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Reference
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:
REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
For details please refer to Read Across Justification Document, Section 13.2

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
For details please refer to Read Across Justification Document, Section 13.2

3. ANALOGUE APPROACH JUSTIFICATION
For details please refer to Read Across Justification Document, Section 13.2

4. DATA MATRIX
For details please refer to Read Across Justification Document, Section 13.2
Reason / purpose for cross-reference:
read-across source
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:
The results of the analysis of the urine from these animals are based on 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:
No bioaccumulation potential for CAS 577-11-7 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).

Description of key information

The toxicokinetics of Butanedioic acid, sulfo-, 4-[1-methyl-2-[(1-oxo-9-octadecenyl)amino]ethyl] ester, disodium salt was assessed based on the physicochemical parameters and information from toxicokinetic literature from structural analogue substances.
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 organism, but accumulation is unlikely. Hydrolysis will take place at the ester site of the substance causing it to split in a polar and non-polar part. Eventually, it is expected that these parts will break down to water, CO2 and 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 read-across substance Docusate sodium (CAS 577 -11 -7), demonstrating rapid and extensive metabolism and excretion in the urine in the form of metabolites. As more than 90% of the radioactivity was detected in the urine both after oral and intravenous application, oral absorption was considered to be relevant and therefore also the most relevant route of testing. Literature data for other anionic surfactants (e.g. alkyl sulfates, alkane sulfonates and α-olefin sulfonates) demonstrated a similar toxicological and toxicokinetic/metabolic profile as for the sullfosuccinate esters/amides. For these surfactants high oral absorption rates (90%) and low dermal absorption rates (<1%) were observed. For risk characterisation of the registered substance, conservative absorption rates of 90, 2 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 (%):
2
Absorption rate - inhalation (%):
10

Additional information

The absorption, distribution, metabolism and excretion of Butanedioic acid, sulfo-, 4-[1-methyl-2-[(1-oxo-9-octadecenyl)amino]ethyl] ester, disodium salt is 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 salt dioctyl sodium sulfosuccinate’)

3)  Literature review of other anionic surfactants

 

Part 1: Physicochemical properties

Absorption of Butanedioic acid, sulfo-, 4-[1-methyl-2-[(1-oxo-9-octadecenyl)amino]ethyl] ester, disodium salt was assessed as follows based on physicochemical/toxicological data.

 

The substance is a sulfosuccinate with molecular formula C25H45NO8SNa2. The freeze-dried substance is a white lumpy powder and is marketed or used in a non solid or granular form.. The substance has a molecular weight of 563.66 g/mol and water solubility is 10-50 g/L (OECD TG 105). The Log P is -2 to -1.3 (OECD TG 107). The vapour pressure is 3.63E-19 Pa at 25°C (EPIwin calculation). The surface tension was determined with the plate method according to EC A.5 and DIN 14370. The surface tension of a 1g solid content /L solution at 20°C was 28.16 mN/m.

 

- Oral/GI absorption:

Although the substance is considered to be less favourable for oral absorption based on physicochemical properties (ionisable, high molecular weight, high water solubility, low Log P), toxicological data indicate systemic availability after oral absorption.

- Respiratory absorption:

Based upon the granular form, low vapuor pressure high water solubility, low Log P, deposition in the airways is assumed to be absent and absorption by inhalation is considered to be negligible.

- Dermal absorption:

Based upon the physicochemical parameters dermal absorption is considered to be limited. When QSAR material was taken into consideration (Dermwin: see below), 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 also taken into account according to ECHA guidance 7c (2017).

 

- Distribution

Based upon water solubility and toxicological data, distribution in the body is expected to take place.  

- Metabolism & accumulation potential:

Based on the hydrophilicity , the substance is not expected to accumulate in the lung. Based on the low log Pow the accumulation in adipose tissues is also unlikely as well as accumulation in the stratum corneum. Taken together there is no direct indication of bioaccumulation potential.

- Excretion:

From the assumptions above, excretion via the urine and bile might be expected because of the high water solubility. Another route of excretion may be applicable (e.g. skin after dermal application). However this is of less relevance.

 

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). Radiolabelled compound carbon-14) was used in animal studies and unlabelled Docusate sodium in certain studies in rats, dogs and man. Both studies show a good absorption of the compound. From the studies with unlabelled Docusate sodium in the rat, the percent excretion of metabolites (2-ethylhexanol derivatives) seem to be similar after oral and intravenous administration demonstrating the good absorption of the compound. Confirmation of extensive absorption was obtained through oral dosage of 10 mg/kg carbon-14 labelled compound.

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 after 48 hours. After 24 hours 89.4% and 72.8% are found after intravenous and oral administration respectively. 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. However compared to the rat and rabbit, excretion via feces is higher than via urine. After 96 hours around 25% is excreted in the urine (20% after 24 hours), while around 71% is excreted in the feces (65-70% after 48 hours). 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. The metabolites found in dog urine are assumed to be incompletely hydrolysed ester derivatives of Docusate sodium.

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 and α-olefin sulfonates)

Anionic surfactants, including alkyl sulfates and 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 (butyric-, propionic-and pentanoic acid-5-sulfate fragments) for the various chain lengths, leading to fairly rapid excretion and low hazard for human health.

References:

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

- SIDS Initial Assessment Report for SIAM 25, Category of Alkyl sulfates, Alkane sulfonates and α-Olefin sulfonates, 2007

- Howes, D., J. Soc. Cosmet. Chem. 26 (1975) 47-63, The percutaneous absorption of some anionic surfactants.

 

Conclusion for the absorption rates

Based on the physicochemical properties, read across and literature, it can be concluded that the registered substance is well absorbed after oral administration (90%). For the other routes, absorption rates were assessed to be lower both after inhalation (assumed 10%) and dermal application (calculated 2%). Although the values were not based on experimental data of the registered substance, they were based on sound scientific background data and still conservative. See also Section 7.0: attached Justification for DNEL calculation & Annexes for support of absorption rates.