Octadecane-1,12-diol

Endpoint summary

Additional information

BASIC TOXICOKINETICS

There are no experimental studies available in which the toxicokinetic behaviour of octadecane-1,12-diol (CAS 2726-73-0) has been assessed.

In accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2008), assessment of the toxicokinetic behaviour of the substance is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physicochemical and toxicological properties according to the relevant Guidance (ECHA, 2008).

The substance octadecane-1,12-diol is a monoconstituent with a molecular weight of 286 g/mol. It is a solid at room temperature, with an estimated water solubility of < 0.1 mg/L at 20 °C. The log Pow was estimated to be 6.58 and the vapour pressure was calculated to be < 0.0001 Pa at 20 °C.

The expected toxickinetic behaviour is derived from the physicochemical properties, the results from the available toxicological studies and the available literature following the information given in guidance document 7c. Please note that the real behaviour may be different but can only be determined with ADME studies, which are not justified based on the very low toxicity of the substance.

 

ABSORPTION

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters to provide information on this potential are the molecular weight, octanol/water coefficient (log Pow) value and water solubility (ECHA, 2008). The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2008). 

 

Oral

The molecular weight of octadecane-1,12-diol is lower than 500 g/mol, indicating that the substance is favorable for absorption (ECHA, 2008). The high log Pow in combination with the low water solubility suggests that any absorption will happen via micellar solubilisation (ECHA, 2008).

The available acute oral toxicity data on octadecane-1,12-diol showed LD50 > 5000 mg/kg bw and no systemic effects.

In a combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test of octadecane-1,12-diol in rats by gavage, no toxicologically relevant effects on systemic toxicity and no effects on fertility and development of the pups were noted up to and including the highest dose level of 1000 mg/kg bw/day (BASF SE 2015, 85R0221/14X229).

In conclusion, based on the available information, the physicochemical properties and molecular weight of octadecane-1,12-diol in combination with the low systemic toxicity potential limited oral absorption is suggested. 

 

Dermal

The dermal uptake of liquids and substances in solution is higher than that of dry particulates, since dry particulates need to dissolve into the surface moisture of the skin before uptake can begin. Substances with molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol may be too large.

Dermal uptake is anticipated to be low, if the water solubility is < 1 mg/L; low to moderate if it is between 1-100 mg/L; and moderate to high if it is between 100-10000 mg/L. Dermal uptake of substances with a water solubility > 10000 mg/L (and log Pow < 0) will be low, as the substance may be too hydrophilic to cross the stratum corneum. Log Pow values in the range of 1 to 4 (values between 2 and 3 are optimal) are favourable for dermal absorption, in particular if water solubility is high. For substances with a log Pow above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Log Pow values above 6 reduce the uptake into the stratum corneum and decrease the rate of transfer from the stratum corneum to the epidermis, thus limiting dermal absorption (ECHA, 2008).

The substance octadecane-1,12-diol is almost insoluble in water, indicating a low dermal absorption potential (ECHA, 2008). The molecular weight of 286 g/mol is not exceeding the limit above which dermal absorption is not expected (MW > 500 g/mol). The log Pow is > 6, which means that the uptake into the stratum corneum is likely to be slow and the rate of transfer between the stratum corneum and the epidermis will be slow (ECHA, 2008).

In summary the dermal uptake of octadecane-1,12-diol is expected to be low.

The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) applying the following equation described in US EPA (2004):

log(Kp) = -2.80 + 0.66 log Pow – 0.0056 MW = - 0.8733

The Kp is thus 0.87 cm/h. Considering the water solubility (< 0.0001 mg/cm³), the dermal flux is estimated to be ca. 0.1 µg/cm²/hr.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2008).

The experimental data on skin and eye irritation do not show any signs of irritation, which excludes enhanced penetration of the substance due to local skin damage (BASF900202, BASF900215).

Overall, based on the available information, the dermal absorption potential of octadecane-1,12-diol is predicted to be low.

 

Inhalation

As the vapour pressure of octadecane-1,12-diol is very low (< 0.0001 Pa at 25 °C), the volatility is also low. Therefore, the potential for exposure and subsequent absorption via inhalation during normal use and handling is considered to be negligible.

If the substance is available as an aerosol, the potential for absorption via the inhalation route is increased. While droplets with an aerodynamic diameter < 100 μm can be inhaled, in principle, only droplets with an aerodynamic diameter < 50 μm can reach the bronchi and droplets < 15 μm may enter the alveolar region of the respiratory tract (ECHA, 2008).

As for oral absorption, the molecular weight, log Pow and water solubility are suggestive of limited absorption across the respiratory tract epithelium by micellar solubilisation.

Due to the limited information available, absorption via inhalation is assumed to be as high as via the oral route in a worst case approach.

 

DISTRIBUTION AND ACCUMULATION

Distribution of a compound within the body depends on the physicochemical properties of the substance; especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and then intracellular concentration may be higher than extracellular concentration, particularly in fatty tissues (ECHA, 2008).

The substance octadecane-1,12-diol is lipophilic (log Pow > 0) and thus, is likely to distribute into cells, resulting in higher intracellular than extracellular concentration, particularly in fatty tissues.

Fatty alcohols are rapidly converted into the corresponding fatty acids by oxidation and distributed in form of triglycerides, which can be used as energy source or stored in adipose tissue. Stored fatty acids underlie a continuous turnover as they are permanently metabolized for energy and excreted as CO2. Bioaccumulation of fatty acids takes place, if their intake exceeds the caloric requirements of the organism.

 

METABOLISM

Diols where the alcohol groups are separated by several carbon centers, generally react as ordinary alcohols. Primary alcohols are usually first metabolized by enzyms (alcohol dehydrogenase) to the corresponding aldehyde. The aldehyde is a transient intermediate that is rapidly converted by further oxidation to the corresponding acid by the aldehyde dehydrogenase. The formed fatty acid id the susceptible to degradation via Acetyl-CoA intermediates by the mitochondrial β-oxidation process. His mechanism removes C2 units in a stepwise process. The rate of the β-oxidation tends to increase with increasing chain length (JECFA, 1999).

A major metabolic pathway for linear and branched fatty acids is the beta-oxidation for energy generation. In this multi-step process, the fatty acids are at first esterified into acyl-CoA derivatives and subsequently transported into cells and mitochondria by specific transport systems. In the next step, the acyl-CoA derivatives are broken down into acetyl-CoA molecules by sequential removal of 2-carbon units from the aliphatic acyl-CoA molecule. Further oxidation via the citric acid cycle leads to the formation of H₂O and CO₂(Lehninger, 1993). Branched-chain acids can be metabolised via the same beta-oxidation pathway as linear, depending on the steric position of the branch, but at lower rates (WHO, 1999). The alpha-oxidation pathway is a major metabolic pathway for branched-chain fatty acids where a methyl substituent at the beta-position blocks certain steps in the beta-oxidation (Mukherji, 2003). Generally, a single carbon unit is cleaved off the branched acid in an additional step before the removal of 2-carbon units continues. Alternative pathways for long-chain fatty acids include the omega-oxidation at high dose levels (WHO, 1999). The fatty acid can also be conjugated (by e.g. glucuronides, sulfates) to more polar products that are excreted in the urine.

  

The acids formed from longer-chain aliphatic alcohols can also enter lipid biosynthesis and may be incorporated in phospholipids and neutral lipids (Bandi et al. 1971a, 1971b; Mukherjee et al. 1980).

 

Furthermore, there is no indication that octadecane-1,12-diol is activated to reactive intermediates under the relevant test conditions. The experimental studies performed on genotoxicity (HPRT test) and QSAR predictions on genotoxicity (Ames test, chromosome aberration assay in mammalian cells in vitro) were negative, with and without metabolic activation. The QSAR prediction for the skin sensitization potential of ocatdecane-1,12-diol did not show a potential to induce skin sensitization. 

 

EXCRETION

The substance octadecane-1,12-diol can be metabolised for energy generation or stored as lipid in adipose tissue or used for further physiological functions e.g. incorporation into cell membranes.

In addition, the octadecane-1,12-diol may also be conjugated to form a more water-soluble molecule and excreted via the urine. In an alternative pathway, the alcohol may be conjugated with e.g. glutathione and excreted directly, bypassing further metabolism steps.

 

Although lipophilic alcohols such as 1-dodecanol have the physiochemical potential to accumulate in breast milk, rapid metabolism to the corresponding carboxylic acid followed by further degradation suggests that breast milk can only be, at most, a minor route of elimination from the body (OECD, 2006).

 

REFERENCES

 

Bandi ZL, Mangold HK, Holmer G and Aaes-Jorgensen E (1971a). The alkyl and alk-1-enyl glycerols in the liver of rats fed long chain alcohols or alkyl glycerols. FEBS Letters 12, 217-220.

 

Bandi ZL, Aaes-Jorgensen E and Mangold HK (1971b). Metabolism of unusual lipids in the rat. 1. Formation of unsaturated alkyl and alk-1-enyl chains from orally administered alcohols. Biochimica et Biophysica Acta 239, 357 -367.

 

ECHA (2008). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

 

JECFA (1999). Evaluation of certain food additives and contaminants. 49thReport of the Joint FAO/WHO Expert Committee on Food Additives. WHO Tech Rep Series No 884. WHO.

 

Lehninger, A.L., Nelson, D.L. and Cox, M.M. (1993).Principles of Biochemistry. Second Edition. Worth Publishers, Inc., New York, USA. ISBN 0-87901-500-4.

 

Mukherjee KD, Weber N, Mangold HK et al.(1980).Competing pathways in the formation of alkyl, alk-1-enyl and acyl moieties in the lipids of mammalian tissues. European Journal of Biochemistry 107, 289-294.

 

Mukherji M. et al. (2003). The chemical biology of branched-chain lipid metabolism. Progress in Lipid Research 42: 359-376.

 

OECD (2006) Long Chain Alcohols. SIDS Initial Assessment Report for 22.

 

US EPA (2004). Risk Assessment Guidance for Superfund (RAGS), Volume I: Human Health Evaluation Manual (Part E, Supplemental Guidance for Dermal Risk Assessment) Interim.http://www.epa.gov/oswer/riskassessment/ragse/index.html

 

WHO (1999). Evaluation of certain food additives and contaminants. Forty-ninth report of the joint FAO/WHO Expert Committee on Food Additives. WHO Technical Report Series 884. ISBN 92 4 120884 8.