Reaction mass of 3a,4,5,6,7,7a-hexahydro-4,7-methanoinden-5-yl acetate and 3a,4,5,6,7,7a-hexahydro-4,7-methanoinden-6-yl acetate

Endpoint summary

Description of key information

For Cyclacet 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 Cyclacet 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

Cyclacet and its toxico-kinetic features

Introduction

The test material Cyclacet has a tricyclodecenyl fused ring backbone structure to which an ethyl ester is attached. It is a clear colourless liquid with a molecular weight of 192 g/mol that does not preclude absorption. The test material may show some hydrolysis in alkaline conditions rather than in acidic conditions because it is an ester. The substance has a low volatility 2 Pa.

Absorption

Oral: The results of the acute oral toxicity show that Cyclacet is absorbed via the oral route (LD50 is 2750 mg/kg bw). Also the repeated dose oral toxicity study shows that the substance is being absorbed by the gastro-intestinal tract following oral administration, because non-adverse alpha-hydrocarbon nephropathy specific for the male rate was seen. The relatively low molecular weight and the moderate octanol/water partition coefficient (Log Kow 3.9) and water solubility (186 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 Cyclacet is likely to be absorbed orally and therefore the oral absorption is expected to be > 50%.

Skin: Based on the physico-chemical characteristics of the substance, being a liquid, its molecular weight (192 g/mol), log Kow (3.9) and water solubility (186 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). Cyclacet is just outside the optimal range and therefore the skin absorption is not expected to exceed the oral absorption.

Lungs: Absorption via the lungs is also indicated based on these physico-chemical properties. Cyclacet is a low volatile substance because of its low vapour pressure of 2 Pa, but the octanol/water partition coefficient (3.9), 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 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 Cyclacet the BA partition coefficient would result in:

Log P (BA) = 6.96 - 1.04 x Log 2 – 0.533 x 3.9 – 0.00495 x 192 = 3.6

This means that Cyclacet 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 Cyclacet being somewhat out of the applicability domain and the exact BA 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 BA partition coefficient can also be considered an equivalent for the Koctanol / air (Koa) partition coefficient. The log Koa is used to assess the retention of the substance in the body and a log Koa of > 5 is used as a screening criterion for biomagnification in air-breathing organisms (ECHA PBT guidance, 2017). It can be seen that for air-breathing organisms (like rat and humans) the log Koa as calculated by EpiSuite, which is 5.01, may overestimate Cyclacet’s retention time in the body even without taking into account metabolism.

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 metabolisation the substance as such would not accumulate in the body fat.

Metabolism

There are no actual data on the metabolisation of Cyclacet. Small chain straight alkyl esters such as this substance (C3), which are not hindered by adjacent bulky groups, will be fully metabolised in the gut and in the liver by human carboxylesterase (hCE-2) (Toxicological handbooks and e.g. Saghir et al., 1997). The de-esterification result in a hydrocarbon secondary alcohol: Cycla-alcohol (3385-61-3) and Acetic acid. The Cycla-alcohol and the Acetic acid are more water soluble, have lower Log Kow values and higher water solubilities. The log Kow of the Cycla-alcohol is 2.4 (see physico-chemical section partition coefficient) and of Acetic acid is < 1. After this Phase I metabolism the Phase 2 metabolism, the conjugation with glucuronic acid will occur. This pathway is considered the same as is presented in the flavour safety evaluation of bicyclic secondary alcohols, ketones and related esters, such as Isobornyl-acetate (WHO, 2006 and confirmed in EFSA, 2012).

 

Fig. 1    The metabolisation pathway of the Cyclacet into Cycla-alcohol (Cas no. 3385-61-3) and Acetic acid (Cas no. 64-19-7) is presented.

 

Excretion

Cycla-alcohol-glucuronate will easily be excreted via the kidneys. Acetic acid is expected to be metabolized because it is a natural constituent of the body (Toxicological handbooks). Effects seen in the rat kidney rats show that excretion is through the urine. Any unabsorbed substance will be excreted via the faeces.

Discussion:

Cyclacet is expected to be readily absorbed, orally and via inhalation, based on the human toxicological information and physico-chemical parameters. 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 and therefore dermal absorption does not exceed oral absorption.

Oral to dermal and to inhalation route extrapolation: In absence of any hazards up to the limit dose there is no DNEL derivation needed for the routes of exposure.

Conclusion

Cyclacet 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.

 

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.

 

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.

 

Saghir. M., Werner, J., Laposta, M., 1997, Rapid in vivo hydrolysis of fatty acid ethyl esters, toxic nonoxidative ethanol metabolites, Am. J. Physiol., 273, G184-G190.