1,3-Dibromopropane

1,3-ジブロモプロパン

[CAS No. 109-64-8]

Molecular formula: C₃H₆Br₂　Molecular weight: 201.89

ABSTRACT

1,3-Dibromopropane was studied for oral toxicity in rats in a 28-day repeated dose toxicity test at doses of 0, 10, 50 and 250 mg/kg.

Salivation, anemic changes (occurring in the recovery period in males), increases in total protein and lipid, increased liver weight, hypertrophy of the centrilobular hepatocytes and decreased vacuolation in the perilobular hepatocytes were observed in both sexes given 250 mg/kg. Of these, hypertrophy of the centrilobular hepatocytes in both sexes and increased liver weight, decreased vacuolation in the perilobular hepatocytes and an increase in total protein were also observed in males given 50 mg/kg. No treatment-related changes were noted in the 10 mg/kg group. Therefore, the NOEL is considered to be 10 mg/kg/day for both sexes.

Reverse mutation assays using microorganisms (Salmonella typhimurium TA100, TA1535, TA98, TA1537 and Escherichia coli WP2 uvrA) were conducted to assess the potential of 1,3-dibromopropane to induce gene mutations. Mutagenic activity was found in S. typhimurium TA100 and TA1535 with metabolic activation under the present experimental conditions.

In vitro tests using cultured Chinese hamster cells (CHL/IU) were conducted to assess the potential of 1,3-dibromopropane to induce chromosomal aberrations. Structural chromosome aberrations were induced under the present experimental conditions, suggesting that the test substance, 1,3-dibromopropane, is clastogenic to cultured mammalian cells.

SUMMARIZED DATA FROM THE STUDIES

1. Single Dose Oral Toxicity ¹⁾

Purity	:	99.8 %
Test species/strain	:	Rat/Crj:CD(SD)IGS
Test method	:	OECD Test Guideline 401
Route	:	Oral (gavage)
Dosage	:	0 (vehicle), 300, 500, 900, 1500 mg/kg
Number of animals/group	:	Males, 5; females, 5
Vehicle	:	Corn oil
GLP	:	Yes

　Test results:

Deaths occurred in females in the 500 mg/kg and in both sexes in the 900 and 1500 mg/kg groups between days 1 and 3 after administration. Salivation in all treated groups and lacrimation in the 500 mg/kg and higher groups were observed in both sexes. In addition, decreased spontaneous movement, abnormal gait, adoption of a prone or lateral position and oligopnea were also evident in some animals which died of either sex. All clinical signs observed in the survivors disappeared by day 1 after the administration. Suppression of gain or decrease of body weights was observed in both sexes in the 500 mg/kg and higher groups but this had disappeared by day 10 after administration in males and day 3 after administration in females.

LD₅₀: Males, 734 mg/kg; females, 671 mg/kg

2. Repeated Dose Oral Toxicity ¹⁾

Purity	:	99.8 %
Test species/strain	:	Rat/Crj:CD(SD)IGS
Test method	:	Guideline for the 28-Day Repeated Dose Toxicity Test in Mammalian Species (Chemical Substances Control Law of Japan)
Route	:	Oral (gavage)
Dosage	:	0 (vehicle), 10, 50, 250 mg/kg/day
Number of animals/group		Males, 6; females, 6
Vehicle	:	Corn oil
Administration period	:	Males and females, 28 days
Terminal killing	:	Days 29 or 43
GLP	:	Yes

　Test results:

Salivation was observed in both sexes given 250 mg/kg. Decreased body weight gain was observed in males given 250 mg/kg. Hematological examination revealed decreases in the red blood cell count, hemoglobin, hematocrit, and lymphocyte fraction ratio and increases in the reticulocyte ratio and segmented neutrophil fraction ratio in females given 250 mg/kg. Blood chemical examinations revealed an increase in total protein in males receiving 50 mg/kg and both sexes given 250 mg/kg. Further, increases in ASAT, ALAT, γ-GTP, albumin, total cholesterol, phospholipids, total bilirubin, chloride and calcium were observed in both sexes given 250 mg/kg and increases in LDH, A/G ratio and triglyceride and a decrease in potassium were observed in females given 250 mg/kg. Urinalysis revealed increases in urinary protein in males given 50 or 250 mg/kg and urine volume in females given 250 mg/kg associated with decrease in osmolality. An increase in water intake was also observed in females given 250 mg/kg. Macroscopically livers were enlarged in males given 250 mg/kg and increased liver weights were observed in females given 50 mg/kg and both sexes given 250 mg/kg. Histopathological examination revealed hypertrophy of the centrilobular hepatocytes in both sexes given 50 and 250 mg/kg and decreased vacuolation in the perilobular hepatocytes in females given 50 mg/kg and both sexes given 250 mg/kg. In addition, increased kidney and decreased thymus weights were observed in females given 250 mg/kg. The changes described above mostly disappeared or were diminished after a 14-day recovery period; however, the difference in body weight in males given 250 mg/kg did not diminish and anemic changes like those in 250 mg/kg females at the end of administration period were observed in males given 250 mg/kg at the end of recovery period.

The NOEL is considered to be 10 mg/kg /day for both sexes.

3. Genetic Toxicity

3-1. Bacterial test ¹⁾

Purity	:	99.8 %
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 and WP2 uvrA), Sodium azide (TA1535) and 2-Methoxy-6-chloro-9-[3-(2-chloroethyl)-aminopropylamino]acridine・2HCl (TA1537) +S9 mix; Benzo[a]pyrene (TA100, TA98, TA1537) and 2-Aminoanthracene (TA1535 and WP2 uvrA)
Dosage	:	-S9 mix; 0, 19.5, 39.1, 78.1, 156, 313, 625, 1250 μg/plate (all strains) +S9 mix; 0, 19.5, 39.1, 78.1, 156, 313, 625, 1250 μg/plate (all strains)
S9	:	Rat liver, induced with phenobarbital and 5,6-benzoflavone
Plates/test	:	3
GLP	:	Yes

　Test results:

Mutagenic activity was found in the S. typhimurium TA100 and TA1535 with metabolic activation. Toxicity was observed at 1250 μg/plate or more (all strains) with and without metabolic activation.

Genetic effects:
S. typhimurium TA100, TA1535

	+	?	-
Without metabolic activation:	[ ]	[ ]	[*]
With metabolic activation:	[*]	[ ]	[ ]

Genetic effects:
S. typhimurium TA98, TA1537

	+	?	-
Without metabolic activation:	[ ]	[ ]	[*]
With metabolic activation:	[ ]	[ ]	[*]

E. coli WP2 uvrA

	+	?	-
Without metabolic activation:	[ ]	[ ]	[*]
With metabolic activation:	[ ]	[ ]	[*]

3-2. Non-bacterial in vitro test (chromosomal aberration test)¹⁾

Purity	:	99.8 %
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 control	:	-S9 mix; Mitomycin C +S9 mix; Cyclophosphamide
Dosage	:	-S9 mix (short-term treatment); 0, 60, 80, 100, 120, 140, 160 and 180 μg/mL +S9 mix (short-term treatment); 0, 60, 80, 100, 120, 140, 160 and 180 μg/mL
S9	:	Rat liver, induced with phenobarbital and 5,6-benzoflavone
Plates/test	:	2
GLP	:	Yes

　Test results:

Structural, but not numerical chromosomal aberrations were observed in the test after the short-term treatment (both -S9 mix and +S9 mix).

Lowest concentration producing cytogenetic effects in vitro		:
	Without metabolic activation (short-term treatment)	:	100 μg/mL (clastogenicity)
	With metabolic activation (short-term treatment)	:	60 μg/mL (clastogenicity)

Genetic effects:

	clastogenicity			polyploidy
	+	?	-	+	?	-
Without metabolic activation:	[*]	[ ]	[ ]	[ ]	[ ]	[*]
With metabolic activation:	[*]	[ ]	[ ]	[ ]	[ ]	[*]

1)	The tests were performed by the Bozo Research Center Inc., 1284 Kamado, Gotemba-shi, Shizuoka, 412-0039, Japan. Tel +81-550-82-2000 Fax +81-550-82-2379