Octahydro-2H-1-benzopyran-2-one

Endpoint summary

Description of key information

No experimental toxico-kinetic data are available for assessing adsorption, distribution, metabolism and excretion of the substance. Based on effects seen in the human health toxicity studies and physico-chemical parameters Bicyclononalactone is expected to be readily absorbed via the oral, dermal and inhalation route. Using the conservative approach, the in absorption percentages: 50% oral absorption, 50% dermal absorption and 100% inhalation absorption, will be used for deriving DNELs.

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

The toxico-kinetic behaviour of Bicyclononalactone (CAS nr. 4430-31-3)

Introduction

The test material Bicyclononalactone (Cas no 4430-31-3) is a lactone in a 6-ring, which is attached to a cyclohexyl-ring. It is a liquid with a molecular weight of 154.21, water solubility (WS) of 39953 mg/L and a log Kow of 1.4, indicative for good absorption. The substance has a low vapour pressure of 0.21 Pa.

Absorption

Oral:The results of the acute and repeated dose oral toxicity of Bicyclononalactone show that the substance is being absorbed by the gastro-intestinal tract following oral administration, because adverse effects were seen. An LD50 of 3900 was derived. In the repeated dose toxicity effects on liver characterized by peribiliary inflammation/necrosis were seen. The relatively low molecular weight and the moderate octanol/water partition coefficient (Log Kow 1.4) favour absorption through the gut. This shows that Bicyclononalactoneis likely to be absorbed orally and therefore the oral absorption is expected to be much > 50%.

Skin: The results of the dermal acute toxicity show that the substance is absorbed to a similar extent: LD50 is 3500 mg/kg bw. Based on the physico-chemical characteristics of the substance, being a liquid, its molecular weight (154.21), log Kow (1.4) and water solubility (39953 mg/L), indicate that dermal absorption is likely to occur. The optimal MW and log Kow for dermal absorption is < 100 and in the range of 1 to 4, respectively (ECHA guidance, 7.12, Table R.7.12-3). Based on the similar LD50s the dermal absorption is also considered to be > 50%, despite the molecular weight being slightly outside the favourable range.

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 (0.21 Pa), the octanol/water partition coefficient (1.4), 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 BA model for humans using the most important and readily available parameters:

Log PBA = 6.96 – 1.04 Log (0.21VP) – 0.533 (Log) Kow – 0.00495 MW.

Log PBA = 6.96 – 0.7 – 0.83 -0.76 = 4.67. Though the regression line is only valid for substances with a vapour pressure >100 Pa it can be seen that the substance will go from air into blood.

Distribution

The good water solubility of the test substance is indicative for 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 low log Kow and the expected metabolism of the substance, it is not expected to accumulate in the body fat.

Metabolism

There are no actual data on the metabolism of Bicyclononalactone. The anticipated metabolism is presented in Fig. 1. The ester will be cleaved by carboxylesterases into a Cyclohexane propionic -acid with an alcohol on the 2^ndposition (Toxicological handbooks, EFSA, 2012). After beta-oxidation in the mitochondrion a cyclohexanoic acid and acetic acid/ethanol are the metabolites formed (EFSA 2012).

Fig. 1 Anticipated metabolic pathway of Bicyclononalactone by carboxylesterases and beta-oxidation.

 

In addition, to this considering P450 metabolism, aliphatic hydroxylation is predicted by ToxTree (v 2.6.6), as indicated below. On the secondary C-atoms OH-groups may appear.

Excretion

Because of the water solubility and the low molecular weight, Bicyclononalactone and its metabolites are expected to be excreted mainly via urine, and likely also via the bile, because some effects were seen in the bile channel. Any unabsorbed substance will be excreted via the faeces.

Discussion

The substance 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.

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 dermal extrapolation: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 metabolized in the gut by micro-organisms because it is a lactone but also in the lung and in the skin metabolisation is anticipated. The toxicity of the dermal route will not be underestimated because absorption will be somewhat 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%.

Oral to inhalation extrapolation: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

 

EFSA Panel, 2012, Scientific Opinion on the safety and efficacy of primary aliphatic saturated or unsaturated alcohols/aldehydes/acids/acetals/esters with a second primary, secondary or tertiary oxygenated functional group including aliphatic lactones (chemical group 9) when used as flavourings for all animal species. EFSA Journal 10(10): 2928

 

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.