Sulfuric acid, C16-C18 (even numbered) alkyl esters, sodium salts and C16-18 (even numbered) alcohols

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

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

Species:

rat

Strain:

not specified

Route of administration:

oral: feed

Vehicle:

not specified

Remarks:

The total dose fed to the 5 rats was 2.5g each of cetyl alcohol .

No. of animals per sex per dose / concentration:

5

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): urine, faeces
- Time and frequency of sampling: collected over a 5 day period


METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled (delete / add / specify): urine, faeces,
- Time and frequency of sampling: collected over a 5 day period


Urine and faeces were collected over a 5 day period.

Details on absorption:

Cetyl alcohol was incompletely absorbed with 20% of the dose recovered unchanged from the faeces.

Details on distribution in tissues:

No data.

Details on excretion:

Faecal excretion was complete within 48 hours.
About 6% of the dose was in the form of glucuronic acid conjugate in the urine.

Metabolites identified:

yes

Details on metabolites:

About 6% of the dose was in the form of glucuronic acid conjugate in the urine.

Conclusions:

Cetyl alcohol was incompletely absorbed with 20% of the dose recovered unchanged from the faeces. Faecal excretion was complete within 48 hours. About 6% of the dose was in the form of glucuronic acid conjugate in the urine.

Executive summary:

In an investigation of the metabolism of cetyl alcohol, groups of 5 rats received doses of the test material in the diet. Urine and faeces were collected over a 5 day period. The total dose fed to the 5 rats was 2.5g each of cetyl alcohol.

Cetyl alcohol was incompletely absorbed with 20% of the dose recovered unchanged from the faeces. Faecal excretion was complete within 48 hours. About 6% of the dose was in the form of glucuronic acid conjugate in the urine.

(Reference: McIsaac, W.M; Williams, R.T., 1958 The metabolism of spermaceti. W.A. Journal Biol. Chem. 2(2)42-44)

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: review/summary of available information

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Remarks:

OECD SIDS summarises the findings of various published studies reporting the toxicokinetics of sodium sulfate.

Principles of method if other than guideline:

no details provided

GLP compliance:

not specified

Species:

other: humans, rats, ruminants

Details on absorption:

In humans, absorption of small amounts of sulfate from the gut occurs rapidly and almost completely. In a study with 8 volunteers, small amounts (60-80 µCi) of radioactive sulfate-35 (35S) were administered orally or intravenously. Plasma equilibrium was reached within 60 to 105 and 60 to 90 minutes respectively, and in both cases 80% or more of the administered amount of radioactivity was recovered in the urine within 24 hours (Bauer et al, 1976). In contrast, absorption studies with very large amounts of sodium sulfate (18.1 gram as decahydrate = 8 g as Na2SO4) demonstrated incomplete absorption (53% urinary recovery of sulfate in 72 hours), which was associated with severe diarrhea (Cocchetto and Levy , 1981). When the same amount was given in four fractions over several hours, urinary recovery was 62% in 72 hours and no or only mild diarrhea occurred. Similar results were obtained with magnesium sulfate, although absorption seems to be less complete and more erratic, thus leading to more adverse effects (Morris and Levy, 1983). Apparently, the capacity of intestinal transport mechanism for sulfates can be exceeded. In a human volunteer study described 3.1.2 (Heizer 1999) , 40-80% of a single dose of 63 mg/kg of sodium sulfate was resorbed and excreted in urine. Effects of saturation of absorption could not be detected over a dose range of 21-63 mg/kg/day in the range-finding part of this study.
Similar data are available from experimental animals: In a study on male Wistar rats using 35S labeled Na2SO4, rapid and almost complete absorption occurred. When the radioactively labeled material was added to a large amount of unlabeled sodium sulfate and subsequently orally administered, the plasma peak occurred at the same time, but the amount of radioactivity decreased as the dose of unlabeled sulfate increased. This indicates that there is a saturation of the absorption mechanism (Krijgsheld, 1979). In male adult Wistar rats, approximately 73% of dietary calcium or magnesium sulfate salts was absorbed, although absorption was partly dependent on other dietary elements (Health Canada, 1994).
In ruminants, excess amounts of sodium sulfate in feed may result in considerable toxicity due to formation of sulfides through bacterial action in the rumen.

Details on distribution in tissues:

After absorption free sulfate ions rapidly distribute over the extracellular space, the apparent volume of distribution being ~ 20% of the body volume. The serum concentration of sulfate in humans ranges between 1.4 and 4.8 mg/100 mL, with a mean of about 3.1 mg/100 mL.
Since disturbances in sulfate metabolism are possibly associated with only one rare form of inherited dwarfism, this area is largely unexplored. Therefore, no attempts have been made to fully describe sulfate metabolism. Sulfate incorporation has been observed with such biologically important compounds as chondroitin, fibrinogen, l-tyrosine derivatives, bilirubin, and steroids. A number of amino acids contain sulfur and take part in the sulfate cycle. Hydrolytic (sulfatase) activity has been demonstrated in liver, kidney, pancreas, serum, and urine. Sulfates play an important role in sulfoconjugation processes, which are of great importance in a variety of detoxification/excretion processes (Percy, 1964).

Details on excretion:

Sulfate is a normal constituent of the blood and is a normal metabolite of sulfur-containing amino acids, and excess sulfate is excreted in the urine. Daily sulfate excretion is reported to be 0.20 to 0.25 mmol/kg bw/day and higher in children (Health Canada, 1994).
Excretion is mainly in urine. The renal clearance is approximately one third of the glomerular filtration rate, indication tubular re-absorption. However, the total free sulfate excretion rate is not dependent on urine flow rate. Organically bound sulfate may follow different excretion patterns. (Cocchetto and Levi, 1981).
About 800 mg of elemental sulfur are eliminated daily through the urine of humans, compared with 140 mg in the faeces. (ICRP, 1984) Some 85% of urinary sulfur is present as inorganic sulfates and a further 10% as organic sulfates, whereas the remainder is excreted as conjugated alkyl sulfates (Diem, 1972).

Conclusions:

Relatively large amounts of sodium sulfate are normally taken up by the gut from food and drinking water through a saturatable mechanism. Absorbed sodium and sulfate ions circulate freely throughout the entire body and form part of a large intra- and extracellular sodium and sulfate pool respectively. Sulfates are normally incorporated in a great variety of body compounds and as such essential to life.

Executive summary:

Sulfate (and sodium) ions are important constituents of the mammalian body and of natural foodstuffs and there is a considerable daily turnover of both ions (several grams/day expressed as sodium sulfate). Near-complete absorption of dietary sulfates may occur at low concentration, depending on the counter-ion, but absorption capacity can be saturated at higher artificial dosages resulting in cathartic effects. Absorption through skin can probably be ignored since sodium sulfate is fully ionised in solution. One source suggests that very high levels of sulfate in urine may occur due to absorption from dust inhalation. At dietary levels, excretion is mainly in the urine. Sulfates are found in all body cells, with highest concentrations in connective tissues, bone and cartilage. Sulfates play a role in several important metabolic pathways, including those involved in detoxification processes.

Description of key information

Literature data are available for the various components of the registered substances.

The Long chain alcohols (LCHO) are well absorbed by various routes, highly efficiently metabolised and there is limited potential for retention or bioaccumulation for the parent alcohols and biotransformation products. There is a chain-length dependent potential for absorption, with shorter chains having a higher absorption potential than longer chains (SIDS, 2006).

Alkyl sulfates (AS) are well absorbed after ingestion; penetration through the skin is however poor. After absorption, AS are distributed mainly to the liver and metabolized by cytochrome P450-dependent oxidation of the aliphatic fatty acids. End products are a C4 sulfate or sulfonate and C3 or C5 sulfate or sulfonate. In addition sulfate is formed as a metabolite. The metabolites are rapidly excreted in the urine (SIDS, 2007).

Sodium sulfate is well taken up by the gut through a saturatable mechanism. Absorption through skin can probably be ignored since sodium sulfate is fully ionised in solution. Absorbed sodium and sulfate ions circulate freely throughout the entire body and form part of a large intra- and extracellular sodium and sulfate pool respectively. Sulfates are found in all body cells, with highest concentrations in connective tissues, bone and cartilage. Excretion is mainly in the urine (SIDS, 2005).

Based on the available information, the registered substance is also considered to be well absorbed dependent on chain length by oral route (less by dermal route), distributed in the blood, and metabolized and excreted. Based on the components, there is limited potential for retention or bioaccumulation.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

No extra testing was performed as literature data are summarised for the various components of the registered substances. A selection of most reliable information was made.

The toxicokinetics of the Long chain alcohols (LCHO) has been summarized by SIDS (2006):

-      Long chained alcohols are generally absorbed, highly efficiently metabolised and there is limited potential for retention or bioaccumulation for the parent alcohols and their biotransformation products.

-      Aliphatic alcohols are 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. This mechanism removes C2 units in a stepwise process and linear acids are more efficient in this process than the corresponding branched acids(WHO, 1999).

-      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 theglucuronide 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).

-      A comparison of the linear and branched aliphatic alcohols shows a high degree of similarity in biotransformation. For both sub-categories the first step of the biotransformation consists of an oxidation of the alcohol to the corresponding carboxylic acids, followed by a stepwise elimination of C2 units in the mitochondrial β-oxidation process. The metabolic breakdown for both the linear and mono-branched alcohols is highly efficient and involves processes for both sub-groups of alcohols. The presence of a side chain does not terminate the β-oxidation process, however in some cases a single Carbon unit is removed before the C2 elimination can proceed.

The toxicokinetics of the Alkyl sulfates (AS) has been summarized by SIDS (2007):

-      Alkyl sulfates are well absorbed after ingestion; penetration through the skin is however poor. After absorption, these chemicals are distributed mainly to the liver. 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 or sulfonate (even numbered chain lengths) and a C3 or C5 sulfate or sulfonate (odd numbered chain lengths). In addition sulfate is formed as a metabolite. The metabolites are rapidly excreted in the urine.

The toxicokinetics of the Sodium sulfate has been summarized by SIDS (2005) and SIAR (2005):

-      Relatively large amounts of sodium sulfate are normally taken up by the gut from food and drinking water through a saturatable mechanism. Absorbed sodium and sulfate ions circulate freely throughout the entire body and form part of a large intra- and extracellular sodium and sulfate pool respectively. Sulfates are normally incorporated in a great variety of body compounds and as such essential to life.

-      Near-complete absorption of dietary sulfates may occur at low concentration, depending on the counter-ion, but absorption capacity can be saturated at higher artificial dosages resulting in cathartic effects. Absorption through skin can probably be ignored since sodium sulfate is fully ionised in solution. At dietary levels, excretion is mainly in the urine. Sulfates are found in all body cells, with highest concentrations in connective tissues, bone and cartilage. Sulfates play a role in several important metabolic pathways, including those involved in detoxification processes.