Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

The toxicokinetics of Absorption of Sulphobutanedioic acid, 1,4-dipentyl ester, sodium 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 apolar 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. 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, 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 Sulphobutanedioic acid, 1,4-dipentyl ester, sodium 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 Sulphobutanedioic acid, 1,4-dipentyl ester, sodium salt was assessed as follows, based on physicochemical/toxicological data following ECHA guidance 7c (ECHA Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance, November 2012 Version 1.1).

The substance is a solid material with molecular weight of 360,4 g/mol and water solubility of 0.286 g/L. The log Kow is 2.77 and vapour pressure is 25 Pa (at 20°C). The structure of the substance shows ionisable groups, and the substance is readily biodegradable. The registered substance is marketed only in non-solid and non-granular form, i.e., as liquid.

-   Oral/GI absorption: Favourable conditions for oral absorption are the molecular weight of 360,4 g/mol and water solubility of 0.268 g/L versus log Kow of 2.77. Based upon Pka (<3), the substance is considered to be partly ionisable and hydrophilic, whereas another part is not ionised. Toxicity was observed in the acute oral toxicity study, however at very high dosages and with limited systemic effects. An oral absorption of 90-100% is assumed from a conservative viewpoint.

-  Respiratory absorption: As the registered substance is marketed only in non solid and non granular form, i.e. as liquid; deposition in the airways is not expected. In worst case situation that inhalation exposure would take place, absorption by inhalation is considered to be limited. From a conservative viewpoint, 30% inhalation absorption is assumed.

-  Dermal absorption: Based upon the physicochemical parameters and skin irritation data, dermal absorption may be considered to be rather high. However, when calculation was performed, the dermal penetration rate (Kp) seems to be very low (0.00103 cm/hr). The maximum dermal flux (Jmax) was also calculated to be very low (296 mg/cm2/h * 10-6), therefore absorption is considered to be limited. When compared with reference anionic substances (showing similar to higher Jmax values and experimental absorption values of <1%), it can be concluded that 10% dermal absorption is a very conservative estimation for dermal absorption

For the assessment of distribution, metabolism and excretion physicochemical and toxicological properties are also taken into account according to ECHA guidance 7c (ECHA Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance, November 2012 Version 1.1).

-  Distribution: Although the molecule is rather small and lipophilic, distribution is expected to be rather limited. Target organs were limited to gastro-intestinal tract after acute oral dosing (above limit dose), whereas no target organs were detected after subchronic dosing at 1% in the diet (corresponding with at least 750 mg/kg bw/day).

- Metabolism: The substance is readily biodegradable. There is no direct indication of bioaccumulation potential in lung, adipose tissue, bone and stratum corneum of skin.

-  Excretion: Excretion via the urine is expected based on the molecule characteristics. Other excretions ways are not expected based on physicochemical properties.

 

 

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 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 oral 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.