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Endpoint:
basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
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:
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).

.
Endpoint:
basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting 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:
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 minues 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.

Endpoint:
basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting 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:
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.

Endpoint:
basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting 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:
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 dsoage, 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.

Description of key information

Data are available for the corresponding sodium salt of the substance, docusate sodium. These data are used for read-across to the substance registered. The substance has a pKa of 0.18 which means that it will be completely dissociated in water solutions.The presence of either of the counterions sodium or potassium is not considered to have an impact on the toxicity. It is therefore considered justified to use the data of the sodium salt for read across to the Potassium salt of 1,2-bis(2-ethylhexyloxycarbonyl) ethanesulphonate.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information

The absorption, excretion and metabolism of docusate sodium have been investigated in rats, rabbits, dogs and man (Cytec, Kelly 1973). Radiolabelled 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 labelled 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 radiolabelled 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.

The excretion at over 90% from both the oral and intra venous routes in rats indicates the same systemic availability of docusate sodium by oral and intravenous dosing. Intravenous dosing ensures 100% of the dose is available systemically, therefore based the identical high level of excretion it can be concluded that oral dosing also results in 100% systemic availability of docusate sodium. As oral dosing results in 100% absorption there is no requirement to adjust when extrapolating to inhalation exposure so the default factor or 2 reducing the oral NOAEL before conversion to an inhalation NOEC in rats is not required.

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. Counter current 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 derivatives 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 faeces (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.

In the absence of specific data on the dermal absorption of docusate sodium in humans’ .i.e. in-vitro dermal penetration study data, the default ECHA assumption of equivalent absorption by the oral routes is used. This will be a very conservative approach.