Methoxycarbonyloxycyclooct-4-ene

Endpoint summary

Description of key information

No experimental toxico-kinetic data are available for assessing adsorption, 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:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Toxico-kinetic behaviour of Violiff

Introduction

The substance is a reaction mass with an EC number 401-620-8. The substance has a large hydrocarbon 8-carbon ring to which a carbonate is attached. It is a liquid with a molecular weight of 184 that does not preclude absorption. The substance is likely to hydrolyse in alkaline conditions rather than in acidic conditions because it is an ester. The substance has a low volatility of 4 Pa.

Oral Absorption: The results of the repeat dose oral toxicity of the substance show that the substance is being absorbed by the gastro-intestinal tract following oral administration, because alpha 2u-globulin type of effects were seen. The relatively low molecular weight and the moderate octanol/water partition coefficient (Log Kow 2.9) and water solubility (377 mg/l) would favour absorption through the gut. According to Martinez and Amidon (2002) the optimal log Kow for oral absorption falls within a range of 2-7. This shows that the substance is likely to be absorbed orally and therefore the oral absorption is expected to be >> 50%.

Skin absorption: Based on the physico-chemical characteristics of the substance, being a liquid, its molecular weight (184), log Kow (2.9) and water solubility (377), 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). These characteristics are just outside optimal range and therefore the skin absorption is not expected to exceed oral absorption.

Lung absorption: 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 (4 Pa), the octanol/water partition coefficient (x), 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.

The B/A partition coefficient would result in:

Log P (BA) = 6.96 – 1.04 (0.6) – 0.533 x 2.9 – 0.00495 x 184 = 3.88

This means that the substance 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 the substance 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 therefore the absorption for the inhalation route will be considered 100%.

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. Due to the expected hydrolysis and metabolisation the substance as such would not accumulate in the body fat.

Metabolism

There are no actual data on the substance’s metabolization in vitro or in vivo. The degradation by micro-organisms showed the removal of the carbonic ester and the presence of the Violiff-alcohol. Also a Violiff-ketone was found at the spot of the alcohol (see biodegradation section).

 

Hydrocarbon secondary alcohol backbone with a small acidic alkyl chain type of esters, which are not hindered by adjacent bulky groups are likely to be fully metabolised in the gut and in the liver into the respective Violiff-alcohol and carbonic acid (Fig. 1). The cyclo-octenol and the carbonic acid are expected to be more water soluble and have a lower Log Kows. The cyclo-octenol will therefore more easily be excreted and carbonic acid is expected to be metabolized because it is a natural constituent of the body. This breakdown is also seen in the MITI biodegradation test where Violiff was metabolised into its alcohol and to a lesser extent into the ketone further supporting the breakdown of the carbonic acid part (see biodegradation section).

 

This pathway is presented in the flavour safety evaluation on (bicyclic) secondary alcohols, ketones and related. The reference used in the EFSA review (2012) is from White et al. (1990). They measured the ester breakdown of Cyclandalate (Cas no. 456-59-7, Fig. 2). This breakdown of Cyclandalate can be considered similar because ester cleavage is done by B-esterases (WHO, 2006, pg 406). These B-esterases are present in liver and all tissues. In monkeys and rabbits these esterases are abundantly present in intestines too as presented by Imai and Ohare (2010) discussing the absorption of pro-drugs. This ester cleavage for this group is almost complete and fast: > 80% and within 15 minutes, based on related substances (WHO, 2006, pg. 400).

In addition, the carbonic acid part of Violiff can be expected to have similar reactivity as the carbonic acid part of Cyclandalate (attached to the benzyl ring).

 

 

 

Fig. 1    The metabolisation of Violiff results in Violiff-alcohol, carbonic acid and methanol.

 

Fig. 2 The metabolization of Cyclandalate resulting in a secondary alcohol and Mandelic acid.

 

During Phase II metabolization Violiff-alcohol is likely to be glucuronidated to facilitate excretion.

 

Excretion

Effects seen in the rat kidney indicate that the primary route of excretion is through the urine. Excretion via the faeces can occur including any unabsorbed substance.

Discussion

The substance’s toxicological information and physico-chemical parameters indicate full oral absorption. The substance also is expected to be absorbed dermally based on the physic-chemical properties. 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 the final absorption values for the risk characterisation.

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. The substance is expected to be metabolise in the gut by micro-organisms because it is an ester. Some first pass effect via the liver may also occur. The toxicity of 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 the substance is not a volatile liquid the inhalation exposure will be considered. The substance 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

The substance 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 partion 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.

 

EFSA, 2012, SCIENTIFIC OPINION Scientific Opinion on Flavouring Group Evaluation 10, Revision 3

(FGE.10Rev3): Aliphatic primary and secondary saturated and unsaturated alcohols, aldehydes, acetals, carboxylic acids and esters containing an additional oxygenated functional group and lactones from chemical groups 9, 13 and 301, https://efsa.onlinelibrary.wiley.com/doi/pdf/10.2903/j.efsa.2012.2563, site visited September, 2018.

 

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

Imai and Ohare, 2010, The role of intestinal carboxylesterase in the oral absorption of prodrugs, Curr Drug Metab,11, 793-805.

 

White, D.A., Heffron, F., Miciak, A., Middleton, B., Knights, S., Knight, D., 1990. Chemical synthesis of dual radiolabelled cyclandelate and its metabolism in rat hepatocytes and mouse J774 cells. Xenobiotica 20(1), 71-79.

 

Joint FAO/WHO Expert Committee on Food Additives. Meeting (‎63rd : 2005 : Geneva, Switzerland)‎ & International Programme on Chemical Safety. (‎2006)‎. Safety evaluation of certain food additives / prepared by the sixty-third meeting of the Joint FAO/WHO Expert Committee on Food Additives (‎JEFCA)‎. World Health Organization, https://apps.who.int/iris/handle/10665/43265