Registration Dossier

Administrative data

Link to relevant study record(s)

Referenceopen allclose all

Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Read across argumentation is provided in Section 13.
Reason / purpose:
read-across source
GLP compliance:
no
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 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.
Metabolites identified:
yes

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 read-across 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 read-across substance 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:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
Read across argumentation is provided in Section 13.
Reason / purpose:
read-across source
GLP compliance:
no
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 read-across 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 read-across substance 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:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
Read across argumentation is provided in Section 13.
Reason / purpose:
read-across source
GLP compliance:
no
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 read-across 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 read-across substance 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.

Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
Read across argumentation is provided in Section 13.
Reason / purpose:
read-across source
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 read-across substance 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 read-across substance 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.

Description of key information

Based on physicochemical properties, oral absorption seems to be possible and absorption by inhalation is considered to be negligible. Dermal absorption was assessed to be low based on physicochemical characteristics and Dermwin calculation.
The absorption, excretion and metabolism of read across substance Docusate sodium were investigated in rats, rabbits, dogs and man by means of radiolabeled read across substance Docusate sodium applied orally and intravenously. Absorption, metabolism and excretion were extensive in the rat and rabbit after oral application as two thirds of the administered radioactivity was found in the urine in the form of metabolites, and 90% of the radioactivity was detected in the urine both after oral and intravenous application. In the dog 71% of the administered radioactivity was excreted. In man, peak concentrations in serum occurred at 2 hours at comparable levels to the dog.
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, distribution, metabolism and excretion of Butanedioic acid, sulfo-, 1,4 -dicyclohexyl ester, sodium saltis assessed on three levels:

1)     Based on the physicochemical properties of the compound itself

2)     Read-across to Docusate sodium (‘Butanedioic acid, sulfo-, 1,4-bis(2-ethylhexyl) ester’, or ‘sodium saltdioctyl sodium sulfosuccinate’)

3)     Literature review of other anionic surfactants

 

Part 1: Physicochemical properties

Absorption of Butanedioic acid, sulfo-, 1,4-dicyclohexyl ester, sodium salt was assessed as follows based on physicochemical/toxicological data:

- It is a solid material with molecular weight of 384 g/mol and water solubility of 74.15 g/L. The logKow has a very low value of -1.5 and the particle size is rather high (X50 >1400 µm).

- Based upon the ionisable and hydrophilic properties, oral absorption is considered to be limited. On the other hand, easy dissolution in the gastro-intestinal tract and toxicity observed in acute oral toxicity studies indicated that oral absorption is possible. Deposition in the airways and absorption by inhalation are considered to be negligible due to the large particle size, low vapour pressure (<0.041 Pa)and high hydrophilic properties of the substance.

- Dermal absorption is considered to be possible but limited taking into account the physicochemical parameters and the fact that the substance has been shown to be a skin irritant. When QSAR (Dermwin calculation) was taken into consideration, the dermal penetration rate seems to be very slow. However, it is more expected that the test material is retained in the dermis than that it is absorbed.

For the assessment of distribution, metabolism and excretion physicochemical and toxicological properties are taken into account.

- Based upon the molecular size, high hydrophilicity and low LogP, distribution is expected to be low, however from the clinical signs observed after oral acute toxicity testing, distribution in the body is expected to take place. 

- There is no direct indication of bioaccumulation potential. The substance is very hydrophilic and has a very low lypophilicity.

- Based upon the low logP and high water solubility excretion in the urine and bile is expected to occur after oral absorption. When dermally exposed, the test substance is not expected to be absorbed, but to be penetrate in the (epi)dermis and to be excreted by exfoliation.

Reference:
ECHA Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance, November 2012 Version 1.1

 

Part 2: Read-across to Docusate sodium

No test data were available for current substance, however read across data were available from Docusate sodium. Justification for read across with the category of Di-ester sulphosuccinates is documented in a separate document attached in Section 13.

- The absorption, excretion and metabolism of read across substance Docusate sodium have been investigated in rats, rabbits, dogs and man (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.

Reference:

Kelly R. G. (1973). The pharmacokinetics and metabolism of dioctyl sodium sulfosuccinate in several animal species and man. Testing laboratory: American Cyanamid. Report no.: 07066. Owner company: Cytec. Study number: 7235-03. Report date: 1973-04-10.

 

Part 3: Literature review of anionic surfactants (alkyl sulfates, alkane sulfonates andα-olefin sulfonates)

Anionic surfactants, including alkyl sulfates, alkane sulfonates and α-olefin sulfonates, have been assessed under the HPV program. These chemicals were shown to have low acute and repeated dose toxicity, no evidence of genetic or reproductive toxicity or carcinogenicity. The toxicological profile was similar to the sulfosuccinate esters/amides, and the absorption rate was high in both situations (90% absorption was demonstrated for a sulfosuccinate ester). Therefore, the toxicokinetic profile of the anionic surfactants can also be used for the sulfosuccinate esters and amides, with special emphasis on the low dermal absorption rate (<1%) and the common metabolic breakdown after oral absorption. The common physiological pathways result in structurally similar breakdown products (fragments) for the various chain lengths, leading to fairly rapid excretion and low hazard for human health.

For risk characterisation, conservative absorption rates of 90, 2 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.

References:

- Wibbertmann et al., Ecotoxicology and Environmental Safety 74 (2011) 1089 -1106, Toxicological properties and risk assessment of the anionic surfactants category alkyl sulfates, primary alkane sulfonates andα-olefin sulfonates.

- SIDS Initial Assessment report for SIAM 25, Category of Alkyl sulfates, Alkane sulfonates andα-Olefin sulfonates, 2007
- Howes, D., J. Soc. Cosmet. Chem. 26 (1975) 47-63, The percutaneous absorption of some anionic surfactants.