1,2-Bis(2-chloroethoxy)ethane

1,2-ビス(2-クロロエトキシ)エタン


[CAS No. 112-26-5]

Triethyleneglycol dichloride

トリエチレングリコールジクロライド

Molecular formula: C6H12Cl2O2　Molecular weight: 187.07

ABSTRACT

A single dose oral toxicity test of 1,2-bis(2-chloroethoxy)ethane was conducted at doses of 0, 180, 270, 400, and 600 mg/kg using male and female rats. Two males receiving 180 mg/kg, 1 male and 2 females receiving 270 mg/kg, 4 males and 2 females receiving 400 mg/kg, and 5 males and 5 females receiving 600 mg/kg were found dead. These animals died within 24 hours after treatment excluding 1 male receiving 180 mg/kg. Clinical signs such as hypoactivity, salivation, lacrimation, diarrhea, adoption of a prone or lateral position, and a subnormal temperature were observed in the treatment groups. The LD50 values were 269 mg/kg for males and 353 mg/kg for females.

A repeated dose oral toxicity test was conducted at doses of 0, 50, 100, and 200 mg/kg/day using male and female rats. One male receiving 200 mg/kg was found dead and another male receiving the same dose was moribund at the termination of the administration period. Salivation was observed in both sexes in the treatment groups but it disappeared during the recovery period. Therefore, salivation was considered to be a conditional reflex to administration of the test substance. Decreased spontaneous motor activity, wasting, piloerection, dirty hair, and abnormal respiratory noises were observed in animals which died or were moribund receiving 200 mg/kg.

A functional observation battery revealed salivation in both sexes in the treatment groups but this was not considered to be a sign of neurotoxicity.

The serum levels of ALT activity and potassium concentration were elevated and the sodium concentration was depressed in males receiving 200 mg/kg as compared to control values.

The relative liver weights in females receiving 100 and 200 mg/kg were higher than in the controls.

Histopathological evaluation revealed degeneration of myocardium and necrosis in the hearts in both sexes receiving 200 mg/kg but these findings disappeared in the recovery period.

The NOEL for the repeated dose oral toxicity test is considered to be 100 mg/kg/day for males and 50 mg/kg/day for females.

Genotoxicity of 1,2-bis(2-chloroethoxy)ethane was studied by a reverse mutation test in bacteria. This substance was mutagenic in Salmonella typhimurium TA1535, with and without an exogenous metabolic activation system.

Genotoxicity of 1, 2-bis(2-chloroethoxy)ethane was studied by chromosomal aberration test in cultured Chinese hamster lung (CHL/IU) cells.

1, 2-Bis(2-chloroethoxy)ethane induced structural chromosomal aberrations in the metabolic activation system. Statistically significant increase in polyploid cells, was observed in the absence of S9 mix, but it was judged to be negative biologically because of the low incidence (1.5 %).

SUMMARIZED DATA FROM THE STUDIES

1. Single Dose Oral Toxicity 1)

Purity:99.7 %
Test species/strain:Rat/Crj:CD(SD)IGS
Test method:OECD Test Guideline 401
　Route:Oral (Gavage)
　Dosage:0 (Vehicle), 180, 270, 400, 600 mg/kg/day
　Number of animals/group:Males and females; 5
　Vehicle:Corn oil
GLP:Yes

　Test results:

Two males receiving 180 mg/kg, 1 male and 2 females receiving 270 mg/kg, 4 males and 2 females receiving 400 mg/kg, and 5 males and 5 females receiving 600 mg/kg were found dead. These animals died within 24 hours after treatment, excluding 1 male receiving 180 mg/kg. Clinical signs such as hypoactivity, salivation, lacrimation, diarrhea, adoption of a prone or lateral position, and a subnormal temperature were observed in the treatment groups. The LD50 value was 269 mg/kg for males and 353 mg/kg for females.

2. Repeated Dose Oral Toxicity 1)

Purity:99.7 %
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)
　Dosage:0 (Vehicle), 50 100, 200 mg/kg/day
　Number of animals/group:Males and females; 5
　Vehicle:Corn oil
　Administration period:Males and females; 28 days
　Terminal killing:Males and females, days 29 or 43
GLP:Yes

　Test results:

One male receiving 200 mg/kg was found dead and another male receiving the same dose was moribund at the termination of the administration period. Salivation was observed in both sexes in the treatment groups but it disappeared during the recovery period. Therefore, salivation was considered to be a conditional reflex to administration of the test substance. Decreased spontaneous motor activity, wasting, piloerection, dirty hair, and abnormal respiratory noises were observed animals which died or were moribund receiving 200 mg/kg.

A functional observation battery revealed salivation in both sexes in the treatment groups but this was not considered to be a sign of neurotoxicity.

The serum levels of ALT activity and potassium concentration were elevated and the sodium concentration was depressed in males receiving 200 mg/kg as compared to the control values. The relative liver weights in female receiving 100 and 200 mg/kg were higher than in the controls.

Histopathological evaluation revealed degeneration of myocardium and necrosis of hearts in both sexes receiving 200 mg/kg but these findings disappeared in the recovery period.

The NOEL for the repeated dose oral toxicity test is considered to be 100 mg/kg/day for males and 50 mg/kg/day for females.

3. Genetic Toxicity

3-1. Bacterial test 2)

Purity:99.7 %
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-Amino-acridine (TA1537)
+S9 mix; 2-Aminoanthracene (five strains)
　Dosage:-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 the cytotoxicity test)
　Number of replicates:2 (plus 1 cytotoxicity test)
GLP:Yes

　Test results:

This chemical induced gene mutations in S. typhimurium TA1535 with and without S9 mix. Growth inhibition was not observed up to 5000 μg/plate in any strain, with or without S9 mix.

Genetic effects:
Salmonella typhimurium TA100, TA98, TA1537
+?-
Without metabolic activation:[ ][ ][*]
With metabolic activation:[ ][ ][*]

Salmonella typhimurium TA1535
+?-
Without metabolic activation:[*][ ][ ]
With metabolic activation:[*][ ][ ]

Escherichia coli WP2 uvrA
+?-
Without metabolic activation:[ ][ ][*]
With metabolic activation:[ ][ ][*]

4. Non-bacterial in vitro test (chromosomal aberration test) 3)

Purity:99.7 %
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 (short-term treatment); 0, 0.48, 0.95, 1.9 mg/mL
+S9 mix (short-term treatment); 0, 0.015, 0.030, 0.060 mg/mL
　S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
　Plates/test:2
GLP:Yes

　Test results:

Cells with structural chromosomal aberrations were increased significantly at the highest dose (0.060 mg/mL) after short-term treatment with metabolic activation. Although statistically significant increase of polyploid cells was observed at the highest dose (1.9 mg/mL) with the short-term treatment without metabolic activation, it was judged to be negative biologically because the incidence was low (1.5 %).

Lowest concentration producing cytogenetic effects in vitro:
With metabolic activation (short-term treatment):0.060 mg/mL

Genotoxic effects:
clastogenicitypolyploidy
+?-+?-
Without metabolic activation:[ ][ ][*][ ][ ][*]
With metabolic activation:[*][ ][ ][ ][ ][*]

1)The tests were conducted at 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