Sodium 1,4-dicyclohexyl sulphonatosuccinate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1973

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

The study was conducted to the highest possible scientific standards in a well renomated laboratory, however only limited materials and methods were provided according to the standards at the time of conduct.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1973

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

The study was conducted to the highest possible scientific standards in a well renomated laboratory, however only limited materials and methods were provided according to the standards at the time of conduct.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Objective of study:

absorption

excretion

metabolism

GLP compliance:

no

Radiolabelling:

yes

Remarks:

carbon-14

Species:

dog

Strain:

not specified

Sex:

not specified

Route of administration:

other: orally and intravenously

Vehicle:

water

Remarks:

Doses / Concentrations:
1. Dog S14 (8.0 kg) received 8.0 mL of a 1% solution of docusate sodium in water intravenously. Dog R300 (9.7 kg) received orally 97 mg docusate sodium in a gelatin capsule.
2. Two male beagle dogs were dosed with 4 mg/kg radiolabeled docusate sodium. Dog R872 (13.3 kg) was given 5.3 mL of a 10 mg/mL aqueous solution intravenously. Dog R613 (8.4 kg) received 33.6 mg in a gelatin capsule.

Control animals:

no

Details on dosing and sampling:

1. Non-radioactive compound: Urine was collected at 0-24h and 24-48 hours. Whole blood (5 mL) was collected from dog S14 at 10, 20 and 30 minutes and from both animals at 1, 2, 4 and 8 hours after dose.
2. Radioactive compound: Plasma was obtained from dog R872 at 5, 10, 15, 20, 30 and 45 minutes after injection and from dog No. R613 at 15 and 35 minutes after dosage. Plasma was taken from both animals at 1, 2, 3, 4, 7 and 48 hours after dosage. Total urine was collected at 0-7, 7-24 and 24-48 hours. Feces were collected at 0-24 and 24-48 hours.

Type:

absorption

Results:

min. 5%

Type:

excretion

Results:

in the urine (25%) and feces (70%)

Details on absorption:

Table 1 shows the results of the analyis of the blood from the 2 dogs receiving unlabeled test compound. Analysis of the urine from the dogs produced values equivalent to 4% of the dose in the 0-24 hour sample of each animal.
As shown in Table 2, the similarity in distribution of activity between urine and feces between intravenous and oral dosage is suggestive that the orally adminstered compound is completely absorbed. There is little difference between the two routes.
Table 3 shows the concentration of radioactivity in the plasma of the two dogs dosed with labeled DSS. A peak concentration of radioactivity occurred in the orally dosed animal at 1 hour. After an initial rapid removal of the compound from the blood stream the half-life of the radioactivity in dog R872 became 19 hours and that for dog R613, 14 hours between 7 and 24 hours afer dosage.

Metabolites identified:

no

Table 1. Concentration of 2-ethylhexanol-forming compounds in the blood of 2 dogs after dosage with 10 mg/kg DSS

Concentrations expressed in µg/mL DSS equivalents

Time after dosage		Dog S14 (I.V.)	Dog R300 (oral)
(min.)	(hour)
10		42	-
20		28	-
30		27	-
	1	10	5
	2	3	3
	4	1	1
	8	0	0

-: not determined

Table 2. Excretion of radioactivity by 2 dogs which received 4 mg/kg carbon-14 labeled DSS

	% of Dose
Hours after dose	Dog R872 (intravenous)			Dog R613 (oral)
	Urine	Feces	Total	Urine	Feces	Total
0-7	14.6	-	14.6	12.3	-	12.3
7-24	4.6	0.4	5.0	7.6	0	7.6
24-48	2.2	66.9	69.1	4.2	65.6	69.8
48-72	1.8	3.6	5.4	1.1	5.2	6.3
72-96	0.8	0.1	0.9	0.3	0.3	0.6
Cummulative totals	24.0	71.0	95.0	25.5	71.1	96.6

-: not determined

Table 3. Concentration of radioactivity in the plasma of 2 dogs which received 4 mg/kg carbon-14 labeled DSS concentrations expressed in µg/mL DSS

Time after dosage	Dog 872 (I.V.)	Dog R6113 (oral)
5 min.	45.1	-
10 min.	28.8	-
15 min.	23.4	0.01
20 min.	18.8	-
30 min.	12.3	-
35 min.	-	1.7
45 min.	7.4	-
1 hour	5.9	7.4
2 hour	2.8	4.2
3 hour	1.9	1.7
4 hour	1.5	1.2
7 hour	1.0	0.68
24 hour	0.52	0.26
48 hour	0.26	0.09
72 hour	0.14	0.03
96 hour	0.11	0.02

- no sample obtained

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
The compound was well excreted after oral administration (75% was found in the faeces, whereas 25% was found in the urine).

Executive summary:

The absorption, excretion and metabolism of dioctyl sodium succinate (DSS) have been investigated in dogs by means of unlabeled and radiolabeled (carbon-14) compound. A peak concentration of radioactivity occurred in the orally dosed animal at 1 hour. Analysis of the urine from the dogs produced values equivalent to 4 -7% of the dose in the 0-24 hour samples. A comparison of an oral and intravenous dose of 4 mg/kg carbon-14 DSS in the dog yielded remarkably similar excretion patterns and metabolic profiles. In each case 71% of the administered radioactivity was excreted in the faeces. Countercurrent distribution curves on the urine of these animals were almost identical.

Cross-reference 2

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1973

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

The study was conducted to the highest possible scientific standards in a well renomated laboratory, however only limited materials and methods were provided according to the standards at the time of conduct.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Objective of study:

absorption

excretion

GLP compliance:

no

Radiolabelling:

yes

Remarks:

carbon-14

Species:

rabbit

Strain:

not specified

Sex:

female

Route of administration:

other: orally and intravenously

Vehicle:

water

Remarks:

Doses / Concentrations:
Rabbit No. 1 (4.0 kg) was given 1.6 mL of a 10 mg/mL solution in water intravenously.
Rabbit No. 2 (3.6 kg) was given 14.4 mg in a gelatin capsule.

Control animals:

no

Details on dosing and sampling:

Urine and faeces were collected at 0-24, 24-48, 48-72 and 72-96 hours.

Type:

absorption

Results:

90%

Type:

excretion

Results:

in the urine (93-99%) and feces (4-5%)

Details on absorption:

Table 1 shows the results of the analyis of the urine and faeces.

Metabolites identified:

no

Table 1. Excretion of radioactivity by 2 rabbits which received 4 mg/kg carbon-14 labeld DSS

	% of Dose
Hours after dose	Rabbit No. 1 (intravenous)			Rabbit No. 2 (oral)
	Urine	Feces	Total	Urine	Feces	Total
0-24	87.1	2.3	89.4	69.7	3.1	72.8
24-48	8.8	0.5	9.3	17.4	1.0	18.4
48-72	2.1	0.4	2.5	5.3	0.7	6.0
72-96	0.9	0.4	1.3	1.1	0.4	1.5
Cummulative totals	98.9	3.6	102.5	93.5	5.2	98.7

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
The compound was well absorbed, metabolised and excreted after oral administration (70% were oberved in the 24 hours urine; 90% in total).

Executive summary:

The absorption and excretion of docusate sodium (dioctyl sodium succinate, DSS) have been investigated in rabbits by means of radiolabeled (carbon-14) compound . The results demonstrate good absorption of the radiolabel by the rabbit following oral dosage, over 90% of administered radioactivity being excreted in the urine. It is concluded that DSS is absorbed intact by the rabbit rather than being hydrolysed in the gastrointestinal tract.

Cross-reference 3

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1973

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

The study was conducted to the highest possible scientific standards in a well renomated laboratory, however only limited materials and methods were provided according to the standards at the time of conduct.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Objective of study:

absorption

excretion

metabolism

GLP compliance:

no

Radiolabelling:

no

Species:

human

Strain:

not specified

Sex:

male

Route of administration:

oral: capsule

Remarks:

Doses / Concentrations:
Two male volunteers were each given two 100 mg capsules.

Control animals:

no

Details on dosing and sampling:

Total urine was collected from the subjects at 0-7.5, 7.5-24, 24-48 hours after dosage. Blood samples (10 mL) were collected at 0, 1.5, 1, 2, 4 and 8 hours after dosage and centrifuged to obtain serum. The sera and urine were frozen immediately and maintained in the frozen stte until analyzed.

Type:

absorption

Results:

min. 5%

Type:

excretion

Results:

in the urine (25%) and feces (70%)

Details on absorption:

Table 1 shows the results of the serum concentration of the 2 human volunteers dosed with 200 mg.

Metabolites identified:

no

Table 1. Concentrations of 2-ethoxylhexanol forming compounds in the serum of 2 subjects after a single 200 mg dose

of DSS (concentrations expressed in µg/mL DSS)

Hours after dosage	Subject 1	Subject 2
0	0	0
0.5	0	2.7
1	4.7	4.0
2	7.9	5.5
4	3.4	1.0
8	2.0	0.3

 

Table 2. Concentrations of 2-ethoxylhexanol forming compounds in the urine of 2 subjects after a single 200 mg dose of

DSS (concentrations expressed in percent of dose)

Hours after dosage	Subject 1	Subject 2
0	0	0
0-7.5	3.8	0.3
7.5-24	0.9	2.0
24-48	0.8	0.2

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Peak concentrations of docusate sodium in serum occurred at 2 hours after dosage. The excretion of 2-ethylhexanol derivatives in the urine of man accounted for only a very small amount of the administered dose of docusate sodium.

Executive summary:

In man, peak concentrations of docusate sodium in serum occurred at 2 hours after dosage with 200 mg. These values, in two men, were 7,9 and 5,5 µg/mL, similar in magnitude to the plasma concentration seen at 1 hour in the orally dosed dog (7,4 µg/mL) which received 4 mg/kg. The analysis of human serum was done by gas chromatography and that of dog plasma by the radiometric method. The excretion of 2-ethylhexanol derivatives in the urine of man accounted for only a very small amount of the administered dose of docusate sodium, a finding similar to that seen in the urine of the dog. An attempt to compare the urine of man and the dog by analysis of 2-ethylhexanol forming compounds in countercurrent distribution fractions did not yield fruitful results.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1973

Report date:

1973

Materials and methods

Objective of study:

absorption

excretion

metabolism

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Docusate sodium

EC Number:

209-406-4

EC Name:

Docusate sodium

Cas Number:

577-11-7

Molecular formula:

C20H38O7S.Na

IUPAC Name:

sodium 1,4-bis[(2-ethylhexyl)oxy]-1,4-dioxobutane-2-sulfonate

Constituent 2

Reference substance name:

Butanedioic acid, sulfo-, 1,4-bis (2-ethylhexyl) ester, sodium salt

IUPAC Name:

Butanedioic acid, sulfo-, 1,4-bis (2-ethylhexyl) ester, sodium salt

Test material form:

other: liquid

Details on test material:

- Name of test material (as cited in study report): dioctyl sodium succinate (DSS)
- Substance type: sulfosuccinate compound
- Physical state: liquid

Radiolabelling:

no

Remarks:

5 rats unlabeled; one male rat carbon-14 labeled

Test animals

Species:

rat

Strain:

not specified

Sex:

not specified

Administration / exposure

Route of administration:

other: oral gavage and intravenously

Vehicle:

water

Doses / concentrations

Remarks:

Doses / Concentrations:
1. Five rats were dosed with unlabeled docusate sodium. Rat No. 1 received 1 mL and rat No. 3 received 2 mL of a 5 mg/mL solution in water by oral gavage. Rats Nos. 4 and 5 received 1 mL of a 1% solution in water by intravenous administration. In addition, one animal (rat No. 2) was given 1.05 mL of a solution of 5.5 mg/mL 2-ethyl-hexanol in 40% ethanol by oral gavage.
2. One male rat (250 g) was given 10 mg/kg 14C labeled docusate sodium by gavage (2.5 mL of a 1 mg/mL solution).

Control animals:

no

Details on dosing and sampling:

1. Total urine and feces were collected from all of the animals at 24 and 48 hours after dosage. Urine and feces from rat No. 1 were also collected at 72 hours and 96 hours.
2. Urine and feces were collected from the rat given 14C labeled DSS at 0-24h and 24-48 hours.

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

at least 65%

Main ADME results 2

Type:

metabolism

Results:

extensive (e.g. 2-ethylhexanol)

Main ADME results 3

Type:

excretion

Results:

in the urine (within 24h) and feces

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Table 1 shows the results of the analysis of the urine from these animals using the 2-ethylhexanol distillation procedure. The 24-48 hour urine samples from any of the animals did not yield measurable quantities of 2-ethylhexanol. Since the percent of dose excreted in the urine after intravenous dosage was comparable to the excretion after oral dosage, it is concluded that the orally administered compound is well absorbed by the rat. Since 2-ethylhexanol derivatives recovered in the urine after administration of the alcohol are appreciably lower than those recovered after DSS administration, it is concluded that the mechanism of absorption of DSS does not include prior hydrolysis of the ester groups in the gastrointestinal tract. This is further substantiated by the finding that the 2-ethylhexanol forming compound in urine after administration with DSS is largely not the free alcohol or its glucuronide conjugate.

Details on excretion:

The male animal given radioactive compound showed that the urine excreted during the first 24 hours accounted for 64.1% of the radioactivity; the feces for 37.4%. The animal was further found to eliminate 1.0% of the dose in the 24-48h urine and 0.9% of the dose in the 24-48h feces.

Metabolite characterisation studies

Metabolites identified:

yes

Any other information on results incl. tables

Table 1. 24 hour excretion of 2-ethylhexanol-forming compounds by the rat after oral dosage with DSS and 2-ethylhexanol

Rat No.	Compound	Dose (mg)	Route	% of dose excreted
				Urine	Faeces
1	DSS	5	oral	18.6	0.9
3	DSS	10	oral	15.5	8.7
4	DSS	10	I.V.	12.3	-
5	DSS	10	I.V.	15.5	-
2	2-ethyl-hexanol	5.8	oral	3.1	3.9

-: not determined

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
The compound was well absorbed, metabolised and excreted after oral administration (two thirds were oberved in the 24 hours urine; one third was found in the feces).

Executive summary:

The absorption, excretion and metabolism of dioctyl sodium succinate (DSS) have been investigated. Unlabeled DSS and radiolabeled compound (carbon-14) were used. Using a gas chromatographic procedure, a similarity in percent excretion of dose into urine was observed in rats dosed orally and intravenously, indicating a high degree of absorption of the oral dose. Confirmation of extensive absorption of DSS was obtained through oral dosage of 10 mg/kg carbon-14 labeled compound. Two thirds of the administered radioactivity was found in the urine at 24 hours after dosage. All of the activity was in the form of metabolites (2-ethylhexanol forming compounds).

.