1,3-diphenylguanidine

Endpoint summary

Description of key information

1,3-Diphenylguanidine is readily absorbed from the gastrointestinal tract of rats, distributed quickly to all tissues examined, metabolized to three major and two minor metabolites (not identified), and excreted in urine and feces.  Slower clearance of a minor component was observed in liver, but the significance of this observation is unknown.

1,3-Diphenylguanidine is slowly absorbed after dermal application to rats, only 10% of the 14C activity penetrated the shaven skin of the back within 5 days with an apparent first-order dermal absorption rate of 0.021 ± 0.002 d-1 and a t½of 33.6 days.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

The absorption, distribution, metabolism and excretion of 1,3-diphenylguanidine was reported by Ioannou & Matthews (1984) after oral administration to male F344 rats.

A comparison of 14C-1,3-diphenylguanidine (the 14C-labelling was done by U-labelling on the phenyl rings) tissue distribution and excretion following single oral (dose levels 1.52 - 151.5 µmol/kg) versus intravenous (dose level 15.15 µmol/kg) administration to male F344 rats, indicates that gastrointestinal absorption of DPG was near complete and that tissue distribution and excretion were not significantly affected by the route of administration.

Within 24 and 72 hours about 80 and >99% respectively of the 14C activity administered orally or intravenously was excreted about equally in the urine and faeces (elimination half-life 9.6 hours). About 30% of the 14C activity eliminated in the bile was subjected to entero-hepatic circulation and excreted in the urine.

Distribution and excretion of radioactivity 1 day after administration of 14C-1,3-diphenylguanidine to F344 male rats.

 

Tissue	Percentage total dose
	Intravenous	Oral
	15.15 µmol/kg	1.52 µmol/kg	15.15 µmol/kg	151.5 µmol/kg
Liver	1.37 ± 0.08	1.31 ± 0.09	1.23 ± 0.11	0.92 ± 0.09
Muscle	1.18 ± 0.08	1.08 ± 0.02	1.08 ± 0.01	1.09 ± 0.08
Adipose	0.56 ± 0.07	0.62 ± 0.03	0.47 ± 0.03	0.49 ± 0.03
Skin	0.52 ± 0.07	0.40 ± 0.01	0.41 ± 0.05	0.39 ± 0.02
Blood	0.24 ± 0.01	0.27 ± 0.01	0.23 ± 0.01	0.24 ± 0.02
Total excreted
In urine	35.50 ± 3.38	31.76 ± 2.68	29.12 ± 1.72	43.61 ± 2.83
In feces	45.67 ± 9.01	48.25 ± 4.49	45.26 ± 2.94	39.39 ± 1.84
Total^a	81.17 ± 6.12	80.01 ± 6.24	74.38 ± 1.27	83.00 ± 2.41

^aDPG-derived radioactivity excreted in urine and faeces in 24 hr. The remainder is still present in tissues and intestinal contents

 

The following table gives an overview of the relative distribution (in %¹⁴C-activity) of¹⁴C-1,3-diphenylguanidine or the metabolites (without identifying them specifically, numbered I to V)) in liver, bile, urine and faeces after single intravenous administration.

 

Relative amounts of DPG and DPG-metabolites present in male F344 rat liver and excreta

 

		DPG metabolite (%)					^14C-DPG (%)
Excreta or Organ^1	Time(h)	I	II	III	IV	V
Liver	0.75	-	12 ± 1.2	-	-	-	88 ± 5.7
	2	-	18 ± 1.9	-	-	-	82 ± 4.3
	6	-	30 ± 2.1	-	-	-	70 ± 6.0
	24	-	30 ± 3.3	60 ± 4.5	-	-	10 ± 1.1
Bile	6	2 ± 1.2	95 ± 1.7	-	-	-	3 ± 0.5
Urine	24	-	37 ± 1.6	32 ± 1.4	-	3 ± 0.8	28 ± 0.8
Faeces	24	-	-	-	2 ± 1.0	94 ± 3.5	4 ± 1.4

¹intravenous administration (15.15 µmol/kg)

 

Three or 9 oral administrations of 15.15 µmol/kg¹⁴C-1,3-diphenylguanidine/kg/day also caused no accumulation in the tissues. In the liver there was a proportional¹⁴C increase, the metabolites II and III being detected. Covalent binding to liver macromolecules was not determined.

Discussion on absorption rate:

The absorption and disposition 1,3-diphenylguanidine was reported by Shah et al. (1985) after dermal administration to female Sprague-Dawley rats.

In female Sprague-Dawley rats, which had received a single dermal application of 0.063 mg 14C-1,3-diphenylguanidine/animal (0.3 µmol), only 10% of the 14C activity penetrated the shaven skin of the back within 5 days with an apparent first-order dermal absorption rate of 0.021 ± 0.002 d^-1and a t½of 33.6 days. Distribution throughout the entire organism also occurred here.

The highest 14C activities after dermal administration were measured in the liver, kidneys, intestines and its content , and excreta. Maximum tissue concentrations after dermal application were reached 3-6 hours after the start of the experiment.

Within 120 hours after dermal application 64% of the absorbed 14C activity was excreted in the urine and 29% in the faeces. Accumulation in the adipose tissue was not observed.

 

Relative amounts of DPG and DPG metabolites present in treated skin and excreta

 

		% metabolites			^14C-DPG (%)
Excreta or Organ	Time(h)	II	IV	V
Urine	24	50 ± 5.3	-	-	50 ± 5.3
	48	53 ± 1.7	-	-	47 ± 1.5
	72	57 ± 5.2	-	-	43 ± 5.2
	96	100	-	-	0
	120	100	-	-	0
Faeces	24	-	-	100	-
	48	-	15	85	-
	72	-	20	80	-
	96	-	26	74	-
	120	-	26	74	-
Skin	6-120	-	-	-	>95