Reaction mass of 3,5,6,6-tetramethyl-4-methyleneheptan-2-one and (E)-3,4,5,6,6-pentamethylhept-3-en-2-one

Endpoint summary

Description of key information

No experimental toxico-kinetic data are available for assessing absorption, distribution, metabolisation and excretion of the substance. Based on effects seen in the human health toxicity studies and physico-chemical parameters the 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

Koavone (81786-75-6) toxico-kinetic assessment

Introduction

Koavone is a branched alkyl chain with a ketone bond. The substance is a liquid with a molecular weight (MW) of 182 that does not preclude absorption. The test material is not likely to hydrolyse. The test material has a low volatility (vapour pressure at 25 ⁰C 100 Pa (< 500 Pa)).

 

Absorption

Oral: The results of an extended dietary repeated dose reproscreen study of circa 90 days shows that the substance is being absorbed by the gastro-intestinal tract following oral administration because effects on kidneys were seen. The relatively low molecular weight and the moderate octanol/water partition coefficient (Log Kow 4.44 and water solubility (42 mg/L) would favour absorption through the gut. According to Martinez and Amidon (2002) the optimal log Kow falls within a range of 2-7 for oral absorption. This shows that Koavone is likely to be absorbed orally for at least 50%.

Skin: The substance is a not a skin and eye irritant but is a weak skin sensitizer which indicates that skin absorption occurs. Also based on the physico-chemical characteristics of the substance, being a liquid, its molecular weight (182), log Kow (4.44) and water solubility (42 mg/L) indicate that (some) dermal absorption can 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). Koavone is somewhat outside this optimal range and therefore less than 50% skin absorption can be anticipated.

Lungs: Absorption via the lungs is also indicated based on these physico-chemical properties. Though the inhalation exposure route is thought to be minor, because of its low volatility (100 Pa), the octanol/water partition coefficient (4.44), 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 Koavone the B/A partition coefficient would result in:

Log P (BA) = 6.96 – (1.04 x 2) – (0.533 x 4.44) – (0.00495 x 182) = 1.61

This means that Koavone has only a slight tendency to partition from air into blood. When the substance is inhaled less than 100% will be absorbed.

 

Distribution

The moderate 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. However, due to the expected metabolisation the substance as such would limitedly accumulate in the body fat. This can be seen in the predicted BCF of 407 of the EpiSuite model being 407, which takes into account metabolisation.

 

Metabolism

The metabolisation of Koavone is predicted using OECD Toolbox 3 liver metabolism simulator. One of the metabolites is presented below as an example in which an OH group is attached to one of the methyl groups of the branched chain. Such an OH group may be attached to every branched methyl group (For the structures see the attached document in IUCLID Endpoint summary section 7.1). These metabolites are expected to be more water soluble, have lower Log Kow values and will therefore be more easily excreted. According to WHO (2000) information on metabolisation of secondary ketones it can be expected that the ketone will be reduced to an alcohol.

 

Excretion

Effects seen in the kidney of the rats indicate that one of the routes of excretion is through the urine. Any unabsorbed substance will be excreted via the faeces.

 

Discussion

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

The IGHRC (2006) document of the HSE and mentioned in the ECHA guidance Chapter 8 will be followed to derive absorption values.

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 to avoid situations where the extrapolation of data would underestimate toxicity resulting from human exposure to a chemical by the route to route extrapolation. Koavone 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 Koavone is not a volatile liquid some inhalation exposure will be calculated. Koavone is not a skin and eye irritant 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

Koavone 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 basic physico-chemical properties, Regul. Toxicol. Pharmacol., 62, 23-28.

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

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.

WHO, 2000, Evaluation of certain food additives, Technical Report Series 891, page 53/54,http://whqlibdoc.who.int/trs/WHO_TRS_891.pdf