2,6-Dichlorotoluene

2,6-ジクロロトルエン


[CAS No. 118-69-4]

Molecular formula: C7H6Cl2 Molecular weight: 161.03

ABSTRACT

2,6-Dichlorotoluene was studied for repeated dose oral toxicity and reproductive/developmental toxicity in rats according to the OECD test guideline 422 at doses of 0, 30, 100, 300 and 1000 mg/kg/day.

With regard to repeated dose toxicity, no animals died in any groups. Decrease in locomotor activity and suppression of body weight gain were observed in males of the groups receiving 300 mg/kg/day or more. Decreases in locomotor activity, body weight gain and food consumption were observed in females of the 1000 mg/kg/day group. Increase in relative kidney weights was observed in males of the 300 and 1000 mg/kg/day groups and in females of the 1000 mg/kg/day group. Centrilobular hypertrophy of hepatocytes was observed in males and females of the 300 and 1000 mg/kg/day groups, along with a ground glass appearance of the cells in the males.

NOELs for toxicity of 2,6-dichlorotoluene are considered to be 300 mg/kg/day in males and 100 mg/kg/day in females.

Regarding reproductive/developmental toxicity, no adverse effects on copulation, fertility and delivery were noted in any groups. Numbers of dead pups were increased and viability on postnatal day 4 was decreased in the 300 and 1000 mg/kg/day groups. Pup weights on postnatal day 4 showed a tendency for decrease in the 1000 mg/kg group. No morphological abnormalities were found in pups of any of the 2,6-dichlorotoluene -treated groups.

The NOELs for reproductive/developmental toxicity are considered to be 1000 mg/kg/day in males, 100 mg/kg/day in females, and 300 mg/kg/day in offspring.

Genotoxicity of 2,6-dichlorotoluene was studied in a reverse mutation test in bacteria. This substance was not mutagenic in Salmonella typhimurium TA100, TA1535, TA98, TA1537 or Escherichia coli WP2 uvrA, with or without an exogenous metabolic activation system.

Genotoxicity of 2,6-dichlorotoluene was studied by a chromosomal aberration test in cultured Chinese hamster lung (CHL/IU) cells.

2,6-Dichlorotoluene did not induce either structural chromosomal aberrations or polyploidy at any dose, with or without a metabolic activation system.

SUMMARIZED DATA FROM THE STUDIES

1. Repeated Dose and Reproductive/Developmental Toxicity 1)

Purity:99.2 %
Test species/strain:Rat/Crj:CD
Test method:OECD Test Guideline 422
 Route:Oral (gavage)
 Doses:0 (vehicle), 30, 100, 300, 1000 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>

1. Males: Decrease in locomotor activity was observed in one animal in the 300 mg/kg group, as well as decrease in locomotor activity (9 animals) and adoption of a prone position (2 animals) in the 1000 mg/kg group. Body weight gain was suppressed in the 300 and 1000 mg/kg groups. Autopsy following treatment for 42 days demonstrated increases in the relative kidney weights in the 300 and 1000 mg/kg groups and the relative liver weights in the 1000 mg/kg group. As histopathological findings, increase in eosinophilic bodies in the kidneys was observed in the groups receiving 100 mg/kg or more, and centrilobular hypertrophy and ground glass appearance of the hepatocytes were observed in those with 300 mg/kg and more. Decrease in the concentration of glucose was determined in the 300 and 1000 mg/kg groups. No effects of 2,6-dichlorotoluene were observed on food consumption and hematology.

2. Females: Decrease in locomotor activity (all animals tested), adoption of a prone position (10 animals) and incomplete eyelid opening (6 animals) were observed in the 1000 mg/kg group. Food consumption was decreased as well as suppression of body weight gain in the 1000 mg/kg group. At autopsy on postpartum day 4, increases in the relative kidney weight and relative liver weight were found in the 1000 mg/kg group. As histopathological findings, vacuolar and fatty degeneration in the proximal kidney tubules and centrilobular hypertrophy of the hepatocytes were observed in the 300 and 1000 mg/kg groups. In addition, decreases in the relative thymus weight and atrophy of the thymus were observed in the 300 mg/kg and more groups. No effects of 2,6-dichlorotoluene were observed on urinalysis.

NOELs for repeated dose toxicity of 2,6-dichlorotoluene are considered to be 30 mg/kg/day in males and 100 mg/kg/day in females.

<Reproductive and developmental toxicity>

No adverse effects of 2,6-dichlorotoluene at any dose level were noted for copulation, fertility or delivery. Numbers of dead pups were increased and viability on postnatal day 4 was decreased in the 300 and 1000 mg/kg groups. Pup weights on postnatal day 4 tended to be decreased in the 1000 mg/kg group. No morphological abnormalities were found in pups of any 2,6-dichlorotoluene -treated group.

NOELs for reproductive and developmental toxicity of 2,6-dichlorotoluene are considered to be 1000 mg/kg/day in males, 100 mg/kg/day in females and 300 mg/kg/day in offspring.

2. Genetic Toxicity

2-1. Bacterial test 1)

Purity:99.6 %
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:Plate incorporation 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)
 Dosage:-S9 mix; 0, 4.69, 9.38, 18.8, 37.5, 75.0, 150 μg/plate (TA100, TA98, TA1537, WP2 uvrA)
-S9 mix; 0, 2.34, 4.69, 9.38, 18.8, 37.5, 75.0, 150 μg/plate (TA1535)
+S9 mix; 0, 18.8, 37.5, 75.0, 150, 300, 600 μg/plate (TA100, TA98, TA1537, WP2 uvrA)
+S9 mix; 0, 9.38, 18.8, 37.5, 75.0, 150, 300, 600 μg/plate (TA1535)
 S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
 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, TA98, TA1535, TA1537 and E. coli WP2 uvrA strains with or without S9 mix. Growth inhibition was observed at 75.0 μg/plate and more (TA100, TA98, TA1537, WP2 uvrA) and 37.5 μg/plate and more (TA1535) without S9 mix, and at 300 μg/plate and more (five strains) with S9 mix.

Genetic effects:
Salmonella typhimurium TA100, TA98, TA1535, 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) 1)

Purity:99.6 %
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
 Dosage:-S9 mix (6 hr short-term treatment); 0, 0.008, 0.017 mg/mL
+S9 mix (6 hr short-term treatment); 0, 0.024, 0.048 mg/mL
-S9 mix (24 and 48 hrs continuous treatment); 0, 0.017, 0.035 mg/mL
 S9:Rat liver, induced with phenobarbital and 5, 6-benzoflavone
 Plates/test:2
GLP:Yes

 Test results:

Cytogenetic effects were not seen under the conditions of this experiment.

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