylphenol did not affect the viability of neonates, sex ratio, body weight changes, and morphological appearance of pups.

The NOEL for reproductive and developmental toxicity is considered to be 300 mg/kg/day in males, females and offspring.

3. Genetic Toxicity

3-1. Bacterial test 2)

Purity:99.15 %
Test species/strain :Salmonella typhimurium TA100, TA1535, TA98, TA1537 Escherichia coli WP2 uvrA
Test method:Guidelines for Screening Mutagenicity Testing of Chemicals (Japan) and OECD Test Guidelines 471 and 472
 Procedures:Pre-incubation method
 Solvent:DMSO
 Positive controls:-S9 mix; 2-(2-Furyl)-3-(5-nitro-2-furyl)acrylamide
(TA100, TA98, WP2 uvrA), Sodium azide (TA1535) and Aminoacridine (TA1537)
+S9 mix; 2-Aminoanthracene (all strains)
 Doses:-S9 mix; 0, 12.5, 25, 50, 100, 200, 400 μg/plate
+S9 mix; 0, 12.5, 25, 50, 100, 200, 400 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 observed at more than 200 μg/plate (TA100, TA1535, TA98, TA1537) and at 400 μg/plate (WP2 uvrA) without an S9 mix, and at more than 200 μg/plate (TA1535, TA1537) and at 400 μg/plate (TA100, TA98, WP2 uvrA) with an 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:99.15 %
Type of cell used:Chinese hamster lung (CHL) cells
Test method:Guidelines for Screening Mutagenicity Testing of Chemicals (Japan) and OECD Test Guideline 473
 Solvent :DMSO
 Positive controls :-S9 mix, 1-methyl-3-nitro-1-nitrosoguanidine
+S9 mix, Benzo[a]pyrene
 Doses:-S9 mix (24 and 48 hr continuous treatment); 0, 40, 60, 80, 100, 120 μg/mL
-S9 mix (6 hr short-term treatment); 0, 60, 80, 100, 120, 140 μg/mL
+S9 mix (6 hr short-term treatment); 0, 5, 10, 20, 30, 40 μg/mL
 S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
 Plates/test:2
GLP:Yes

 Test results:

After 48 hr continuous treatment, structural chromosomal aberrations including gaps were induced at 80 and 100 μg/mL (6.5 and 10.0 %) without an S9 mix. With the 6 hr short-term treatment, structural chromosomal aberrations including gaps were induced at 20, 30 and 40 μg/mL (5.0, 9.0 and 5.0 %) with an S9 mix. Polyploidy was not induced in any treatment group.

Cytotoxicity was observed at 120 μg/mL with 24 and 48 hr continuous treatment without an S9 mix.

Lowest concentration producing cytogenetic effects in vitro:
 Without metabolic activation (48 hr continuous treatment):80 μg/mL (clastogenicity)
 With metabolic activation (6 hr short-term treatment):20 μg/mL (clastogenicity)

Genotoxic effects:
clastogenicitypolyploidy
+?-+?-
 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, 257-8523, Japan. Tel +81-463-82-4751 Fax +81-463-82-9627
2)The test were performed by the Research Institute for Animal Science in Biochemistry and Toxicology, 3-7-11 Hashimotodai, Sagamihara-shi, Kanagawa, 229-1132, Japan. Tel +81-427-62-2775 Fax +81-427-62-7979