Indeno[4,3a-b]furan, decahydro-2,2,7,7,8,9,9-heptamethyl-

Endpoint summary

Description of key information

No experimental toxicokinetic data are available for assessing adsorption, distribution, metabolisation and excretion of the test substance. Based on effects seen in the human health toxicity studies and physico-chemical parameters the test substance is expected to be readily absorbed via the oral and inhalation route and somewhat lower via the dermal route. Using the precautionary principle for route to route extrapolation the final absorption percentages derived are: 50% oral absorption, 50% dermal absorption and 100% inhalation absorption.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Toxico-kinetic profile of Amber Xtreme (EC Number: 449-360-4; Cas no. CAS Number: 449-360-4)

Introduction 

The test material Amber Xtreme is a tricyclic hydrocarbon with an ether group in its first ring. It is a liquid with a molecular weight of 264.25 that does not preclude absorption. The test material is unlikely to hydrolyse and has a low volatility (0.38 Pa). 

Absorption 

Oral: The results of the 28-day repeat oral dose (gavage) and oral (dietary) reproductive toxicity show that the substance is being absorbed by the gastro-intestinal tract following oral administration because effects on liver and thyroid gland were seen at the high dose: 1000 mg/kg bw. The relatively low molecular weight and the moderate to high octanol/water partition coefficient (Log Kow 4.42 and low water solubility (0.2 mg/l) do not exclude absorption through the gut, although they are not within the optimal range in accordance with the ECHA guidance (7.12, Table R.7.12-1). According to Martinez and Amidon (2002) the optimal log Kow for oral absorption falls within a range of 2-7. This shows that Amber Xtreme is likely to be absorbed orally and therefore the oral absorption is expected to be > 50%. 

Skin: Some skin absorption is expected to occur based the substance, being a liquid, its molecular weight (264.25), log Kow (4.42) and water solubility (0.2 mg/l), indicate that (some) dermal absorption is likely to occur. The optimal MW and log Kow for dermal absorption is < 100 and in the range of 1-4, respectively (ECHA guidance, 7.12, Table R.7.12-3). Amber Xtreme is just outside this optimal range and therefore the skin absorption is not expected to exceed 50%. 

Lungs: Absorption via the lungs is also indicated based on these physico-chemical properties. Though the inhalation exposure route is thought minor, because of its low volatility (0.38 Pa), the octanol/water partition coefficient (4.42), indicates that inhalation absorption is possible. The blood/air (BA) partition coefficient is another partition coefficient indicating lung absorption. Buist et al. 2012 have developed BA model for humans using the most important and readily available parameters: 

Log PBA = 6.96 – 1.04 Log (VP) – 0.533 (Log) Kow – 0.00495 MW.

For Amber Xtreme the B/A partition coefficient would result in: 

Log P (BA) = 6.96 – (1.04 *(-0.47) – (0.533 * 4.42) – 0.00495 * 264.25) = 3.8 

This means that the substance has a high tendency to go from air into the blood. It should, however, be noted that this regression line is only valid for substances which have a vapour pressure > 100 Pa. Despite Amber Xtreme being somewhat out of the applicability domain and the exact B/A may not be fully correct, it can be seen that the substance will be readily absorbed via the inhalation route and will be close to 100%. This PBA value can also be used as a substitute for the log Koa.

Distribution 

The low water solubility of the test substance would limit distribution in the body via the water channels. The log Kow would suggest that the substance would pass through the biological cell membrane.

Metabolism 

The metabolisation of the substance is assessed using OECD Toolbox 3 liver metabolism simulator. These metabolites show that each of the external methyl groups can be oxygenated into alcohols, aldehydes or acids. Thereafter glucuronidation can be expected. One example is shown in the figure below. 

 

Fig. 1 Amber Xtreme’s chemical structure. The arrows indicate where the sites of attack are for metabolization. These are on the methyl groups, which can be become oxidized into alcohols, aldehydes and/or acids (based on the OECD Toolbox rat liver simulator). 

 

Excretion: Based on the available physico-chemical properties and anticipated metabolism it is expected that unabsorbed material will end up in the faeces. The absorbed part is likely metabolised in the liver and may be excreted via the bile or via the urine. 

Discussion 

The substance is expected to be readily absorbed, orally and via inhalation, based on the human toxicological information and physico-chemical parameters. Amber Xtreme also is expected to be absorbed dermally due to the observed skin sensitisation properties. The MW and the log Kow are higher than the favourable range for dermal absorption but some absorption is likely. 

Conclusion for route to route extrapolation 

The IGHRC (2006) document of the HSE, which is mentioned in the ECHA guidance Chapter 8, will be followed to derive the final absorption values for the risk characterisation. 

Oral to dermal extrapolation: There are adequate data via the oral route and the critical toxic effect is related to systemic effects and therefore route to route extrapolation is applicable. The toxicity of the substance will be due to the parent compound but also to its metabolites. The overriding principle will be used to avoid situations where the extrapolation of data would underestimate toxicity resulting from human exposure to a chemical by the route to route extrapolation. Amber Xtreme is not expected to be detoxified in the gut because it is hydrolytically stable. Though some first pass effect via the liver may occur the toxicity via the dermal route will not be underestimated because absorption will be slower and the compound will also pass the liver. Therefore it will be assumed that the oral absorption will equal dermal absorption. Using the asymmetric handling of uncertainty the oral absorption will be considered 50% (though likely to be higher) and the dermal absorption will be considered also 50% (though likely to be lower). 

Oral to inhalation extrapolation: Though Amber Xtreme is not a volatile liquid some inhalation exposure will be calculated. Amber Xtreme is not a corrosive for skin and eye and the systemic effect will overrule the effects at the site of contact. In the absence of bioavailability data it is most precautionary that 100% of the inhaled vapour is bioavailable. For the oral absorption 50% has been used for route to route extrapolation to be precautionary for the dermal route. For inhalation absorption 100% will be used for route to route extrapolation, because this will be precautionary for the inhalation route. 

Conclusion: Amber Xtreme is expected to be readily absorbed via the oral and inhalation route and somewhat lower via the dermal route based on toxicity and physico-chemical data. Using the precautionary principle for route to route extrapolation the final absorption percentages derived are: 50% oral absorption, 50% dermal absorption and 100% inhalation absorption. 

References 

Buist, H. E., Wit-Bos de, L., Bouwman, T., Vaes, W. H. J., 2012, Predicting blood: air partition coefficient using basis physico-chemical properties, Regul. Toxicol. Pharmacol., 62, 23-28.

Martinez, M. N., And Amidon, G. L., 2002, Mechanistic approach to understanding the factors affecting drug absorption: a review of fundament, J. Clinical Pharmacol., 42, 620-643. 

IGHRC, 2006, Guidelines on route to route extrapolation of toxicity data when assessing health risks of chemicals, http: //ieh. cranfield. ac. uk/ighrc/cr12[1]. pdf