1-Bromo-3-chloropropane

1-ブロモ-3-クロロプロパン

[CAS No. 109-70-6]

1-Chloro-3-bromopropane

1-クロロ-3-ブロモプロパン

Molecular formula: C₃H₆BrCl　Molecular weight: 157.44

ABSTRACT

1-Bromo-3-chloropropane was studied for oral toxicity in rats in a 28-day repeat dose toxicity test at doses of 0, 20, 100 and 500 mg/kg. Nine of 10 male animals in the 500 mg/kg group died or were sacrificed because of a moribund condition. Repeated administration at 500 mg/kg caused vacuolar degeneration in the hypothalamus and thalamus, and a neurogenic syndrome featuring convulsions in the male animals which died later. Centrilobular hypertrophy of hepatocytes in the animals of both sexes, and atrophy of seminiferous tubules in the male animals were observed at 100 mg/kg and more. In addition, anemia occurred with enhanced hemosiderosis in the spleen. Thus, the NOEL for the 28-day repeat dose oral toxicity test of 1-bromo-3-chloropropane is considered to be 20 mg/kg/day for males and females.

Reverse mutation assays using microorganisms (Salmonella typhimurium, Escherichia coli) were conducted to assess the potential of 1-bromo-3-chloropropane to induce gene mutations.

1-Bromo-3-chloropropane induced gene mutations in bacteria under the conditions of this study.

In vitro chromosomal aberration tests using cultured cells (CHL/IU) were conducted to assess the potential of 1-bromo-3-chloropropane to induce chromosomal aberrations.

1-Bromo-3-chloropropane induced chromosomal aberrations in cultured cells under the conditions of this study.

SUMMARIZED DATA FROM THE STUDIES

1. Single Dose Oral Toxicity ¹⁾

Purity	:	99.9 area%
Test species/strain	:	Rat/Crj:CD(SD)IGS
Test method	:	OECD Test Guideline 401
Route	:	Oral(gavage)
Doses	:	Males, 0(vehicle), 500, 800, 1300, 2000 mg/kg Females, 0(vehicle), 800, 1300 mg/kg
Number of animals/group	:	Males, 5; females, 5
Vehicle	:	Corn oil
GLP	:	Yes

　Test results:

Deaths occurred in both sexes of groups receiving 1300 mg/kg or more. Clinical signs of salivation, decrease in locomotor activity, a prone position and ataxic gait were observed. Depressed body weight gain and/or depressed body weight was observed on the second day in the groups of both sexes given more than 800 mg/kg. At autopsy, insufficient retraction and dark red areas in the lung and pale discoloration of the spleen were observed in dead animals. Histopathological examination further showed pulmonary edema and atrophy of the spleen.

The LD₅₀ values were estimated to be between 1300 and 2000 mg/kg for males and between 800 and 1300 mg/kg for females.

2. Repeat Dose Toxicity ¹⁾

Purity	:	99.9 area%
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)
Doses	:	0(vehicle), 20, 100, 500 mg/kg/day
Number of animals/group	:	Males, 10; females, 10(0, 500 mg/kg) Males, 5; females, 5(20, 100 mg/kg)
Vehicle	:	Corn oil
Administration period	:	Males and females, 28 days
Terminal kill	:	Males and females, on days 29 and 43
GLP	:	Yes

　Test results:

Nine of 10 male animals in the 500 mg/kg group died or were sacrificed because of a moribund condition. In the 3rd week and later during the administration period, the animals in the 500 mg/kg group showed stereotyped scratching behavior with forelimbs, and then, clonic or tonic convulsions occurred in the male animals on the 20th day and later. On hematological examination, significant decrease in the packed cell volume and increase in MCHC were found in the male animals of the 100 mg/kg group. At the end of the administration period, no marked changes in hematological values were observed in the female animals, but at the end of recovery period, the erythrocyte count, hemoglobin concentration and packed cell volume were decreased significantly. The absolute liver weights or weights relative to body weights were significantly increased in the animals given 100 mg/kg and more, and the absolute or relative weights of kidneys were increased significantly in the male animals of the 100 mg/kg group and in the female animals of the 500 mg/kg group. On histopathological examination, centrilobular hypertrophy of the hepatocytes was observed in animals of both sexes given 100 mg/kg and more, including both dead and sacrificed animals. In the 500 mg/kg group, vacuolar degeneration was observed in the thalamus and hypothalamus in the brain and enhanced hemosiderosis was observed in the spleen. Scarcely any extramedullary hematopoiesis but atrophy of the spleen was observed in some of the dead and the sacrificed animals. In the testes, seminiferous tubular atrophy was apparent in animals given 100 mg/kg and more, and cell debris in the lumen of epididymis ducts and decrease in sperm were observed in some of the animals in the 500 mg/kg group.

Thus, the NOEL for the 28-day repeat dose oral toxicity is considered to be 20 mg/kg/day for males and females.

3. Genetic Toxicity

3-1. Bacterial test ²⁾

Purity	:	99.9 area%
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	:	DMSO
Positive controls	:	-S9 mix; 2-(2-Furyl)-3-(5-nitro-2-furyl)acrylamide (TA100, TA98 and WP2 uvrA), Sodium azide (TA1535) and 9-Aminoacridine hydrochloride (TA1537) +S9 mix; 2-Aminoanthracene (all strains)
Doses	:	-S9 mix; 0, 39.1, 78.1, 156, 313, 625, 1250 μg/plate(TA100, TA1535, TA1537) -S9 mix; 0, 156, 313, 625, 1250, 2500, 5000 μg/plate(TA98) -S9 mix; 0, 288, 412, 588, 840, 1201, 1715, 2450, 3500, 5000 μg/plate(WP2 uvrA) +S9 mix; 0, 39.1, 78.1, 156, 313, 625, 1250 μg/plate(TA1537) +S9 mix; 0, 78.1, 156, 313, 625, 1250, 2500 μg/plate(TA100, TA1535) +S9 mix; 0, 156, 313, 625, 1250, 2500, 5000 μg/plate(TA98) +S9 mix; 0, 288, 412, 588, 840, 1201, 1715, 2450, 3500, 5000 μg/plate(WP2 uvrA)
S9	:	Rat liver, induced with phenobarbital and 5,6-benzoflavone
Plates/test	:	3
Number of replicates	:	2
GLP	:	Yes

　Test results:

Increase in revertant colonies was observed with WP2 uvrA at the non-activation method (-S9) and with TA100, TA1535 and WP2 uvrA, in the presence of a metabolic activation system (+S9).

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	:	99.9 area%
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	:	DMSO
Positive controls	:	-S9 mix; Mitomycin C +S9 mix; Cyclophosphamide
Doses	:	-S9 mix(short-term treatment); 0, 394, 787, 1574 μg/mL +S9 mix(short-term treatment); 0, 62.5, 125, 250, 500 μg/mL -S9 mix(short-term treatment, confirmative test); 0, 1147, 1275, 1417, 1574 μg/mL +S9 mix(short-term treatment, confirmative test); 0, 200, 250, 300, 350 μg/mL
S9	:	Rat liver, induced with phenobarbital and 5,6-benzoflavone
Plates/test	:	2
GLP	:	Yes

　Test results:

Dose-dependent increase in chromosomal structural aberrations was observed after short-term treatment, with or without metabolic activation.

Genetic 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, 257-8523, Japan. Tel +81-463-82-4751 Fax +81-463-82-9627
2)	The tests were performed by the Biosafety Research Center, Foods, Drugs and Pesticides (An-pyo Center), 582-2 Shioshinden, Fukude-cho, Iwata-gun, Shizuoka, 437-1213, Japan. Tel +81-538-58-1266 Fax +81-538-58-1393