3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-indenyl propionate

Endpoint summary

Description of key information

For Cyclaprop 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 Cyclaprop 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

Introduction

The test material Cyclaprop (Cas no 68912-13-0) is a propyl ester attached to a tricyclodecenyl fused ring structure. It is a clear colourless liquid with a molecular weight of 206 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 0.67 Pa.

Absorption:

Oral: The results of the repeated dose oral toxicity study from the read across substance Cyclacet and Cyclobutanate (IUCLID section 7.5) show 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 4.4) and water solubility (57 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 Cyclaprop 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 (206), log Kow (4.4) and water solubility (57 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). Cyclaprop is just outside the 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. Cyclaprop is a low volatile substance because of its low vapour pressure of 0.67 Pa, but the octanol/water partition coefficient (4.4), 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 Cyclaprop the BA partition coefficient would result in:

Log P (BA) = 6.96- 1.04 x Log 0.67 – 0.533 x Log 4.4 – 0.00495 x 206= 3.78

This means that Cyclaprop 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 Cyclaprop 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%.

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 Cyclaprop. 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 Propionic acid. The Cycla-alcohol and the acid are more water soluble and have lower Log Kow values. The log Kow of the Cycla-alcohol is 2.4 and of Propionic acid is < 1. After this Phase 1 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). Another conjugation pathway is the conjugation with alpha-2u glolublin because this protein is sedimented in the male rat kidneys after exposure to Cyclacet and Cyclobutanate.

Fig. 1   The metabolic pathway of Cyclaprop into Cycla-alcohol (3385-61-3) and Propionic acid (Cas no. 79-09-4) is presented.

Excretion:

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

Discussion

Cyclaprop 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 physico-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. Oral to inhalation and dermal route extrapolation: In absence of any human health hazard there is no DNEL derivation needed.

Conclusion

Cyclaprop 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.