4-Chloro-o-cresol

4-クロロ-o-クレゾール


[CAS No. 1570-64-5]

4-Chloro-2-methylphenol

4-クロロ-2-メチルフェノール

Molecular formula: C7H7ClO Molecular weight: 142.60

ABSTRACT

4-Chloro-o-cresol was studied for oral toxicity in rats in a 28-day repeat dose toxicity test at doses of 0, 15, 60, 250 and 1000 mg/kg/day. There were clinical signs of decreased locomotor activity, deep respiration, flaccidity, adoption of a prone position and salivation in both sexes, and suppression of body weight gain was noted in males of the 1000 mg/kg group. One male and three females receiving the highest dose died during the study. Blood chemical examination revealed increases of total bilirubin in 250 and 1000 mg/kg males and GPT in 1000 mg/kg males, and a decrease of cholinesterase in 1000 mg/kg females. Relative kidney weights were increased in 250 and 1000 mg/kg females. Histopathological examination revealed epithelial hyperplasia of the urinary bladder mucosa and squamous hyperplasia of the forestomach mucosa in both sexes given doses of 250 mg/kg or more. Hepatocellular hypertrophy and adrenocortical cell vacuolization were also observed in 1000 mg/kg females and males, respectively. All changes related to the test substance had disappeared or showed a tendency to for decrease after a 14-day recovery period. The NOEL for repeat dose toxicity is considered to be 60 mg/kg/day for both sexes.

4-Chloro-o-cresol was not mutagenic to Salmonella typhimurium, TA100, TA1535, TA98, TA1537 and Escherichia coli WP2 uvrA. In the presence of an exogenous metabolic activation system, this chemical substance induced structural chromosomal aberrations in CHL/IU cells. Polyploidy was not induced under the conditions of the present study.

SUMMARIZED DATA FROM THE STUDIES

1. Repeat Dose Toxicity 1)

Purity:93.6% (Other contents : isomers, 3.3% ; cresol, 1.5%)
Test species/strain:Rat/Crj:CD (SD)
Test method:Guidelines for 28-Day Repeat Dose Toxicity Testing of Chemicals (Japan)
　Route:Oral (gavage)
　Doses:0 (vehicle), 15, 60, 250, 1000 mg/kg/day
　Number of animals/group:Males, 5 or 10 (0 and 1000 mg/kg/day)
Females, 5 or 10 (0 and 1000 mg/kg/day)
　Vehicle:Sesami oil
　Administration period:Males and females, 28 days
　Terminal kill:Males and females, days 29 or 43
GLP:Yes

　 Test results:

Clinical signs of decreased locomotor activity, deep respiration, flaccidity, adaption of a prone position and salivation were noted in 1000 mg/kg males and females. Body weight gain decreased in 1000 mg/kg males. One male and three females died in this highest dose group. Blood chemical examination revealed increases of total bilirubin in 250 and 1000 mg/kg males and of GPT in 1000 mg/kg males, and a decrease of cholinesterase in 1000 mg/kg females. At autopsy, slightly enlarged cecums were noted in 1000 mg/kg males and females. Relative kidney weights were increased in 250 and 1000 mg/kg females. Histopathological examination revealed epithelial hyperplasia of the urinary bladder mucosa and squamous hyperplasia of the forestomach mucosa in both sexes at a dose of 250 mg/kg or more. Hepatocellular hypertrophy and adrenocortical cell vacuolization were also observed in 1000 mg/kg females and males, respectively. All changes related to the test substance had disappeared or showed a tendency for decrease after a 14-day recovery period. The NOEL is considered to be 60 mg/kg/day for both sexes.

2. Genetic Toxicity

2-1. Bacterial test 2)

Purity:93.9%
Test species/strains:S.typhimurium TA100, TA1535, TA98, TA1537,
Escherichia coli WP2 uvrA
Test methods:OECD guidelines (No. 471, 472) and Guidelines for Screening Mutagenicity Testing of Chemicals (Japan)
　Procedures:Pre-incubation method
　Solvent:DMSO
　Positive controls:-S9 mix, AF-2 (TA100, TA98), sodium azide (TA1535),
ENNG (WP2 uvrA) and 9-aminoacridine (TA1537)
+S9 mix, 2-aminoanthracene (all strains)
　Doses:-S9 mix: 19.5, 39.1, 78.1, 156, 313, 625, 1250 μg/plate (Salmonella strains)
39.1, 78.1, 156, 313, 625, 1250 μg/plate (WP2 uvrA)
+S9 mix: 39.1, 78.1, 156, 313, 625, 1250 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 a concentration of 625 μg/plate, with or without metabolic activation.

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

Escherichia coli WP2 uvrA
+?-
without metabolic activation[ ][ ][*]
with metabolic activation[ ][ ][*]

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

Purity:93.9%
Type of cell used:Chinese hamster CHL/IU cells
Test method:OECD guideline (No. 473) and Guidelines for Screening Mutagenicity Testing of Chemicals (Japan)
　Solvent:DMSO
　Positive controls:-S9 mix, Mitomycin C
+S9 mix, Benzo[a]pyrene
　Doses:-S9 mix (24 h treatment): 0, 15, 30, 60 μg/ml
-S9 mix (48 h treatment): 0, 5, 10, 20 μg/ml
-S9 mix (6 h pulse treatment): 0, 31.3, 62.5, 125 μg/ml
+S9 mix (6 h pulse treatment): 0, 20, 40, 80, 120 μg/ml
　S-9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
　Plates/test:2
GLP:Yes

　 Test results:

This chemical induced structural chromosomal aberrations in the presence of an exogenous metabolic activation system.

Lowest concentration producing cytogenetic effects in vitro:
　With metabolic activation (6 h pulse treatment): 120 μg/ml

Genotoxic effects:
clastogenicitypolyploidy
+?-+?-
without metabolic activation:[ ][ ][*][ ][ ][*]
with metabolic activation:[*][ ][ ][ ][ ][*]

1)The tests were performed by the Research Institute for Animal Science in Biochemistry and Toxicology, 3-7-11 Hashimotodai, Sagamihara-shi, Kanagawa 229, Japan. Tel +81-427-62-2775 Fax +81-427-62-7979
2)The tests were performed by the Mitsubishi Chemical Safety Institute Ltd., 14 Sunayama, Hasaki-machi, Kashima-gun, Ibaraki, 314-02, Japan. Tel +81-479-46-2871 Fax +81-479-46-2874