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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Minor structural differences (alkyl chain length) of test item and members of SIDS alkylsulfate substance group are found. Read across for toxicokinetics is justified based on structural similarities of the substance, which mainly consists of long chain alkylsulfates and alkylethersulfates. Read-across is justified taking into account that linear, even numbered alkylsulfates with C20 and longer alkylchains are expected to be metabolize in a similar way as presented in SIDS report. Lower absorbtion of AS with C20 and longer alkylchains in line with decreasing watersolubility can be expected in comparison to SIDS substance group.

Data source

Reference
Reference Type:
publication
Title:
SIDS Initial Assessment Report For SIAM 25
Author:
OECD
Year:
2007
Bibliographic source:
www.aciscience.org/docs/Alkyl_Sulfates_SIAR.pdf

Materials and methods

Objective of study:
toxicokinetics
GLP compliance:
no

Test material

Constituent 1
Reference substance name:
various salts of alkylsulfates with C10, C11, C12, C16, C18 carbon chain length
IUPAC Name:
various salts of alkylsulfates with C10, C11, C12, C16, C18 carbon chain length
Constituent 2
Chemical structure
Reference substance name:
Sulfuric acid, mono-C16-18-alkyl esters, sodium salts
EC Number:
273-258-7
EC Name:
Sulfuric acid, mono-C16-18-alkyl esters, sodium salts
Cas Number:
68955-20-4
IUPAC Name:
sodium heptadecyl sulfate
Details on test material:
Various substances, for details see SIDS and references
Radiolabelling:
yes
Remarks:
Study on distribution in tissue of 35Sulfur labelled alkylsulfates (potassium decyl sulfate, potassium dodecyl sulfate, potassium octadecyl sulfate) (Denner et al., 1969; Burke et al., 1975)

Test animals

Species:
other: rat, dog and human
Sex:
male/female

Administration / exposure

Route of administration:
other: oral, dermal, i.v., i.p.
Details on exposure:
Various, for details see SIDS and references
Duration and frequency of treatment / exposure:
Various, for details see SIDS and references
Doses / concentrations
Remarks:
Doses / Concentrations:
Various, for details see SIDS and references
No. of animals per sex per dose / concentration:
Various, for details see SIDS and references
Details on study design:
Various, for details see SIDS and references
Details on dosing and sampling:
Various, for details see SIDS and references

Results and discussion

Preliminary studies:
After oral administration, alkyl sulfates are well absorbed in rats, dogs and humans.
Main ADME resultsopen allclose all
Type:
absorption
Results:
The lipophilic nature of the substance suggests that the gastro-intestinal tract provides a route of absorption, following oral administration, before entering the circulatory system via the blood.
Type:
distribution
Results:
After repeated oral application of alkyl sulfates with chain lengths from C12 - C18, the liver was the only target organ for systemic toxicity. Slight skin sensitizing properties suggest that it may bind to carrier proteins in the circulatory system.
Type:
metabolism
Results:
The major metabolite for even-chained alkyl sulfates was identified as the 4-carbon compound, butyric acid 4-sulfate. The results of the genotoxicity assays have shown that genotoxicity is neither enhanced or diminished in the presence of the S9 mix.
Type:
excretion
Results:
The major path of excretion of the alkyl sulfates is the urine.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
After oral administration, alkyl sulfates are well absorbed in rats, dogs and humans (Denner et al., 1969; Burke et al., 1975; Merits, 1975; Black & Howes, 1980). This was indicated by excretion of up to 98 % of the dose administered (maximum for C12) in the urine and by comparison of excretion after oral and i.v. or i.p. application for C11 (Burke et al., 1976), C12 (Denner et al., 1969) and C18 (Burke et al., 1975) alkyl sulfates.
Absorption by the percutaneous route is limited, since anionic surfactants tend to bind to the skin surface (Howes, 1975; Black & Howes, 1980).
Details on distribution in tissues:
After application of 14.4 mg/kg of the erythromycin salt of C16ASO4 to dogs or 250 mg/person to humans, radioactivity in plasma was maximal within 30 minutes to 2 hours of oral administration in both species indicating rapid absorption (Merits, 1975). 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 35S-C10ASO4K (Burke et al., 1975), C12ASO4K (Denner et al., 1969) and C18ASO4K (Burke et al., 1975) 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 the liver and the kidney (Burke et al., 1975, 1976; Denner et al., 1969). The levels (not quantified) were highest 1 h after application. C10 AS was cleared from tissues more rapidly than C18. After 6 hours, only traces of the C10 salt remained in the kidney, whereas it took 12 hours for the C18 salt to be cleared from the kidney (Burke et al., 1975; 1976).
Details on excretion:
The major path of excretion of the alkyl sulfates is the urine. 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 (Denner et al., 1969; Burke et al., 1975, 1976). 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 after application. 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 hrs after oral application. This indicates faster metabolism of the C12 compound than for the other chain lengths. Lower amounts of the alkyl sulfates are excreted via the feces within 48 hrs 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 the feces are mainly due to metabolism and not to unabsorbed compound. In addition the distribution of label in urine and feces from orally administered potassium dodecyl 35S-sulfate (C12A35SO4K) 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 (Denner et al., 1969).

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
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 (Denner et al., 1969; Burke et al., 1975, 1976; Merits 1975; Greb & Wingen, 1980).
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 (Greb & Wingen, 1980). The 4-butyrolactone has been found as a minor metabolite which is also formed after application of butyric acid 4-sulfate (Ottery et al., 1970). Dog and human urine also contained one other minor metabolite, glycolic acid sulfate (Merits, 1975).
Metabolism of odd numbered chains (specifically, C11) in rats was postulated to follow a similar degradation pathway: propionic acid-3-sulfate was the major urinary metabolite and pentanoic acid-5-sulfate and inorganic sulfate were minor metabolites (Burke et al., 1976).
The C2 fragments enter the C2 pool of the body and are either oxidized to CO2 (Merits, 1975) or found in the body (Burke et al., 1975). In addition about 10 to 20 % of the dose usually is eliminated as inorganic sulfate (Denner et al., 1969; Burke et al., 1975; Merits, 1975). See Table 3-2 for an overview of the metabolites.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:
The test item is composed, as listed in the Section 1.2 of IUCLID. It is an ivory coloured solid and the molecular weight ranges from 242.4 to approx. 629.9 g/mol (majority of components < 500 g/mol). The relatively low vapour pressure value (1.3 Pa at 20°C) and predicted negative explosive and oxidising properties shows that the substance is non volatile therefore inhalation is not a significant route of exposure. The substance has a moderate to high log octanol/water partition coefficient value (Log Kow 2.11) and moderate water solubility. The available acute oral/dermal studies and the repeated dose/reproductive screening studies of homologues showed evidence of absorption, metabolism and excretion. The test item is non-mutagenic in bacteria, non-clastogenic in mammalian cells in vitro and non-mutagenic in mammalian cells in vitro in either the absence or presence of an auxiliary metabolising system. The test item is a slight skin sensitizer and shows mild skin irritant properties.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
The test item is composed, as listed in the Section 1.2 of IUCLID. It is an ivory coloured solid and the molecular weight ranges from 242.4 to approx. 629.9 g/mol (majority of components < 500 g/mol) containing fatty alcohols, alkylsulfates and alkylethersulfates. The low vapour pressure value (1.3 Pa at 20°C) and predicted negative explosive and oxidising properties shows that the substance is non volatile therefore inhalation is not a significant route of exposure. The substance has a moderate to high log octanol/water partition coefficient value (Log Kow 2.11) and moderate water solubility. The available acute oral/dermal studies and the repeated dose/reproductive screening studies of relevant components showed evidence of absorption, metabolism and excretion. The test item is non-mutagenic in bacteria, non-clastogenic in mammalian cells in vitro and non-mutagenic in mammalian cells in vitro in either the absence or presence of an auxiliary metabolising system. The test item is a slight skin sensitizer and shows mild skin irritant properties.
Executive summary:

Alkyl sulfates are well absorbed after ingestion; penetration through the skin is however poor. After absorption, these chemicals are distributed mainly to the liver and excreted principally via the urine or faeces. Alkyl sulfates are metabolized by cytochrome P450-dependent ω-oxidation and subsequent ß-oxidation of the aliphatic fatty acids. End products of the oxidation are a C4 sulfate (even numbered chain lengths). For the alkyl sulfates, in addition sulfate is formed as a metabolite. The metabolites are rapidly excreted in the urine. Due to significantly lower water solubility of long alkyl chain AS substances lower excretion in the urine and higher excretion via faeces can be expected.