sulfuric acids, C9-11-iso-C10 rich, alkyl esters, sodium salt

Endpoint summary

Description of key information

Absorption: 100% via oral route, 1% via dermal route
Distribution: Unquantified amounts of three different alkyl sulfates were found only in the kidney and the liver.
Metabolism: Alkylsulfates (AS) have a common metabolic fate that involves omega- and beta-oxidation to the respective C2 and C4 (even numbered AS) and the C3 and C5 (odd numbered AS). The oxidation products are mainly sulfated and excreted. C2-fragments may enter the C2 pool of the body and are either oxidized to CO₂ or found in the body. Hydrolysis of the ether bond between the fatty alcohol and the sulfate chain may occur to a small degree. About 10 to 20% of the administered dose usually is eliminated as inorganic sulfate.
Excretion: The majority of administered Alkylsulfates was excreted via urine. Only smaller amounts are excreted via the faeces. Elimination is fastest for the C12 chain length compared to other chain lengths, as it is completed within approx. 6 hour

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

1

Additional information

In the absence of study data for the target compound and to draw a coherent picture of the toxicokinetics, metabolism, distribution and excretion of Sulfuric acids, C9-11-iso-C10 rich, alkyl esters, sodium salt, this endpoint is covered by read across to structurally related alkyl sulfates (AS). The possibility of read-across to other alkyl sulfates in accordance with Regulation (EC) No. 1907/2006 Annex XI 1.5. 'Grouping of substances and read-across approach' was assessed. In Annex XI 1.5 it is given that a read-across approach is possible for substances, whose physico-chemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity. The AS reported within the AS read-across approach show structural similarity. The alkyl chain length varies from C8 to C18. In addition most source chemicals are not defined substances, but mixtures of homologues with different alkyl chain lengths (UVCBs). The most important common structural feature of the source and target substances is the presence of a predominantly linear aliphatic hydrocarbon chain with a polar sulfate group, neutralized with a counter ion. This structural feature confers the surfactant properties of the alkyl sulfates. The surfactant property of the source and target substances in turn represent the predominant attribute in mediating effects on mammalian health. Due to the structural similarities also the disposition within the body is comparable throughout the substances. The AS of the AS read-across approach also have similar physico-chemical, environmental and toxicological properties. The approach of grouping different AS for the evaluation of their toxicokinetics, metabolism and distribution as well as their effects on human health and the environment was also made by the OECD in the SIDS initial assessment profile [1] and by a voluntary industry programme carrying out Human and Environmental Risk Assessments (HERA [2]). Data reported within the discussion below summarize the information of the SIDS and HERA reports.

Absorption:

After oral administration, alkyl sulfates are well absorbed in rats, dogs and humans (SIDS, 2007). This was indicated by excretion of up to 98% of the dose administered (maximum for C12 AS Na) in the urine and by comparison of excretion after oral and i.v. or i.p. application for several alkyl sulfates. Hence, oral absorption is assumed to be 100%.

Absorption by the percutaneous route is limited, since anionic surfactants tend to bind to the skin surface (SIDS, 2007). Early studies with isolated human skin were unable to detect penetration of a homologous series of AS, ranging from C8 to C18 carbon chain lengths. Animal studies confirmed a low level of percutaneous absorption of AS. Less than 0.4% of a 3 μmol dose of 35S-labeled C12 AS Na was percutaneously absorbed in guinea pigs, based on recovery of the radiolabel in urine, faeces and expired air. Studies with rats indicated that pre-washing of the skin with surfactant enhanced AS skin penetration. Early studies with isolated human skin (not specified further) were unable to detect dermal penetration of C12 AS Na (SIDS, 2007).

Based on experimental data on animals and humans, a default assumption of 1% dermal absorption was considered for deriving the DNEL. Since dermal absorption decreases with increasing concentration of a solution, this percentage can be used for workers as a worst case approach.

Distribution:

After oral administration of 14.4 mg/kg bw of the radiolabelled erythromycin salt of C16 AS to dogs or 250 mg/person to humans, radioactivity in plasma was maximal within 30 minutes to 2 hours of exposure in both species indicating rapid absorption (SIDS, 2007). The plasma concentration declined rapidly afterwards and reached 10 % of the maximum concentration after 6 hours, indicating rapid elimination.

Whole body autoradiography has been performed to follow the distribution of the potassium alkyl sulfates ³⁵S-C10 AS K, C12 AS K and C18 AS K or their metabolites within the body with time in experiments with rats after i.p. injection. For all compounds the only organs, where radioactivity was detected were liver and kidney. The levels (not quantified) were highest 1 h after application. C10AS K was cleared from tissues more rapidly than C18 AS K. After 6 hours, only traces of the C10 AS K salt remained in the kidney, whereas it took 12 hours for the C18 AS K salt to be cleared from the kidney.

Metabolism/Excretion:

Alkyl sulfates are extensively metabolized in rats, dogs and humans. This was tested with radiolabelled C10, C11, C12, C16 and C18 alkyl sulfates, potassium salts (SIDS, 2007).

The postulated mechanism is degradation involving omega-oxidation, followed by beta-oxidation, to yield metabolites with chain lengths of C2 and C4 for even-chain carbon alkyl sulfates. The major metabolite for even-chained alkyl sulfates was identified as the 4-carbon compound, butyric acid 4-sulfate. The 4-butyrolactone has been found as a minor metabolite which is also formed after application of butyric acid 4-sulfate. Dog and human urine also contained one other minor metabolite, glycolic acid sulfate.

Metabolism of odd numbered chains (specifically, C11) in rats was postulated to follow a similar omega-, beta-degradation pathway: propionic acid-3-sulfate was the major urinary metabolite and pentanoic acid-5-sulfate and inorganic sulfate were minor metabolites. The C2 fragments enter the C2 pool of the body and are either oxidized to CO₂ or found in the body. About 10 to 20% of the dose usually is eliminated as inorganic sulfate.

The major path of excretion of the alkyl sulfates is the urine. The data show, that there are only minor differences for the alkyl sulfates of different chain lengths in the overall excretion after i.p. application. There are also no major differences in overall excretion between male and female rats or after oral, intraperitoneal or intravenous application. The rate of excretion in the urine, however, is somewhat different. After oral as well as i.p. application, excretion of the C12 compound is complete within 6 hours. In contrast the excretion amounts only to about 60% (C10), 40% (C11), 15% (C18) after i.p. application, and to 25% for C11 or C18 6 hours after oral application. This indicates faster metabolism of the C12 compound than for the other chain lengths.

In rats, somewhat smaller amounts of the alkyl sulfates are excreted via the faeces within 48 hours after oral application for the C12, C16 and C18 compounds. The lowest value was obtained for the C12, while the highest values with considerable variation of 2.5 - 19.9% (2 m, 2f) were found for C11. In the bile from <1 to 7.7% (highest amount with C11) of the dose applied was found up to 6 hours after i.v. application, indicating that the amounts in faeces are mainly due to metabolism and not to unabsorbed compound. In addition the distribution of radioactivity in urine and faeces from orally administered radiolabelled potassium dodecyl-³⁵S-sulfate (C12 A35S K) was similar in both antibiotic-treated and untreated rats, indicating that the intestinal flora does not play a significant role in the metabolism of this compound.

Based on the above mentioned data, rapid and almost complete excretion is expected and thus, accumulation in tissues can be excluded.

Influence of counter ions on ADME

Due to dissociation, there is no effect of the counter ion on absorption, distribution, metabolism and excretion of the alkyl sulfate moiety expected (HERA, 2002). This is supported by comparable results achieved with alkyl sulfates having different counter ions reported within this section.

Discussion on absorption rate:

Absorption by the percutaneous route is limited, since anionic surfactants tend to bind to the skin surface (SIDS, 2007). Both, studies with isolated human skin and animal tests confirmed a low level of percutaneous absorption. Based on experimental data on animals and humans, a default assumption of 1% dermal absorption was taken for deriving the DNEL. Since the dermal absorption decreases with increasing concentration of a solution this percentage can be used for workers as a worst case approach.

[1] SIDS initial assessment profile, (2007); http://www.aciscience.org/docs/Alkyl_Sulfates_Final_SIAP.pdf

[2] (HERA Draft report, 2002); http://www.heraproject.com/files/3-HH-04-%20HERA%20AS%20HH%20web%20wd.pdf