3,4-Dichloro-1-butene

3,4-ジクロロ-1-ブテン

[CAS No. 760-23-6]

Molecular formula: C4H6Cl2 Molecular weight: 124.99

ABSTRACT

With regard to repeat dose toxicity, a decrease of food consumption as well as changes in general condition, such as decreased locomotor activity and increased salivation, were noted on the first dosing day in 50 mg/kg males and females. One 50 mg/kg female was sacrificed in a moribund condition on day 2 of lactation. Histopathological examination revealed hepatocellular hypertrophy and increased hyaline droplets in the renal tubular epithelium in 10 and 50 mg/kg males. Liver and kidney weights were increased in males receiving a dose of 10 mg/kg or more. Hepatocellular hypertrophy and increased kidney weights were also observed in 50 mg/kg females.The NOELs for repeat dose toxicity are considered to be 2 mg/kg/day for males and 10 mg/kg/day for females. In terms of reproductive/developmental toxicity, the test substance showed no effects on any relevant parameters. NOELs for both reproductive performance and offspring development are considered to be 50 mg/kg/day.

3,4-Dichloro-1-butene was mutagenic to Salmonella typhimurium TA1535, with or without an exogeneous metabolic activation system, but not mutagenic.

3,4-Dichloro-1-butene induced structural chromosomal aberrations and polyploidy in CHL/IU cells with and without an exogeneous metabolic activation system.

SUMMARIZED DATA FROM THE STUDIES

1. Single Dose Oral Toxicity 1)

Purity	:	99.7%
Test species/strain	:	Rat/Crj:CD (SD)
Test method	:	OECD Guidelines 401
Route	:	Oral (gavage)
Doses	:	0 (vehicle), 670, 804, 965, 1158, 1389, 1667 mg/kg
Number of animals/group	:	Males, 5 ; females, 5
Vehicle	:	Sesame oil
GLP	:	Yes

　 Test results:

Fatalities were found for both sexes at doses of more than 804 mg/kg. Clinical signs of decreased locomotor activity, deep respiration, ptosis, salivation, flaccidity, adoption of a prone position, piloerection and perinasal soiling with nasal discharge were observed in the treated groups. Body weights in the treated groups were lower than those of the control group on the day after dosing. At autopsy, lung enlargement, urine retention and crystalline materials in the urinary bladder, and hemorrhagic black spots in the glandular stomach mucosa were observed in animals. The LD50 values were 943 mg/kg for males and 946 mg/kg for females.

2. Repeat Dose and Reproductive/Developmental Toxicity 1)

Purity	:	99.7%
Test species/strain	:	Rat/Crj:CD (SD)
Test method	:	OECD Combined Repeat Dose and Reproductive/Developmental Toxicity Screening Test
Route	:	Oral (gavage)
Doses	:	0 (vehicle), 0.4, 2, 10, 50 mg/kg/day
Number of animals/group	:	Males, 10 ; females, 10
Vehicle	:	Sesame oil
Administration period	:	Males, 44 days ; Females, from 14 days before mating to day 3 of lactation
Terminal kill	:	Males, day 45 ; Females, day 4 of lactation
GLP	:	Yes

　 Test results:

<Repeat dose toxicity>

In males, histopathological examination revealed hepatocellular hypertrophy and increased hyaline droplets in the renal tubular epithelium with doses of 10 and 50 mg/kg. Absolute kidney weights were increased with 10 mg/kg and absolute and relative weights of the liver and kidneys with 50 mg/kg. Additionally, at the dose of 50 mg/kg, a decrease in food consumption as well as changes in general condition, such as decreased locomotor activity and increased salivation, were noted on the first dosing day. Blood chemical examination revealed an increase in total protein and a decrease in blood urea nitrogen.

In females, similar changes in general condition and food consumption to those in treated males were observed with the 50 mg/kg dose. One female was sacrificed in a moribund condition on day 2 of lactation. Hepatocellular hypertrophy and an increase in relative kidney weights were also observed at the dose of 50 mg/kg. However, no histopathological changes considered to be related to the change of the kidney weight were detected.

The NOELs for repeat dose toxicity are considered to be 2 mg/kg/day for males and 10 mg/kg for females.

<Reproductive and developmental toxicity>

The parental animals exhibited no effects on reproductive parameters including the copulation index, fertility index, gestation length, number of corpora lutea or implantation index, gestation index, delivery index, and behavior at delivery and lactation. There were no significant differences in the number of offspring, sex ratio, live birth index, viability index and body weight. Number of pups alive on day 4 of lactation tended to be slight decreased with the 50 mg/kg dose, caused by litter loss in one dam sacrificed in extremis on day 2 of lactation. No external or visceral anomalies related to the test substance administration were detected in any of the offspring.

The NOELs for both reproductive performance and offspring development are considered to be 50 mg/kg/day.

3. Genetic Toxicity

3-1. Bacterial test 2)

Purity	:	99%
Test species/strains	:	S.typhimurium TA100, TA1535, TA98, TA1537, Escherichia coli WP2 uvrA
Test methods	:	Guidelines for Screening Mutagenicity Testing of Chemicals (Japan) and OECD (471 and 472)
Procedures	:	Plate incorporation method
Solvent	:	Acetone
Positive controls	:	-S9 mix, 2-(2-Furyl)-3-(5-nitro-2-furyl)acrylamide (TA100, WP2, TA98), Sodium azide (TA1535)and 9-Aminoacridine (TA1537), +S9 mix, 2-Aminoanthracene (five strains)
Dosage	:	-S9 mix, 0, 250 -2500 μg/plate (TA100 and TA1535), 0, 39 - 2500 μg/plate (WP2), 0, 78 - 2500 μg/plate (TA98) and 39 - 2500 μg/plate (TA1537) +S9 mix, 0, 1000 - 3000 (TA100), 0, 500 - 2500 μg/plate (TA1535), 0, 39 - 2500 μg/late (TA1537 and WP2) and 0, 39 - 5000 μg/plate (TA98)
S9	:	Rat liver, induced with phenobarbital and 5,6-benzoflavone
Plates/test	:	3
Number of replicates	:	2
GLP	:	Yes

　 Test results:

This chemical induced gene mutations in the S. typhimurium and E. coli strains. Toxicity was observed at 625 μg/plate (TA98 and TA1537), 850 μg/plate (TA100), 1000 μg/plate (TA1535) and 1250 μg/plate (WP2) with the -S9 mix, and at 1250 μg/plate (WP2, TA98 and TA1537), 1500 μg/plate (TA1535) and 2200 μg/plate (TA100) with the +S9 mix.

Genetic effects:

Salmonella typhimurium TA1535

	+	?	-
without metabolic activation	[*]	[ ]	[ ]
with metabolic activation	[*]	[ ]	[ ]

Salmonella typhimurium TA100, 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%
Type of cell used	:	Chinese hamster lung (CHL/IU) cells
Test method	:	Guidelines for Screening Mutagenicity Testing of Chemicals (Japan)
Solvent	:	Acetone
Positive controls	:	-S9 mix, Mitomycin C +S9 mix, Cyclophosphamide
Doses	:	-S9 mix (continuous treatment): 0, 0.0250, 0.050, 0.10 mg/ml -S9 mix (short-term treatment): 0, 0.050, 0.10, 0.20 mg/ml +S9 mix (short-term treatment): 0, 0.00250, 0.0050, 0.010 mg/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 and polyploidy in the absence and presence of an exogeneous metabolic activation system.

Lowest concentration producing cytogenetic effects in vitro:

Without metabolic activation (continuous treatment)	:	0.05 mg/ml (clastogenicity) 0.1 mg/ml (polyploidy)
Without metabolic activation (short-term treatment)	:	0.2 mg/ml (clastogenicity)
With metabolic activation (short-term treatment)	:	0.01 mg/ml (clastogenicity) 0.01 mg/ml (polyploidy)

Genotoxic effects:

	clastogenicity			polyploidy
	+	?	-	+	?	-
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 Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano-shi, Kanagawa, 257, Japan. Tel +81-463-82-4751 Fax +81-463-82-9627