4,4a,5,9b-tetrahydroindeno[1,2-d]-1,3-dioxin

Endpoint summary

Description of key information

No studies are available. The molecular weight, physicochemical properties incl. water solubility and octanol-water partition coefficient of the substance suggest that oral, inhalative and dermal absorption occur. Widely distribution within the water compartment of the body after systemic absorption is because of lipophilicity of the test substance not expected. Based on its log Pow the test substance is not considered to accumulate. The test substance might be metabolized after absorption. Excretion is expected to be predominantly via the urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

In accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) No 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014), assessment of the toxicokinetic behaviour of the test substance was conducted to the extent that can be derived from the relevant available information on physicochemical and toxicological characteristics. There are no studies available evaluating the toxicokinetic properties of the substance.

The test substance is a white powder at 20 °C with a molecular weight of 176.21 g/mol and a water solubility of 3.89 g/L at 20 °C. The substance has a low vapour pressure of 0.35 Pa at 25 °C and the log Pow is 1.76 at 22.8 °C.

Absorption

The major routes by which the test substance can enter the body are via the lung, the gastrointestinal tract, and the skin. To be absorbed, the test substances must transverse across biological membranes either by active transport mechanisms or - as being the case for most compounds - by passive diffusion. The latter is dependent on compound properties such as molecular weight, lipophilicity, or water solubility (ECHA, 2014).

 

Oral

In general, low molecular weight (MW≤500) and moderate lipophilicity (log Pow values of -1 to +4) are favourable for membrane penetration and thus absorption. The molecular weight of the test substance is relatively low with 176.21 g/mol, favouring oral absorption of the compound. This is supported by the determined log Pow value of 1.76, being advantageous for oral absorption. Moreover, water-soluble substances will readily dissolve in the gastrointestinal fluids which favour oral absorption. One other mechanism, by which small water-soluble molecules (molecular weight up to around 200) can be absorbed in the GI tract include the passage through aqueous pores or carriage of such molecules across membranes with the bulk passage of water (Renwick, 1994). Moreover, the observation of systemic toxicity following exposure by any route is an indication for substance absorption; however, this will not provide any quantitative information.

Data from an acute oral toxicity limit test in rats (1990) revealed signs of systemic toxicity. Common signs of toxicity noted on the first day were hunched posture, lethargy, piloerection, decreased respiratory rate and ataxia. No mortalities occurred until the end of the study. Thus, the LD50 for male and female rats was > 2000 mg/kg bw.

In two conducted combined repeated dose oral toxicity studies with the reproduction/developmental toxicity screening studies (2015 and 2017) with dose levels between 1 and 500 mg/kg bw/day (1^ststudy: 1, 5 and 20 mg/kg bw/day; 2^ndstudy: 20, 100 and 500 mg/kg bw/day), one female at 1 mg/kg bw/day, in total six females at 20 mg/kg bw/day, two females at 100 mg/kg bw/day, and five females at 500 mg/kg bw/day were dead in the main groups during the dosing period. Chromaturia, salivation and hematuria were observed at 500 mg/kg bw/day. Lower values in body weights were noted in males at 500 mg/kg bw/day of main and recovery groups and in females of the main groups. In the first study decreases in hindlimb grip strength were noted in females at 20 mg/kg bw/day and in both sexes at 500 mg/kg bw/day. In the second study, in spontaneous motor activity, vertical count decreased dose-dependently in females at 1, 5 and 20 mg/kg bw/day in the main group. In surviving animals, an accumulation of hyaline droplets in the kidneys was evident in cortical tubules in males at 20, 100 and 500 mg/kg bw/day. Tubular degeneration in the kidney cortex was noted in one female at 100 mg/kg bw/day. Centrilobular vacuolation of hepatocytes in the liver was noted in both sexes at 500 mg/kg bw/day. Therefore, for systemic toxicity the LOAEL in males and the NOAEL in females was considered to be 20 mg/kg bw/day.

Based on available data from the acute oral and repeated dose toxicity studies, oral toxicity was observed with the test substance and thus absorption of the test via the gastrointestinal tract has evidently occurred.

 

Dermal

The dermal uptake of dry particles is generally slower than that of liquids because they have to dissolve into surface moisture of the skin before uptake can begin. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Thus, for the molecular weight level of the test substance dermal uptake can be seen to be moderate. A log Pow value between 1 and 4 favours dermal adsorption of the test substance. Additionally, sufficient water solubility is needed for the partitioning from the stratum corneum into the epidermis. Therefore, if the water solubility is between 100 and 10000 mg/L the dermal absorption is anticipated to be moderate to high (ECHA, 2014).

The dermal permeability constant Kp of the substance was estimated to be 0.00238 cm/h using DermwinTM (v.2.01) and taking into account the molecular weight of 176.21 g/mol and the log Pow of 1.76. Thus taking also into account the water solubility of 3.89 g/L, the absorption of the test substance is anticipated medium high. Data from an acute dermal toxicity limit test revealed no mortality or any signs of systemic toxicity and thus, the dermal LD50 value was greater than 2000 mg/kg bw (1999).

 

Inhalation

Moderate log Pow values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract (ECHA 2014). The particle size distribution values for the test substance were determined to be 50.1 µm (D10), 165.1 µm (D50) and 369.2 µm (D90). Since onlyapprox. 30 Vol% of the test substance has a diamater < 100 µm and only 10 Vol% of the substance has a diameter < 50.1 µm, the potential to be inhaled is low. Moreover, as the vapour pressure is 0.35 Pa at 20 °C, the inhalation exposure due to evaporation is very unlikely.

 

Distribution

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 the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA, 2014).

Since the test substance is lipophilic (log Pow 1.73) the distribution into cells is likely and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues, if the substance is absorbed systemically. Substances with log P values of 3 or less would be unlikely to accumulate in adipose tissues with the repeated intermittent exposure patterns normally encountered in the workplace but may accumulate if exposures are continuous. Once exposure to the substance stops, the substance will be gradually eliminated at a rate dependent on the half-life of the substance.

 

Metabolism

No metabolism studies are available with the test substance itself. Prediction of compound metabolism based on physicochemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo. The potential metabolites following enzymatic metabolism were predicted using the QSAR OECD toolbox (v3.4, OECD, 2016). This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. 12 hepatic and 6 dermal metabolites were predicted for the test substance, respectively. Primarily, hydroxylation of the substance occurs in the liver. In general, the hydroxyl groups make the substances more water-soluble and susceptible to metabolism by phase II-enzymes. Up to 77 metabolites were predicted to result from all kinds of microbiological metabolism for the test substance. There was no evidence for differences in genotoxic potencies due to metabolic changes in in vitro genotoxicity tests. The studies performed on genotoxicity (Ames test and HPRT test and micronucleus test in mammalian cells in vitro) were negative, with and without metabolic activation (1999, 2015, 2015).

 

Excretion

Only limited conclusions on excretion of a compound can be drawn based on physicochemical data. Due to metabolic changes, the finally excreted compound may have few or none of the physicochemical properties of the parent compound. In addition, conjugation of the substance may lead to very different molecular weights of the final product. The molecular weight (< 300 g/mol) and the water solubility of the molecule are properties favouring excretion via urine. Thus the test substance is expected to be excreted predominantly via the urine.

 

References

ECHA (2014): Guidance on information requirements and chemical safety assessment – Chapter 7c: Endpoint specific guidance. European Chemicals Agency, HelsinkiLiterature

Renwick, A.G. (1994) Toxicokinetics - pharmacokinetics in toxicology. In Hayes, A.W. (ed.) Principles and Methods of Toxicology.Raven Press, New York, p 103 as cited in ECHA 2014