Alcohols, C16-18 (even numbered, C18-unsatd.), ethoxylated, and alcohols C20-22 (even numbered), sulfates, ammonium salts

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
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 omega-oxidation and subsequent beta-oxidation of the aliphatic fatty acids.
Following oral exposure, Alkylethersulfates (AES) are readily absorbed in the gastrointestinal tract in man and rat and excreted principally via the urine. The length of the ethoxylate portion in an AES molecule seem to have an important impact on the biokinetics of AES in humans and in the rat. AES with longer ethoxylate chains (>7-9 EO units) are excreted at a higher proportion in the faeces. Once absorbed, AES is extensively metabolized by beta- or omega oxidation.
Long chained alcohols are generally highly efficiently metabolised and there is limited potential for retention or bioaccumulation for the parent alcohols and their biotransformation products. The initial step in the mammalian metabolism of primary alcohols is the oxidation to the corresponding carboxylic acid, with the corresponding aldehyde being a transient intermediate. These carboxylic acids are susceptible to further degradation via acyl-CoA intermediates by the mitochondrial β-oxidation process.  Longer chained aliphatic alcohols within this category may enter common lipid biosynthesis pathways and will be indistinguishable from the lipids derived from other sources (including dietary glycerides) (Kabir, 1993; 1995a,b).

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

Alkylsulfates (AS) and alkylethersulfates (AES) of medium to long alkyl chain length are a widely used class of anionic surfactants including some high production volume chemicals (e.g. sodium dodecyl sulfate). Common use includes household cleaning products (laundry and liquid dishwashing detergents, dispersing agents, hard surface cleaners), personal care products (shampoos, hair conditioners, liquid soaps, shower gels, toothpaste), and in additives for plastics and paints. Through its presence in many commonly used household detergents, consumers are exposed to AES mainly via the dermal route, but to some extent also via the oral and the inhalatory route (if marketed or used in a non solid or granular form). Due to wide and dispersive use of AS and AES scientifically sound human health risk assessment reports from industry associations and competent authorities are publicly available and were quoted in the followig summary. Based on this data and structural assessment of the parent UVCB substance as well as conclusion by analogy to assessed HPV AS and AES substances basic information on toxicokinetics are provided. Taking into account long chain fatty alcohol residues additional supporting information on toxicokinetics of long chain alcohols (FA C16 - C28) is provided.

References:

1. Alkylsulfates (AS) - SIDS Initial Assessment Report For SIAM 25, 16-19 October 2007, Helsinki.

2. Alkylethersulfates (AES) - Human & Environmental Risk Assessment on ingredients of European household cleaning products, Alcohol Ethoxysulphates, Human Health Risk Assessment, 2003.

3. Long chain fatty alcohols (FA) - SIDS Initial Assessment Report For SIAM 22, Paris, France, 18 – 21 April 2006, TOME 1: SIAR Long Chain Alcohols

1. Absorption

1.1 Oral route

Alkylsulfates (SIDS Initial Assessment Report For SIAM 25, 16-19 October 2007, Helsinki):

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.

Alkylethersulfates (Human & Environmental Risk Assessment on ingredients of European household cleaning products, Alcohol Ethoxysulphates, Human Health Risk Assessment, 2003):

McDermott et al. (1975) studied the absorption of C16AE3S and C16AE9S, labelled with 14C in the 1-position of the alkyl chain, after oral exposure in man and rats. Seventy-two hours after administration of C16AE3S, radioactive material was mainly excreted via urine (man: 80%; rat: 50%) and to a lesser extent via faeces (man: 9%; rat: 26%) and air (man: 7%; rat: 12%). For C16AE9S however, the radioactivity was mainly excreted via faeces (man: 75%; rat: 82%) and to a lesser extend via urine (man: 4%; rat: 0.6%) and air (man: 6%; rat: 4%). Following oral exposure, AES is readily absorbed in the gastrointestinal tract in man and rat and excreted principally via the urine. The length of the ethoxylate portion in an AES molecule seem to have an important impact on the biokinetics of AES in humans and in the rat. Alcohol ethoxysulphates with longer ethoxylate chains (>7-9 EO units) are excreted at a higher proportion in the faeces.

Long chain fatty alcohols (SIDS Initial Assessment Report For SIAM 22, Paris, France, 18 – 21 April 2006, TOME 1: SIAR Long Chain Alcohols):

Similar to the dermal absorption potential, it is expected that orally administered aliphatic alcohols also show a chain-length dependant potential for gastro-intestinal absorption, with shorter chain aliphatic alcohols having a higher absorption potential than longer chain alcohols.

1.2 Dermal route

Alkylsulfates (SIDS Initial Assessment Report For SIAM 25, 16-19 October 2007, Helsinki):

Absorption by the percutaneous route is limited, since anionic surfactants tend to bind to the skin surface (Howes, 1975; Black & Howes, 1980).

Alkylethersulfates (Human & Environmental Risk Assessment on ingredients of European household cleaning products, Alcohol Ethoxysulphates, Human Health Risk Assessment, 2003):

The dermal absorption of AES is relatively poor as can be expected from an ionic molecule. The percutaneous absorption of C12AE3S was measured in a rat in vivo study. The study determined a dermal flux of the tested compound of 0.0163 μg/cm2/h.

Dermal absorbtion of long chain anionic AS substances are expected to be even lower than for C12AE3S.

Long chain fatty alcohols (SIDS Initial Assessment Report For SIAM 22, Paris, France, 18 – 21 April 2006, TOME 1: SIAR Long Chain Alcohols):

Aliphatic alcohols are expected to be absorbed by all common routes of exposure. Based on comparative in vitro skin permeation data and dermal absorption studies in hairless mice, aliphatic alcohols show an inverse relationship between absorption potential and chain length with the shorter chain alcohols having a significant absorption potential (Iwata et al., 1987). Consequently alcohols with a carbon chain length of 20 and higher are expected to show negligible dermal absorbtion.

1.3 Inhalative route

The parent UVCB substance is marketed and used in a non solid or granular form and can be considered as non-volatile due to low vapour pressure. Nevertheless inhalative exposure during application can not be excluded, hence DNELs for inhalation exposure were derived according to relevant ECHA guidance documents.

2. Distribution

2.1 Alkylsulfates (SIDS Initial Assessment Report For SIAM 25, 16-19 October 2007, Helsinki) - oral distribution:

Whole body autoradiography has been performed to follow the oral distribution of 35S-C10ASO4 K (Burke et al., 1975), C12ASO4 K (Denner et al., 1969) and C18ASO4 K (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).

2.2 Alkylsulfates (SIDS Initial Assessment Report For SIAM 25, 16-19 October 2007, Helsinki) - repeated oral distribution:

After repeated oral application of alkyl sulfates with chain lengths between C12 and C18, the liver was the only target organ for systemic toxicity. Adverse effects on this organ included an increase in liver weight, enlargement of liver cells, and elevated levels of liver enzymes.

2.3 Alkylethersulfates (Human & Environmental Risk Assessment on ingredients of European household cleaning products, Alcohol Ethoxysulphates, Human Health Risk Assessment, 2003) - repeated oral distribution:

Repeated dose toxicity of NaC16 -18E4S was tested at doses of 0%, 0.023%, 0.047%, 0.094%, 0.188%, 0.375%, 0.75%, 1% and 1.5% in a 3-week dietary feeding study [Unilever, 1980b]. Three animals per sex per dose and 6 animals of each sex in the control group were used. In summary, the organ mostly affected by the feeding of NH4C12 -15E3S was the liver.

2.4 Long chain fatty alcohols (SIDS Initial Assessment Report For SIAM 22, Paris, France, 18 – 21 April 2006, TOME 1: SIAR Long Chain Alcohols) - repeated oral distribution:

1-Octadecanol [CAS 112-92-5] was tested in Wistar rats in a combined repeated dose and reproductive/developmental screen. Animals received dietary concentrations of 1500, 7500 or 30,000 ppm during all phases in the production of a single generation; the composition of the diet was adjusted to take into account the caloric value due to the incorporation of the test material. Male animals were exposed for 37 days including the mating period. Females were allowed to litter and were terminated at post-natal day 5. In male animals (females were not investigated) reductions were recorded in the levels of plasma glucose (>15% reduction in all treatment groups) and triglycerides (>37% reduction all treated level level); free cholesterol levels were increased 25% or more in all treated groups; these changes were without a clear dose-response. No treatment-related histopathological changes were recorded. The clinical chemical changes may be indicative of mild effects in the liver, the differences in the composition of the test diets may have contributed to these results. The NOAEL was 30,000 ppm (2000 mg/kg/day); the NOEL was <1500 ppm (<100 mg/kg/day) based on the changes in the clinical chemistry (Hansen, 1992b). In a 4-week oral study 1-octadecanol was administered daily (5 times/week) in olive oil to groups of 10 male and female Sprague-Dawley rats at levels of 0 (control), 100, 500 and 1000 mg/kg/day. There were no adverse effects reported in this study during all stages of the study (Henkel, 1986a).

1-Docosanol [CAS 661-19-8; C22 alcohol] was administered daily to groups of rats at levels up to 1000 mg/kg for 26 weeks. Body weight and food consumption was not affected by treatment. Haematology, clinical chemistry and gross necropsy investigations showed no evidence of toxicity. There were no treatment related microscopic changes (Iglesias et al., 2002a).

3. Metabolism and Excretion

3.1 Alkylsulfates (SIDS Initial Assessment Report For SIAM 25, 16-19 October 2007, Helsinki)

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 ω-oxidation, followed by β-oxidation, to yield metabolites with chain lengths of C2 and C4 for even-chain carbon alkyl sulfates (Greb & Wingen, 1980). 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 (Ottery et al., 1970). Dog and human urine also contained one other minor metabolite, glycolic acid sulfate (Merits, 1975). 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). 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 (C12 A35SO4 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 (Denner et al., 1969).

3.2 Alkylethersulfates (Human & Environmental Risk Assessment on ingredients of European household cleaning products, Alcohol Ethoxysulphates, Human Health Risk Assessment, 2003)

The length of the ethoxylate portion of an AES molecule appears to determine the metabolic fate of the compound following oral administration in both man and rat. There was no evidence of hydrolysis of the sulphate group or of metabolism of the ethoxylate portion of the molecule. The major metabolite found in urine had the following structure: -OOCCH2(OCH2CH2)xOSO3- where x equals either 3 or 9, respectively [McDermott et al., 1975]. Taylor et al. (1978) studied the metabolic fate of orally, intraperitoneally or intravenously administered 14C-C11AE3S and 14C-C12AE3S in the rat. The authors observed that both compounds were extensively metabolized (ω, β oxidation) with the proportion of radioactivity appearing in urine and respired air generally independent of the route of administration. Some sex differences in the proportions of radioactivity excreted in urine and respired air was seen, but total recoveries for both compounds were comparable. By the oral route, 67% of the administered radioactivity with C11AE3S appeared in the urine of male rats compared to 45% in females; expired air contained 19% and 35% of administered radioactivity respectively; 4-5% was present in faeces for both sexes. The major urinary metabolite of C12AE3S was identified as 2-(triethoxy sulphate) acetic acid, with C11AE3S, the major urinary metabolite was tentatively identified as 3-(triethoxysulfate) propionic acid.

Taylor et al. (1978) measured the percutaneous absorption of 14C-labelled NaC12AE3S. The NaC12AE3S was applied to rats as 150 μl of a 1% v/v solution. The 14C-levels were measured in urine collected over 48 hours. Penetration of NaC12AE3S was 0.39 +/- 0.12 μg/cm2. In experiments in which application was continued for up to 20 minutes, skin penetration was proportional to the duration of the contact. It was also proportional to the number of applications.

3.3 Long chain fatty alcohols (SIDS Initial Assessment Report For SIAM 22, Paris, France, 18 – 21 April 2006, TOME 1: SIAR Long Chain Alcohols)

The initial step in the mammalian metabolism of primary alcohols is the oxidation to the corresponding carboxylic acid, with the corresponding aldehyde being a transient intermediate. These carboxylic acids are susceptible to further degradation via acyl-CoA intermediates by the mitochondrial β-oxidation process. This mechanism removes C2 units in a stepwise process and linear acids are more efficient in this process than the corresponding branched acids. An alternative metabolic pathway for aliphatic acids exists through microsomal degradation via ω-or ω–1 oxidation followed by β-oxidation. This mechanism provides an efficient stepwise chainshortening pathway for branched aliphatic acids (Verhoeven, et al., 1998). The long chain aliphatic carboxylic acids are efficiently eliminated and aliphatic alcohols are therefore not expected to have a tissue retention or bioaccumulation potential (Bevan, 2001). Longer chained aliphatic alcohols within this category may enter common lipid biosynthesis pathways and will be indistinguishable from the lipids derived from other sources (including dietary glycerides) (Kabir, 1993; 1995a,b).

4. Conclusion (including ADME summary on residue fatty alcohol components)

4.1 Alkylsulfates (SIDS Initial Assessment Report For SIAM 25, 16-19 October 2007, Helsinki)

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.

4.2 Alkylethersulfates (Human & Environmental Risk Assessment on ingredients of European household cleaning products, Alcohol Ethoxysulphates, Human Health Risk Assessment, 2003)

Following oral exposure, AES is readily absorbed in the gastrointestinal tract in man and rat and excreted principally via the urine. The length of the ethoxylate portion in an AES molecule seem to have an important impact on the biokinetics of AES in humans and in the rat. Alcohol ethoxysulphates with longer ethoxylate chains (>7-9 EO units) are excreted at a higher proportion in the faeces. Once absorbed, AES is extensively metabolized by beta- or omega oxidation. The dermal absorption of AES is relatively poor as can be expected from an ionic molecule. The percutaneous absorption of C12AE3S was measured in a rat in vivo study. The study determined a dermal flux of the tested compound of 0.0163 μg/cm2/h.

4.3 Long chain fatty alcohols (SIDS Initial Assessment Report For SIAM 22, Paris, France, 18 – 21 April 2006, TOME 1: SIAR Long Chain Alcohols)

Aliphatic alcohols are expected to be absorbed by all common routes of exposure. Based on comparative in vitro skin permeation data and dermal absorption studies in hairless mice, aliphatic alcohols show an inverse relationship between absorption potential and chain length with the shorter chain alcohols having a significant absorption potential (Iwata et al., 1987). The initial step in the mammalian metabolism of primary alcohols is the oxidation to the corresponding carboxylic acid, with the corresponding aldehyde being a transient intermediate. These carboxylic acids are susceptible to further degradation via acyl-CoA intermediates by the

mitochondrial β-oxidation process.

An alternative metabolic pathway for aliphatic acids exists through microsomal degradation via ω- or ω–1 oxidation followed by β-oxidation. This mechanism provides an efficient stepwise chainshortening pathway for branched aliphatic acids (Verhoeven, et al., 1998). The acids formed from the longer chained aliphatic alcohols can also enter the lipid biosynthesis and may be incorporated in phospholipids and neutral lipids (Bandi et al, 1971a&b and Mukherjee et al. 1980). A small fraction of the aliphatic alcohols may be eliminated unchanged or as the glucuronide conjugate (Kamil et al., 1953). Similar to the dermal absorption potential, it is expected that orally administered aliphatic alcohols also show a chain-length dependant potential for gastro-intestinal absorption, with shorter chain aliphatic alcohols having a higher absorption potential than longer chain alcohols. With regards to the blood-brain barrier a chain-length dependant absorption potential exists with the lower aliphatic alcohols and acids more readily being taken up than aliphatic alcohols/acids of longer chain-length (Gelman, 1975). Taking into account the efficient biotransformation of the

alcohols and the physico-chemical properties of the corresponding carboxylic acids the potential for elimination into breast milk is considered to be low. The long chain aliphatic carboxylic acids are efficiently eliminated and aliphatic alcohols are therefore not expected to have a tissue retention or bioaccumulation potential (Bevan, 2001). Longer chained aliphatic alcohols within this category may enter common lipid biosynthesis pathways and will be indistinguishable from the lipids derived from other sources (including dietary glycerides) (Kabir, 1993; 1995a,b).

References listed in this section refer to the respective reports and publications listed above.

Note: A justification to use read-across data from supporting substances is provided in Section 13 of the IUCLID dossier.

Abbreviations:

AES = Alkylethersulfates

AS = Alkylsulfates

EO = Ethylene oxide monomer unit

Formulas:

C12AE3S = Poly(oxy-1,2-ethanediyl), alpha-sulfo-omega-(dodecyloxy)-, (3 EO)

C16AE3S = Poly(oxy-1,2-ethanediyl), alpha-sulfo-omega-(hexadecyloxy)-, (3 EO)

C16AE9S = Poly(oxy-1,2-ethanediyl), alpha-sulfo-omega-(hexadecyloxy)-, (9 EO)

35S-C10ASO4 K = 35Sulfur labelled substance, potassium decyl sulfate

35S-C12ASO4 K = 35Sulfur labelled substance, potassium dodecyl sulfate

35S-C18ASO4 K = 35Sulfur labelled substance, potassium octadecyl sulfate

NaC16 -18E4S = Alcohols C16 -18, ethoxylated, sulfates, sodium salts (4 EO)

NH4C12 -15E3S = Alcohols C12 -15, ethoxylated, sulfates, ammonium salts (3 EO)

14C-C11AE3S = 14Carbon labelled substance, Poly(oxy-1,2-ethanediyl), alpha-sulfo-omega-(undecyloxy)-, (3 EO)

14C-C12AE3S = 14Carbon labelled substance, Poly(oxy-1,2-ethanediyl), alpha-sulfo-omega-(dodecyloxy)-, (3 EO)

NaC12AE3S = Sodum laureth sulfate (3 EO)