Octa-1,7-diene

Endpoint summary

Description of key information

No studies are available. The molecular structure, molecular weight, water solubility and octanol-water partition coefficient of 1,7 -octadiene favours oral and inhalative absorption. Dermal absorption is considered moderate. 1,7-Octadiene may be distributed throughout the body. It is assumed, that 1,7-octadiene does not build reactive metabolites, and it is expected to be excreted via the urine/feces.

Additional information

The following remarks on the toxicokinetics of 1,7-octadiene are based on physicochemical properties as well as on data obtained in a basic dataset. There are no experimental toxicokinetic studies available and generation of new data is not required as the assessment of the toxicokinetic behaviour of the substance should be performed to the extent that can be derived from the relevant available information (REACh Annex VIII, 8.8.1).

 

1,7 -Octadiene has a molecular weight of 110.2 g/mol. It is a liquid at room temperature with a density of 0.73 g/mL (Everett and Kon, 1950). The vapour pressure of 1,7-octadiene is determined to be 25 hPa at 25 °C (2012-0454-DGP). The estimated octanol/water partition coefficient Log Pow is 4.00 at 25 °C (2000-0168-DKB) and its water solubility is approx. 10.45 mg/L at 25 °C (Yaw’s Handbook, 2008).

 

Absorption

The observation of systemic toxicity following exposure by any route is an indication for substance absorption; however, this will not provide any quantitative information. In general, absorption is likely because of the predominant lipophilic character as well as the low molecular weight of 1,7-octadiene.

 

In an acute oral toxicity study, in which the limit dose of 2000 mg/kg bw was administered to rats, clinical signs including slightly reduced motility, slight ataxia, slightly increased muscle tone, salivation and pilo-erection were reported during the first hours after administration. These observations indicate that absorption of the compound via the gastrointestinal tract (at least to some extent) has evidently occurred. This assessment is confirmed by the results from a 90-day oral repeat-dose study in rats. Here, at the highest dose of 1000 mg/kg systemic effects (increase in water consumption and plasma levels of total cholesterol and triglycerides as well as increased kidney and lever weights, histopathological findings in kidney and stomach) were observed, which clearly indicate systemic absorption. The gastrointestinal absorption is reported as 100% for a dose of 1 mg (Danish EPA Database, 2004).

Based on its slight water solubility and the rather lipophilic properties, dissolving into the gastrointestinal fluids will be limited. No additional data from oral studies is available.

An acute inhalation toxicity study is available, in which rats were exposed to vapours of 1,7-octadiene. 2 of 6 animals died at a vapour concentration of 36 mg/L within the observation period of 14 days. Thus, it can be assumed that 1,7-octadiene can be absorbed via the respiratory tract. Furthermore, the moderate log Pow value of 4 favours absorption directly across the respiratory tract epithelium by passive diffusion. Moreover, the slight water solubility, like small particle size might enable penetration to the lower respiratory tract.

In an acute dermal toxicity study in rats an LD50 value of 14.1 mL/kg bw corresponding to 10293 mg/kg bw was reported. However no details on results were given, therefore, no conclusion based on experimental data can be drawn concerning dermal absorption. Based on the physical parameters dermal absorption will be possible based on the molecular weight of 110.2 g/mol (maximal dermal uptake with MW < 100 g/mol;above 500 g/mol the molecule may be to large). The water solubility of 10.45 mg/L of 1,7-octadiene is rather low and thus, dermal absorption is anticipated to be low to moderate. Log P values between 1 and 4 favour dermal absorption, particularly if water solubility is high. The latter point (high water solubility) is not the case for 1,7-octadiene and, moreover, its Log P value (Log P = 4.00) is at the upper limit and therefore, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis. However, uptake into the stratum corneum might be high.

 

To gain more information on dermal absorption, the permeability of the skin can be calculated based on the physico-chemical properties of 1,7-octadiene. The dermal permeability constant Kp of 1,7-octadiene was estimated to be 0.266 cm/h using the QSAR published by Potts and Guy (1992) considering the log P of 4 and the molecular weight of 110.2 g/mol. Furthermore, the maximum flux Imax (Imax = Kp [cm/h] x water solubility [mg/cm³]) was calculated similar to the approach taken by Kroes et al. (2007) and resulted in a value of 2.77459 µg/cm²/h for 1,7-octadiene. This flux value represents a medium high dermal absorption potential and can be assigned to a dermal absorption of 40% (Mostert and Goergens, 2011). Therefore, the dermal bioavailability can be considered moderate.

 

Rarely, exogenous compounds (e. g. similar to a nutrient) may be taken up via a carrier mediated or active transport mechanism. However, prediction in this direction is not generally possible. Active transport (efflux) mechanisms also exist to remove exogenous substances from gastrointestinal epithelial cells thereby limiting entry into the systemic circulation. From physicochemical data, identification of substances ready for efflux is not possible.

 

Distribution

Some information or indication on the distribution of the compound in the body might be derived from the available physico-chemical and toxicological data. Once a substance has entered the systemic circulation, its distribution pattern is likely to be similar for all administration routes. However, first pass effects after oral exposure influence the distribution pattern and distribution of metabolites is presumably different to that of the parent compound.

The smaller a molecule, the wider is its distribution throughout the body. Membrane-crossing substances with a moderate log Pow and molecular weight will be able to cross the blood-brain and blood-testes barrier and reach the central nervous system (CNS) or testes, respectively. Thus, distribution of 1,7-octadiene throughout the body – at least to some extent – can be presumed, which is confirmed by data from a 90-day repeat-dose study in rats revealing diffuse systemic effects and histopathological changes in kidney and stomach. Neurotoxicological effects and effects on reproductive organs were not observed, so distribution of the substance to brain and testes cannot be confirmed.

 

Bioaccumulation

Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, highly lipophilic (log P > 4) compounds tend to have longer half-lives. Thus, they potentially accumulate within the body in adipose tissue, especially after frequent exposure (e.g. at daily work) and the body burden can be maintained for long periods of time. After the stop of exposure, the substance will be gradually eliminated dependent on its half-life. During mobilization of fat reserves, e.g. under stress, during fasting or lactation, release of the substance into the serum or breast milk is likely, where suddenly high substance levels may be reached. After dermal exposure, highly lipophilic compounds may persist in the stratum corneum, as systemic absorbance is hindered.

As the Log P value of 1,7-octadiene is rather high, accumulation in adipose tissue during 8 h-workday scenarios cannot be excluded.

 

Metabolism

Prediction of compound metabolism based on physico-chemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo. An important role plays the liver where many metabolites may arise. 10 possible liver metabolites were predicted with the OECD Toolbox 3.0, three thereof with a certain hazard potential as they contain an epoxide structure element. However, no elevated toxicity was observed after oral treatment, nor were there evidence for differences in toxic potencies due to metabolic changes in in vitro genotoxicity tests. No difference could be seen with respect to the addition of metabolic activation in an Ames test (91-0240-DGM), a chromosome aberration test (2009-0124-DGM), or a HPRT assay (90-0204-DGM) with 1,7-octadiene (i.e. no increased mutagenicity or cytotoxicity in treatments with metabolic activation). There is, thus, no indication for reactive metabolites of 1,7-octadiene.

 

Excretion

Only limited conclusions on excretion of a compound can be drawn based on physico-chemical data. Due to metabolic changes, the finally excreted compound may have few or none of the physico-chemical properties of the parent compound. In addition, conjugation of the substance may lead to very different molecular weights of the final product. 1,7-octadiene and its potential metabolites (OECD Toolbox 3.0) have a molecular weight lower than 500 g/mol, thus, excretion via faeces/urine is likely.

 

References:

Danish EPA Database, 2004: http://130.226.165.14/

 

Kroes et al. (2007) Application of the threshold of toxicological concern (TTC) to the safety evaluation of cosmetic ingredients.Food Chem Toxicol 45:2533-2562

 

Mostert and Goergens (2011) Dermal DNEL setting: using QSAR predictions for dermal absorption for refined route-to-route extrapolation. The Toxicologist: 107

 

Potts, R.O. and Guy, R.H. (1992) Predicting skin permeability. Pharm. Res. 9: 663-669