2-(4-Morpholinyldithio)benzothiazole

2-(4-モルホリニルジチオ)ベンゾチアゾール


[CAS No. 95-32-9]

4-Morpholinyl-2-benzothiazyl disulfide

4-モルホリニル-2-ベンゾチアジルジスルフィド

Molecular formula: C11H12N2OS3　Molecular weight: 284.43

ABSTRACT

2-(4-Morpholinyldithio)benzothiazole was studied for oral toxicity in rats of both sexes in a single dose toxicity test at doses of 0 and 2000 mg/kg. LD50 values were estimated to be more than 2000 mg/kg for both sexes.

2-(4-Morpholinyldithio)benzothiazole was studied for oral toxicity in rats in a 28-day repeated dose toxicity test at doses of 0, 100, 300, and 1000 mg/kg/day.

Neither dead nor moribund animals were noted in either sex in any group. No changes attributable to the test substance were noted in general signs or body weights. Transiently low food consumption and transiently high water intake were noted in both sexes at 1000 mg/kg. In the organ weight measurement, the absolute liver weights tended to be high, and the relative liver weights were high in the males given 1000 mg/kg and in the females receiving 300 or 1000 mg/kg. No changes in liver weight were noted in either sex at the end of the recovery period. No changes attributable to the test substance were noted in behavior, sensory response, grip strength, spontaneous motor activity, urinalysis, hematological examination, blood chemical analysis, necropsy findings, or histopathological findings.

The NOELs for repeated dose toxicity are considered to be 300 mg/kg/day for males and 100 mg/kg/day for females.

2-(4-Morpholinyldithio)benzothiazole was studied for oral toxicity in rats in an OECD preliminary reproduction toxicity screening test at doses of 0, 100, 300, and 1000 mg/kg/day.

Neither dead nor moribund animals were noted in either sex in any group. No changes attributable to the test substance were noted in general signs. Male body weights were low, and female body weights were low during the pregnancy period at 1000 mg/kg. Transiently low food consumption was noted in both sexes at 300 mg/kg and in the males at 1000 mg/kg, and low food consumption was noted in the females at 1000 mg/kg. No changes attributable to the test substance were apparent in either sex in necropsy findings, organ weights, or histopathological findings. Also, no changes attributable to the test substance were noted in sperm analysis. The NOEL for repeated dose toxicity is considered to be 100 mg/kg/day for both sexes.

Regarding the reproductive and developmental toxicity, no changes attributable to the test substance were noted in parental animals or pups. The NOEL for reproductive performance is considered to be 1000 mg/kg/day for parental animals and pups.

Reverse mutation tests using microorganisms (Salmonella typhimurium, Escherichia coli) were conducted to assess the potential of 2-(4-morpholinyldithio)benzothiazole to induce gene mutations. 2-(4-Morpholinyldithio)benzothiazole did not induce gene mutations in the bacteria under the conditions of this study.

In vitro chromosomal aberration tests using cultured Chinese hamster cells (CHL/IU) were conducted to assess the potential of 2-(4-morpholinyldithio)benzothiazole to induce chromosomal aberrations. 2-(4-Morpholinyldithio)benzothiazole induced chromosomal aberrations in cultured cells under the conditions of this study.

SUMMARIZED DATA FROM THE STUDIES

1. Single Dose Oral Toxicity 1)

Purity:98.4 %
Test Species/strain:Rat/Crj:CD(SD)IGS
Test method:OECD Test Guideline 401
　Route:Oral (Gavage)
　Dosage:0 (Vehicle), 2000 mg/kg
　Number of animals/group:Males, 5; females, 5
　Vehicle:0.5 % Sodium carboxymethylcellulose solution
GLP:Yes

　Test results:

No deaths were observed in either sex. No abnormal signs were noted in either sex. Lowering of body weights was noted in females at 2000 mg/kg. At necropsy, no abnormalities were noted in either sex. LD50 values were estimated to be more than 2000 mg/kg for both sexes.

2. Repeated Dose Oral Toxicity 1)

Purity:98.4 %
Test Species/strain:Rat/Crj:CD(SD)IGS
Test method:OECD Test Guideline 407
　Route:Oral (Gavage)
　Dosage:0 (Vehicle), 100, 300, 1000 mg/kg
　Number of animals/group:Males, 12; females, 12 (0, 300, 1000 mg/kg)
Males, 6; females, 6 (100 mg/kg)
　Vehicle:0.5 % Sodium carboxymethylcellulose solution
　Administration period:Males and females, 28 days
　Terminal killing:Males and females, day 29 or 43
GLP:Yes

　Test results:

Neither dead nor moribund animals were noted in either sex in any group. No changes attributable to the test substance were noted in general signs or body weights. Transiently low food consumption and transiently high water intake were noted in both sexes at 1000 mg/kg. No changes attributable to the test substance were noted in behavior, sensory response, grip strength, and spontaneous motor activity. In the organ weight measurement, the absolute liver weights tended to be high, and the relative liver weights were high in the males at 1000 mg/kg and in the females at 300 and 1000 mg/kg. No changes in liver weights were noted in either sex at the end of the recovery period. No changes attributable to the test substance were noted in urinalysis, hematological examination, blood chemical analysis, necropsy findings, or histopathological findings.

The NOELs for repeated dose toxicity are considered to be 300 mg/kg/day for males and 100 mg/kg/day for females.

3. Preliminary Reproductive Toxicity 1)

Purity:98.4 %
Test Species/strain:Rat/Crj:CD(SD)IGS
Test method:OECD Test Guideline 421
　Route:Oral (Gavage)
　Dosage:0 (Vehicle), 100, 300, 1000 mg/kg
　Number of animals/group:Males, 12; females, 12
　Vehicle:0.5 % Sodium carboxymethylcellulose solution
　Administration period:Males, 50-52 days
Females, from 14 days before mating to day 3 of lactation
　Terminal killing:Males, days 51-53
Females, day 4 of lactation
GLP:Yes

　Test results:

<Repeated dose toxicity>

Neither dead nor moribund animals were noted in either sex in any group. No changes attributable to the test substance were noted in general signs. Male body weights were low, and female body weights were low during the pregnancy period at 1000 mg/kg. Transiently low food consumption was noted in both sexes at 300 mg/kg and in the males at 1000 mg/kg, and low food consumption was noted in the females at 1000 mg/kg. No changes attributable to the test substance were noted in either sex for necropsy findings, organ weights, or histopathological findings. Also, no changes attributable to the test substance were noted on sperm analysis.

The NOEL for repeated dose toxicity is considered to be 100 mg/kg/day for both sexes.

<Reproductive and Developmental Toxicity>

Regarding the reproductive and developmental toxicity, no changes attributable to the test substance were noted in terms of the number of estrous cases, copulation index, number of conceiving days, fertility index, length of gestation, gestation index, delivery conditions, nursing conditions, number of corpora lutea, number of implantation sites, or the implantation index.

The NOEL for reproductive performance of parental animals is considered to be 1000 mg/kg/day for both sexes.

Regarding the pups, no changes attributable to the test substance were noted in terms of their number, the numbers of stillbirths, and live pups on Day 0 of lactation, sex ratio, delivery index, birth index, live birth index, general signs, number of live pups on Day 4 of lactation, viability index on Day 4 of lactation, external features, body weight change, or necropsy findings.

The NOEL for pups is considered to be 1000 mg/kg/day.

4. Genetic Toxicity

4-1. Bacterial test 2)

Purity:98.4 %
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 hydrochloride (TA1537)
+S9 mix; 2-Aminoanthracene (all strains)
　Dosage:-S9 mix; 0, 2.29, 6.86, 20.6, 61.7, 185, 556, 1667, 5000 μg/plate (all strains for the dose-finding study)
+S9 mix; 0, 2.29, 6.86, 20.6, 61.7, 185, 556, 1667, 5000 μg/plate (all strains for the dose-finding study)
-S9 mix; 0, 2.34, 4.69, 9.38, 18.8, 37.5, 75.0, 150 μg/plate (all strains for the main study)
+S9 mix; 0, 18.8, 37.5, 75.0, 150, 300, 600 μg/plate (TA100 for the main study)
+S9 mix; 0, 4.69, 9.38, 18.8, 37.5, 75.0, 150, 300 μg/plate (TA1535, WP2 uvrA, TA98, TA1537 for the main study)
-S9 mix; 0, 2.34, 4.69, 9.38, 18.8, 37.5, 75.0, 150 μg/plate (all strains for the additional study)
+S9 mix; 0, 4.69, 9.38, 18.8, 37.5, 75.0, 150, 300 μg/plate (TA100 for the additional study)
　S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
　Plates/test:3
　Number of replicates:3
GLP:Yes

　Test results:

No increase in revertant colonies was observed in the test with either the non-activation method (-S9 mix) or the activation method (+S9 mix).

Genetic effects:
Salmonella typhimurium TA100, TA1535, TA98, TA1537
+?-
Without metabolic activation:[ ][ ][*]
With metabolic activation:[ ][ ][*]

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

4-2. Non-bacterial in vitro test (chromosomal aberration test) 2)

Purity:98.4 %
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, 14.0, 23.3, 38.9 μg/mL (main study)
+S9 mix (short-term treatment); 0, 38.9, 64.8, 108 μg/mL (main study)
-S9 mix (short-term treatment); 0, 20.0, 30.0, 40.0 μg/mL (confirmation study)
+S9 mix (short-term treatment); 0, 80.0, 90.0, 100, 110, 120 μg/mL (confirmation study)
　S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
　Plates/test:2
GLP:Yes

　Test results:

A dose-dependent increase in structural aberrations was observed in the test with the short-term treatment(+S9 mix).

Lowest concentration producing cytogenetic effects in vitro
<Confirmation test>		:
With metabolic activation (short-term treatment):80.0 μg/mL (clastogenicity)

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

1)The tests were performed by Nihon Bioresearch Inc., 6-104, Majima, Fukuju-cho, Hashima, Gifu, 501-6251, Japan. Tel +81-58-392-6222 Fax +81-58-392-1284
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