Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

The toxicokinetics of ‘Reaction products of ricinoleic acid with 2-aminoethanol and maleic acid and sodium hydrogensulfite’ was assessed based on the physicochemical parameters and information on 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 organisms 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, CO2and sulfur. 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, CO2and sulfur. 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 rat and rabbit after oral application as two thirds of the administered radioactivity was found in the urine in the form of 2-ethylhexanol derivatives metabolites, and 90% of the radioactivity was detected in the urine both after oral and intravenous application. In the dog 95% of the administered radioactivity was excreted. 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, 2 and 30% 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 (%):
30

Additional information

The absorption, distribution, metabolism and excretion of Reaction products of ricinoleic acid with 2-aminoethanol and maleic acid and sodium hydrogensulfite 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
Reaction products of ricinoleic acid with 2-aminoethanol and maleic acid and sodium hydrogensulfite was assessed as follows based on physicochemical/toxicological datafollowing 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 UVCB mainly consisting of C18OH chains (70-80%). Therefore molecular formula, molecular weight and LogPow are based on the C18OH chain. The compound is a solid material with a molecular weight of about 565 g/mol and water solubility > 560 g/L. The logPow is around -1.81 and the mean particle size is >5000 µm.The vapour pressure is 0.035 Pa. The structure of the substance shows ionisable groups, the surface tension of a watery solution is 31.7 mN/m and the substance is readily biodegradable.

-Oral/GI absorption:
Based upon the ionisable, hydrophilic properties and the molecular weight above 500 g/mol, oral absorption might be considered to be limited, however the good solubility in GI fluids favors oral absorption. Furthermore the observed toxicity in acute oral toxicity studies indicated a systemic availability of the substance underlining an oral absorption. Nevertheless the extent of absorption stays unclear.

-Respiratory absorption:
The respiratory absorption is limited by the amount of inhalable substance and the fraction reaching the lower respiratory system. Due to the large particle size and low vapour pressure (0.035 Pa) inhalation and/or deposition of significant amount of the substance seems unlikely. Additionally the high hydrophilic properties of the substance may retain the substance in the upper mucosa. As a result the respiratory uptake and absorption is assumed to be limited.

-Dermal absorption:
Due to the molecular weight of above 500 and the water solubility of above 10 g/l dermal absorption is not expected. Furthermore the LogPow below -1 makes it impossible for the substance to cross the lipophilic areas of the stratum corneum. The surface tension is above 10mN/m pointing to no enhanced absorption, however due to the low vapor pressure a dermally attached substance may stay on the skin for a longtime. No skin irritations were observed for structural analog substances or with in vitro tests performed with the target substance. Therefore a limited dermal absorption is expected from this information. Calculation shows a very slow dermal absorption and dermal penetration coefficient Kp (see attachments). In summary, the dermal absorption is assumed to be very limited due to the high hydrophilicity and based on the irritation test information received.

 

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, November 2012 Version 1.1)

Metabolism:

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.

-Distribution:
Based on the molecular size of above 500g/mol and the high hydrophilicity a less wide distribution is expected but cannot be excluded. Nevertheless the low LogPow of below 0 indicates that a distribution into cells is less likely. However from the clinical signs observed after oral acute toxicity testing, distribution in the body is expected to take place. 

-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 Pow 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 high hydrophilicity and low logPow excretion in the urine is expected to be the favourable route. Nevertheless also excretion via bile is expected to occur after oral absorption but in less amounts than via urine. As the substance has a low vapour pressure , exhalation is not expected. Nevertheless the cleavage products of the substance may be included in the energy cycle and exhalation as CO2may 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 and 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 sulfossuccinate 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 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 30%) 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.