1,3-Diphenylguanidine

1,3-ジフェニルグアニジン


[CAS No. 102-06-7]

N,N'-Diphenylguanidine

N,N'-ジフェニルグアニジン

Molecular formula: C13H13N3 Molecular weight: 211.26

ABSTRACT

1,3-Diphenylguanidine was studied for oral toxicity in rats of both sexes in a single dose toxicity test at doses of 0, 50, 65, 85, 110 and 143 mg/kg. The single dose toxicity test revealed LD50 values of 111 mg/kg for males and 107 mg/kg for females.

1,3-Diphenylguanidine was studied for oral toxicity in rats in a 28-day repeat dose toxicity test at doses of 0, 10, 30, and 90 mg/kg. Dead or moribund animals in the 90 mg/kg group were observed during weeks 2 to 4 of the administration period. Salivation was observed in both sexes in the 30 and 90 mg/kg groups, and many other clinical signs including startle response were observed in both sexes in the 90 mg/kg group. Body weight gain and food consumption were suppressed in both sexes in the 90 mg/kg group. Hematological examination revealed an increase in platelet counts in females in the 30 mg/kg group. Blood chemistry examination revealed a decrease in blood glucose in males in the 30 and 90 mg/kg groups, and increases in blood urea nitrogen, total birilubin, A/G ratio, ALT and ALP values in males in the 90 mg/kg group. Urinalysis revealed an increase in urine volume and a decrease in specific gravity in both sexes in the 90 mg/kg group. Histopathological examination revealed increased incidences of hydropic changes in renal collecting tubules in both sexes in the 90 mg/kg group.

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

1,3-Diphenylguanidine was not mutagenic in Salmonella typhimurium TA100, TA1535, TA98, TA1537 and Escherichia coli WP2 uvrA, with or without an exogenous metabolic activation system.

1,3-Diphenylguanidine did not induce structural chromosomal aberrations or polyploidy in CHL/IU cells with or without an exogenous metabolic activation system.

SUMMARIZED DATA FROM THE STUDIES

1. Single Dose Oral Toxicity 1)

Purity:99.9 %
Test species/strains:Rat/Crj:CD(SD)IGS
Test method:OECD Test Guideline 401
　Route:Oral (gavage)
　Doses:0, 50, 65, 85, 110 and 143 mg/kg
　Number of animals/group:Males, 5; females, 5
　Vehicle:Corn oil
GLP:Yes

　Test results:

Deaths occurred in the 85 mg/kg and higher groups for males, and in the 65 mg/kg and higher groups for females. Abnormal gait, hypoactivity, and a lateral position were observed in both sexes. Tremors, lacrimation, and closed eyelids were also observed in some animals.
The LD50 values were estimated to be 111 mg/kg for males and 107 mg/kg for females.

2. Repeat Dose Toxicity 1)

Purity:99.9 %
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
　Doses:0(vehicle), 10, 30, 90 mg/kg/day
　Number of animals/group:Males, 5; females, 5
　Vehicle:Corn oil
　Administration period:Males and females, 28 days
　Terminal kill:Males and females, on days 29 and 43
GLP:Yes

　Test results:

Dead animals in the 90 mg/kg group were observed during weeks 2 to 4 of the administration period, with The 10 % of the males and 70 % of the females in the 90 mg/kg group dying within the administration period. Pathological examination revealed no obvious changes accounting for the deaths. Salivation was observed in both sexes in the 30 and 90 mg/kg groups, and adoption of a prone or lateral position, staggering gait, decrease in spontaneous motor activity and startle response were observed in both sexes in the 90 mg/kg group. Body weight gain and food consumption were suppressed in both sexes in the 90 mg/kg group. All clinical signs in surviving animals disappeared during the recovery period.
Hematological examination revealed an increase in platelet counts in females in the 30 mg/kg group. Blood chemistry examination revealed a decrease in blood glucose in males in the 30 and 90 mg/kg groups, and increases in blood urea nitrogen, total birilubin, A/G ratio, ALT and ALP values in males in the 90 mg/kg group. Urinalysis revealed an increase in urine volume and a decrease in specific gravity in both sexes in the 90 mg/kg group.
Organ weight analysis revealed no changes attributable to the administration of the test substance. Macroscopic examination revealed an increased incidence of brown liver in males in the 30 mg/kg group and in both sexes in the 90 mg/kg group and reddish thympanic bulla in both sexes in the 90 mg/kg group. Histopathological examination revealed increased incidences of hydropic changes in renal collecting tubules in both sexes in the 90 mg/kg group.
The NOEL for repeat dose toxicity is considered to be 10 mg/kg/day for both sexes.

3. Genetic Toxicity

3-1. Bacterial test 2)

Purity:99.9 %
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), Sodium azide (TA1535), 9-Aminoacridine
(TA1537) and N-Ethyl-N'-nitro-N-nitrosoguanidine (WP2 uvrA)
+S9 mix; 2-Aminoanthracene (all strains)
　Doses:-S9 mix; 156, 313, 625, 1250, 2500 and 5000 μg/plate(TA100, WP2 uvrA, TA98 and TA1537)
-S9 mix; 39.1, 78.1, 156, 313, 625, 1250 and 2500 μg/plate(TA1535)
+S9 mix; 39.1, 78.1, 156, 313, 625 and 1250 μg/plate(all strains)
　S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
　Plates/test:3
　Number of replicates:2
GLP:Yes

　Test results:

This chemical did not induce gene mutations in the Salmonella typhimurium and Escherichia coli strains. Toxicity was observed at 2500 μg/plate or more (TA100, WP2 uvrA, TA98 and TA1537) and at 1250 μg/plate or more (TA1535) without metabolic activation, and at 625 μg/plate or more with metabolic activation.

Genetic effects:
Salmonella typhimurium TA100, TA1535, TA98 and 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 %
Type of cell used:Chinese hamster CHL/IU cells
Test method:Guidelines for Screening Mutagenicity Testing of Chemical
(Chemical Substances Control Law of Japan) and
OECD Test Guideline 473
　Solvent:1 % Sodium carboxymethylcellulose solution
　Positive controls:-S9 mix; Mitomycin C
+S9 mix; Benzo[a]pyrene
　Doses:-S9 mix(6 hr short-term treatment); 0, 50, 100, 200, 400 μg/mL
　S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
　Plates/test:2
GLP:Yes

　Test results:

This chemical did not induce structural chromosomal aberrations or polyploidy under the conditions of this experiment.

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

1)The tests were performed by the Biosafety Research Center, Foods, Drugs and Pesticides (An-pyo Center), Japan, 582-2 Shioshinden, Arahama, 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 Mitsubishi Chemical Safety Institute Ltd., 14 Sunayama, Hasaki-machi, Kashima-gun, Ibaraki, 314-0255, Japan. Tel +81-479-46-2871 Fax +81-479-46-2874