Exo-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl propionate

Endpoint summary

Description of key information

Isobornyl propionate 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 Isobornyl propionate

Introduction

Isobornyl propionate (CAS#2756-56-1) hasa n exo-1,7,7 Trimethylbicyclo[2.2.1]heptane-2-ol (Isobornyl alcohol) backbone structure, with a propanoic ester attached.The substance is a liquid with a molecular weight of 210.32 g/mol, a water solubility of 19.8 mg/L, a vapour pressure of 3.1 Pa and a Log Kow of 5.0.

Absorption, oral: In an acute oral toxicity study a single dose of 5.0 g/kg bw resulted in mortality (2/10 animals). Also in the repeated dose toxicity study increased liver weight and alpha-hydrocarbon nephropathy in male rats only (both effects non-adverse) show the substance is absorbed via the oral route, which can also be deduced from the physico-chemical parameters. Based on the relatively low molecular weight (210.32 g/mol), moderate water solubility (19.8 mg/L) and log Kow of 5, 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 to 7. Together this information indicates that the substance is likely to be absorbed orally and therefore the oral absorption is expected to be > 50%.

Dermal route: There are no effects seen in the dermal acute toxicity and therefore dermal absorption cannot be derived based on this. Some dermal absorption is indicated based on its molecular weight, the substance being a liquid and its physico-chemical properties such as water solubility and log Kow. These values are outside the optimal values for molecular weight and log Kow for dermal absorption are < 100 and in the range of 1-4, respectively (ECHA guidance, 7.12, Table R.7.12-3) but some dermal absorption is expected. The dermal absorption is, however, not expected to exceed the oral absorption.

Inhalation route:In the absence of experimental data, absorption via the lungs is also indicated based molecular weight and on these physico-chemical properties. Though the inhalation exposure is anticipated to be minor because of the low volatility of the substance (vapour pressure of 3.1 Pa), the Log Kow and water solubility indicate, as for oral uptake, 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 B/A portioning 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 Isobornyl propionate the B/A partition coefficient would result in:

Log (PBA) = 6.96 – (1.04 x 0.49) – (0.533 x 5.0) – (0.00495 x 210.32) = 2.74

 

This means that the substance has a tendency to go from air into the blood. It should, however, be noted that this regression is only valid for substances which have a vapour pressure > 100 Pa. Despite the fact that substance is out of the applicability domain and the exact B/A may consequently not be fully correct, it is suggested 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 some distribution via the water channels. In addition, the log Kow (5.0) suggests that the substance is able to pass through biological cell membranes. The substance is not expected to bioaccumulate based on its metabolism and the derived BCF value of 156 from Verdox (see bioaccumulation section).

Metabolism

No experimental data on the metabolism of the substance is available. Propionic and acetic esters will be cleaved by carboxyl esterases (e.g. Toxicological handbooks, Wu et al., 2010). After metabolisation Isobornyl alcohol and propionic acid will be available for systemic exposure. Isobornyl alcohol is expected to be conjugated (EFSA, 2008). Borneol and Bornyl acetate metabolisation information is available which indicates that cleavage of the ester bond followed by glucuronidation is extensive and the major route of elimination. Rabbits excrete 80 to 95% of the administered substance as bornyl glucuronide, which was slightly higher compared to human (80%) (Williams, 1959 also referenced in Gaunt et al.,1971). Isoborneol will also be conjugated with alpha-2u globuline in male rates because alpha-hydrocarbon nephropathy is seen in these animals. Propionic ester is a normal constituent of the body and will be metabolised as such.

 

Fig. Isobornyl propionate metabolism resulting in isoborneol and propionic acid.

 

Excretion

Based on the relatively low molecular weight and predicted metabolites, mainly excretion via theurinary tract is anticipated. In the sub-chronic repeated dose toxicity study with the structurally very similar substance Isobornyl acetate renal effects were observed, which indicate excretion via this route.

Discussion

The substance is expected to be readily absorbed orally and via inhalation (although the exposure is expected to be low based on the low vapour pressure), based on the experimental toxicological information and physico-chemical parameters of the substance. Dermal absorption is also anticipated based on 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: The substance is absorbed orally. Since dermal absorption will be (s)lower and the substance will also pass the liver during systemic circulation, it is assumed that the oral absorption will equal dermal absorption as a conservative approach.

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% (though likely to be lower).

Oral to inhalation extrapolation:Although the substance is not volatile, exposure via inhalation 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 is worst case 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.

 

EFSA, Flavouring Group Evaluation 87, (FGE.87)1, 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).

 

Gaunt Consuole, I.F., Agrelo, E., Lansdown, A.B.G., and Grasso, P, 1971, Short-term Toxicity of Isobornyl Acetate in Rats, Fd Cosmet. ToxicoL Vol. 9, pp. 355-366,

 

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

 

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.

 

Williams, R. T. (1959). Detoxication Mechanisms. The Metabolism and Detoxication of Drugs, Toxic Substances and Other Organic Compounds. 2nd ed. Chapman & Hall Ltd.

 

Wu, S., Blackburn, K., Amburgery, J., Jaworska, J., Federle, T., 2010, A framework for using structural, reactivity, metabolic and physico-chemical similarity to evaluate the suitability of analogs for SAR-based toxicological assessments, Regul. Toxicol. Pharmacol., 56, 67-81.