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Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reason / purpose:
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:
Interpretation of results: 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

A basic toxicokinetic assessment was made of the absorption, distribution, metabolism and excretion of Registered substance based on physicochemical and toxicological properties according to ECHA Guidance on Information Requirements and Chemical Safety Assessment (Chapter R.7c: Endpoint specific guidance, June 2017 Version 3.0).

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 andα-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, 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 Registered substance 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

 

1) Based on the physicochemical properties of the compound itself

Absorption of Butanedioic acid, sulfo-, 4-isodecyl ester, disodium salt (CAS 37294-49-8) was assessed as based on physicochemical/toxicological data following ECHA guidance 7c (ECHA Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance, June 2017 Version 3.0).

 

The substance is a monoconstituent with molecular formula C14-H26-O7-S.2Na. The compound is white powder with a molecular weight of 402.413g/mol and with water solubility ≥ 485 g/L (20°C) The log Pow of the substance at 25°C is calculated to be -2.53 using the software program KOWWIN (version 1.68), part of EPI Suite v.4.11. The structure of the substance shows ionisable groups and the surface tension is 46.1 mN/m (20°C, 1 g/L).

-          Oral/GI absorption:

Based upon the molecular weight and easy dissolution in the gastro-intestinal tract, oral absorption is considered to be likely. This was confirmed by the toxicity observed in acute and repeated oral toxicity. 

-          Respiratory absorption:

Based upon low vapor pressure, high hydrophilicity and low lipophilicity, deposition in the lower airways is assumed to be absent to non-existing and absorption by inhalation is considered to be negligible compared to oral exposure.

-          Dermal absorption:

Although water solubility was high enough for partition from the stratum corneum into the epidermis, the low LogPow below -1 makes it unlikely for the substance to cross the lipophilic areas of the stratum corneum. A rather high surface tension and absence of skin irritation and sensitization also pointed towards a limited dermal absorption. Calculation of dermal penetration by Dermwin (Episuite) confirmed that dermal penetration rate seems to be very slow (Kp: 2.38e-008 cm/hr), therefore dermal absorption is rather unlikely. 

 

For the assessment of distribution, metabolism and excretion physicochemical and toxicological properties are taken into account according to ECHA guidance 7c (ECHA Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance, June 2017 Version 3.0).

-          Distribution:

Based upon the molecular weight and water solubility, distribution is likely, which is confirmed by clinical signs observed after oral acute and repeated dose toxicity observations. 

-          Accumulation:

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

-          Excretion:

Derived from the molecular weight, the high hydrophilicity and low low logP, excretion in the urine is expected to be the most favourable route. Nevertheless also excretion via bile is expected to occur after oral absorption. As the substance has a low vapour pressure, exhalation is not expected. Nevertheless it cannot be excluded that cleavage products of the substance may be included in the energy cycle and exhalation as CO2 may be possible.

 

 

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 and α-olefin sulfonates)

Anionic surfactants, including alkyl sulfates, alkane sulfonates and α-olefin sulfonates, have been assessed under the HPV program. These chemical 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.

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.

 

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.