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Description of key information

No experimental toxico-kinetic data are available for assessing adsorption, distribution, metabolism and excretion of the substance. Orivone 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:
no bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

Toxico-kinetic information on Orivone

Introduction

Orivone (CAS# 16587-71-6) has a cyclohexanone backbone substituted with a (1,1)dimethyl-propyl moiety on thepara-position. Orivone has a molecular weight of 168.28 g/mol, and is a liquid with a melting point below -20°C, a boiling point of 246.8 °C, a water solubility of 370.8 mg/L, a vapour pressure of 4.2 Pa and a log Kow of 3.9.

Absorption

Oral route: In an acute oral rat toxicity study 3/10, 6/10 and 9/10 of the animals died after exposure to 4000, 5000 and 6300 mg/kg respectively (at 3200 mg/kg bw no mortality occurred). These toxicological responses indicate that the substance is, at least partially, absorbed via the oral route. Based on the relatively low molecular weight (168.28 g/mol), the moderate log Kow (3.9) and moderate water solubility (370.8 mg/L) absorption through the gut is expected. According to Martinez and Amidon (2002) the optimal log Kow for oral absorption falls within a range of 2-7. This information indicates that Orivone is likely to be absorbed orally and therefore the oral absorption is expected to be over 50%.

Dermal route: In the available study on dermal acute toxicity in rabbits 1/6, 5/6 and 6/6 animals died after exposure to 4000, 5000 and 6300 mg/kg respectively (no mortality occurred at 3200 mg/kg bw). These toxicological responses indicate that Orivone is absorbed via the dermal route. Based on the physico-chemical characteristics of the substance, being a liquid, its relatively low molecular weight (168.28 g/mol), moderate log Kow (3.9) and moderate water solubility (370.8 mg/L), it is indeed suspected that dermal absorption is likely to occur. The optimal molecular weight 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). The substance is within the optimal range for log Kow and is above the optimal range for molecular weight. In view of the similar oral and dermal LD50s in rat and rabbits the oral and dermal absorption is expected to be similar.

Inhalation route:Absorption via the lungs is also indicated based on these physico-chemical properties. Though the inhalation exposure is thought to be minor because of the low volatility of the substance (vapour pressure of 4.2 Pa), the octanol/water partition coefficient (3.9) indicates that absorption via the lungs is possible. The blood/air (B/A) partition coefficient (log(PBA)) is another coefficient indicating lung absorption. Buist et al. 2012 have developed a 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 Orivone the B/A partition coefficient would result in:

Log (PBA) = 6.96 – (1.04 x 0.62) – (0.533 x 3.9) – (0.00495 x 168.28) = 3.4

 

This means that Orivone has a 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 Orivone being 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%.

Distribution

The moderate water solubility and low molecular weight allow distribution via the water channels. In addition, the log Kow (3.9) suggests that the substance is able to pass through biological cell membranes and does not indicate bioaccumulation risk.

Metabolism

No experimental data on the metabolism of Orivone is available. Literature on metabolism of structurally relatedtert-butyl cyclohexanones in rabbits shows efficient reduction of the ketone moiety to an alcohol and subsequent conjugation to glucuronic acid in rabbits (Cheo et al. 1967). In view of the alpha-2u globulins hydrocarbon nephropathy also transport via these globulins can occur.

TheOECD QSAR Toolbox (version 3.4) in addition predictoxidative metabolism of the tert-pentyl chain, which may result in alcohol and carboxylic acid metabolites (Data not shown).

 

Figure 1: Metabolism of Orivone based on theoretical and experimental information.

 

Excretion

The metabolic study of structurally relatedtert-butyl cyclohexanones show extensive urinary excretion of alcohol metabolites conjugated to glucuronic acid (Cheoet al.1967). The extrapolation of this excretion route to Orivone is supported by the effects on the urinary tract in the repeated dose study with the analogue trans-4-tert-butylcyclohexanol. Based on this information urinary excretion of Orivone, after phase I and phase II metabolism, is anticipated.

Discussion

The substance is expected to be readily absorbed, orally and via inhalation based on the human toxicological information and physico-chemical parameters. The substance is also expected to be absorbed dermally significantly based on the effects seen in the acute dermal toxicity test and its physico-chemical properties. The IGHRC (2006) document of the HSE mentioned in the ECHA guidance Chapter 8 will be followed to derive the final absorption values for the risk characterisation.

Oral to dermal extrapolation: Orivone is absorbed orally but also dermally based on similar LD50 values for rat and rabbits. Therefore there is experimental information 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 also be considered 50% (similar to the oral route).

Oral to inhalation extrapolation:Though Orivone is not volatile the inhalation exposure will be considered. In the absence of bioavailability data it is most precautionary that 100% of the inhaled vapour is bioavailable. For inhalation absorption 100% will be used for route to route extrapolation, because this will be precautionary for the inhalation route.

 

References

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

 

Cheo, K.L., Elliott, T.H., and Tao, R.C.C., The metabolism of isomeric tert-butylcyclohexanones, Biochem. J., 104, 198-204. 1967.

 

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