Butanoic acid, 3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-indenyl ester

Endpoint summary

Description of key information

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

Cyclobutanate and the assessment of its toxico-kinetic behaviour

Introduction: The test material Cyclobutanate is a butyl ester attached to a tricyclodecenyl fused ring structure. It is a clear colourless liquid with a molecular weight of 220 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: 11.2 Pa.

Absorption

Oral: The results of the repeat dose oral toxicity 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 4.48) and water solubility (11.5 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 Cyclobutanate 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 (220), log Kow (4.48) and water solubility (11.5), 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). Cyclobutanate is just outside optimal range and therefore the skin absorption is not expected to exceed the oral route.

Lungs: 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 (11.2 Pa), the octanol/water partition coefficient (4.48), 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 Cyclobutanate the B/A partition coefficient would result in:

Log P (BA) = 6.96- 1.04 x (1.04) – 0.533 x 4.48 – 0.00495 x 220= 2.4

This means that Cyclobutanate 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 Cyclobutanate 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 may 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 metabolization, presented below, the substance as such would not accumulate in the body fat.

Metabolism

There are no actual data on the metabolisation of Cyclobutanate in mammals. Hydrolysis is limitedly seen: at pH4 and pH7 no hydrolysis occurs. At pH 9 the half-life was 13 days at 25oC. Small chain straight alkyl (C4) esters such as this substance will be fully metabolised in the gut and liver into the respective Cycla-alcohol (3385-61-3) and butanoic acid (107-92-6) (fig. 1). This can be done by micro-organisms in the gut (Imai and Ohare, 2010) and/or human carboxylesterase (hCE-2) in the liver (WHO, 2006, White et al. 1990 as presented by EFSA (2008). EFSA uses Cyclandalate (456-59-7) metabolism as an example for de-esterification and formation of a secondary alcohol.

The Cycla-alcohol metabolite found in the biodegradation study with Cyclobutanate support the degradation of the ester by micro-organism (see biodegradation section, additional information). The “Cycla-alcohol” is too bulky to be further cleaved in the mitochondrion and needs glucuronidation for excretion (EFSA, 2008) (Fig. 1). Another pathway of excretion is seen in male rat which is via alpha 2u-globulin. Butanoic acid can be metabolised and be used as energy source or building block (EFSA, 2008 referencing Nelson and Cox, 2000a).

Fig. 1    Cyclobutanate metabolises into the alcohol (3385-61-3) and butanoic acid (107-92-6). Thereafter Cyclobutanate will be glucuronidated and butanoic acid will be further metabolises in mitochondrion.

 

Air-breathing organisms: These organisms may bioaccumulate substances which are limitedly metabolised (Gobas et al., 2020). This would leave excretion via the lungs as the key route. For substances with log Kow > 2 (and Koa 5), this may result in bioaccumulation. The presented metabolism for Cyclobutanate results in ester cleavage, glucuronidation, and excretion via the urine. The glucuronidated Cycla-alcohol has a low log Kow because glucuronic acid has a low log Kow – 1.87 (Pubmed). This log Kow presents absence of bioaccumulation in air-breathing organism. Gobas et al., 2020, figure 6, D, show that oxygen containing substances in general are no concern for air-breathing organism due to Phase 1 and/or Phase 2 (conjugation e.g. by glucuronidation) pathways.

Excretion

Glucuronidation of the substance or its metabolite will result in excretion in the kidneys. Effects seen in the kidney of the male rats (alpha 2u globulin hydrocarbon nephropathy) also show that excretion is through the urine. Any unabsorbed substance will be excreted via the faeces.

Discussion:

Cyclobutanate 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 but significant absorption is likely.

In absence of any human health hazard there is no DNEL derivation needed and therefore no route to route extrapolation.

Conclusion

Cyclobutanate 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.

In absence of any human health hazard there is no route to route extrapolation needed.

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.

EFSA, 2008, Scientific opinion on Flavouring groups evaluation, 47, (FGE.47), Bicyclic secondary alcohols, ketones and related esters form chemical group 8, Scientific opinion of the panel on food additives, flavouring, processing aids and materials in contact with food, https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2008.743: See Annex 3 for references on carboxylesterases; Heymann, 1980 and White et al, 1990.

EFSA, 2012, (FGE.87Rev1): Consideration of bicyclic secondary alcohols, ketones and related esters evaluated by JECFA (63rd meeting) structurally related to bicyclic secondary alcohols, ketones and related esters evaluated by EFSA in FGE.47 (2008), EFSA Journal 2012, 10(2), 2564. Follow up of the more elaborated EFSA, 2008 review.

Gobas, F.A.P.C., Lee, Y-S, Lo, J.C., Parkerton, T.F., Letinskid, D.J., 2020, A Toxicokinetic Framework and Analysis Tool for Interpreting Organisation for Economic Cooperation and Development Guideline 305 dietary bioaccumulation test, Environ. Toxicol. Chem., 39, 171-188.

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

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

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.

WHO, 2006, Food Additive Series 54, Safety evaluation of certain food additives, http://www.inchem.org/documents/jecfa/jecmono/v54je01.pdf; page 385 and 399 and 400, of the report.