Docusate sodium

Endpoint summary

Link to relevant study record(s)

Reference

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:

other: 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

Objective of study:

absorption

excretion

metabolism

GLP compliance:

no

Radiolabelling:

yes

Remarks:

carbon-14

Species:

rat

Strain:

not specified

Sex:

not specified

Route of administration:

other: oral gavage and intravenously

Vehicle:

water

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.

Type:

absorption

Results:

at least 65%

Type:

metabolism

Results:

extensive (e.g. 2-ethylhexanol)

Type:

excretion

Results:

in the urine (within 24h) and feces

Details on absorption:

Table 1 shows the results of the analyis 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 precent of dose excreted in the urine after intravenous dosage was comparable to the excretion after oral dosage, it is concluded that the orally administered comound is well absorbed by the rat. Since 2-ethylhexanol dervatives reovered in the urine after administration of the alcohol are apprecialby lower than those reovered after DSS administration, it is concluded that the metchanism 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 alchol 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.

Metabolites identified:

no

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

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).

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Description of key information

The toxicokinetics of Docusate sodium was assessed based on the physicochemical parameters and toxicokinetic studies. In summary the substance is anticipated to be orally absorbed to a high extent,  whereas inhalation or dermal uptake is very unlikely. The substance may be distributed within the organisms but accumulation is unlikely. Hydrolysis will take place at the ester site of the substance causing it to split in a polar and apolar part. Eventually, it is expected that these parts will break down to water, CO2and sulfur. The major path of excretion seems to be via kidney, although some excretion via the bile is also possible. This was confirmed by experimental study of  Docusate sodium, demonstrating rapid and extensive metabolism and excretion in the rat and rabbit after oral application as two thirds of the administered radioactivity was found in the urine in the form of 2-ethylhexanol derivatives metabolites, and 90% of the radioactivity was detected in the urine both after oral and intravenous application. In the dog 95% of the administered radioactivity was excreted. Literature data are available for anionic surfactants (alkyl sulfates, alkane sulfonates and α-olefin sulfonates ) which have similar breakdown products to sulfosuccinates. For these surfactants high oral absorption rates (90%) and low dermal absorption rates (<1%) were observed. For risk characterisation, conservative absorption rates of 90, 10 and 10% were taken into account for oral, dermal and inhalation routes, respectively.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

90

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

10

Additional information

The absorption, excretion and metabolism of docusate sodium have been investigated in rats, rabbits, dogs and man (Cytec, Kelly 1973). Radiolabeled compound (carbon-14) was used in animal studies and unlabeled docusate sodium in certain studies in rats, dogs and man.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. A similar experiment in dogs yielded much lower values.

Confirmation of extensive absorption of docusate sodium in the rat was obtained through oral dosage of 10 mg/kg carbon-14 labeled compound. Two thirds of the administered radioactivity was found in the urine in the form of metabolites. A comparison of an intravenous and an oral dose of 4 mg/kg of radiolabeled docusate sodium in the rabbit also indicated a high degree of absorption following oral dosage in this species. Each route of administration resulted in the excretion of over 90% of the radioactivity in the urine. As in the case of the rat, extensive metabolism was observed in the rabbit.

A comparison of an oral and an intravenous dose of 4 mg/kg carbon-14 docusate sodium in the dog yielded remarkably similar excretion patterns and metabolic profiles. In each case 71% of the administered radioactivity was excreted. Countercurrent distribution curves on the urine of these animals were almost identical.

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.

According to chapter R.7C of the endpoint specific guidance, physicochemical data may be used for a qualitative TK assessment. Next to the literature that was worked out in specific endpoint records, the data below were used for additional pharmacokinetic assessment. More specific data and interpretation is provided in the document 'Basic toxicokinetics docusate sodium' attached to the dossier. Experimental results support the oral absorption of docusate sodium in various species, including rats, dogs, rabbits, man, as described above.  Dermal absorption is also considered to be possible based upon physicochemical characteristics, however, when Dermwin was taken into consideration, the dermal penetration rate seems to be very slow (0.0001 cm/hr leading to a dermally absorbed dose in 70kg adults of 0.386 µg/kg/day . Therefore, based on the skin irritation studies, it is more expected that the test material is rather active at/in the dermis than that it is absorbed. Finally, absorption by inhalation is considered to be less relevant based upon physicochemical data. Distribution, metabolism and excretion takes place rapidly, as demonstrated by experimental results showing that within 24 hours, over 90% of the substance is excreted mainly in the urine after both oral and intravenous dosing (Cytec, Kelly 1973).Two thirds of the administered radioactivity was found in rat urine 24 hours after dosage. All of the activity was in the form of metabolites (2-ethylhexanol forming compounds). The excretion of 2-ethylhexanol derivates in the urine of man accounted for only a very small amount of the administered dose of docusate sodium, a finding similar to the dog, where most of the compound was excreted in the feces (both after oral and intravenous dosing). Therefore, there is no suspicion for accumulation, except maybe in the stratum corneum of the skin after dermal application, where continued irritation could be observed, however this does not lead to systemic toxicity.

For risk characterisation, conservative absorption rates of 90, 10 and 10% were taken into account for oral, dermal and inhalation routes, respectively. See also Section 7.0: attached Justification for DNEL calculation & Annexes for support of absorption rates.