[3R-(3α,3aβ,6α,7β,8aα)]-octahydro-6-methoxy-3,6,8,8-tetramethyl-1H-3a,7-methanoazulene

Endpoint summary

Description of key information

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

Cedramber (CAS no. 19870-74-7) and the assessment of its toxico-kinetic behaviour

Introduction

The test material Cedramber ((8alpha)-8-methoxycedrane) (Cas no.19870-74-7) is a liquid with a melting temperature of -20°C and boiling point of 280.8°C. The molecular weight of 236.4 g/mol does not preclude absorption. The test substance is not expected to hydrolyse based on the absence of hydrolysable groups. The substance has a low volatility of 0.5 Pa at 24°C. 

Absorption

Oral: The combined repeated dose and reproductive toxicity test (OECD TG 422) shows that Cedramber is being absorbed by the gastro-intestinal tract following oral administration, because non-adverse alpha-hydrocarbon nephropathy specific for the male rat was seen. In the dose range finder and in the repeated dose toxicity study liver and kidney weight increase were also seen further supporting oral absorption of the substance. The relatively low molecular weight and the moderate octanol/water partition coefficient (Log Kow 5.1) and water solubility (4.3 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 Cedramber is likely to be absorbed orally and therefore the oral absorption is expected to be moderate to high at least >=50%.

Skin: Cedramber is a skin sensitiser indicating that some uptake must have occurred although it may only have been small fractions of the applied dose. Based on the physico-chemical characteristics of the substance, being a viscous liquid, its molecular weight (236.4), log Kow (5.1) and water solubility (4.3 mg/L), indicate that (some) dermal absorption is likely to occur. The optimal MW and log Kow for dermal absorption is < 100 g/mol and in the range of 1-4, respectively (ECHA guidance, 7.12, Table R.7.12-3). Cedramber is outside optimal range and therefore the skin absorption is expected to be <=50%.

Lungs: Absorption via the lungs is also indicated based on these physico-chemical properties. Though the inhalation exposure route is thought to be minor, because of its low volatility (0.5 Pa), the octanol/water partition coefficient (5.1), indicates that inhalation absorption is possible. The blood/air (B/A) partition coefficient is another partition coefficient indicating lung absorption. Buist et al. 2012 have developed 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 Cedramber the B/A partition coefficient would result in:

Log P (BA) = 6.96 – 1.04 x -0.301 – 0.533 x 5.1 – 0.00495 x 236.4= 3.38

This means that Cedramber has a slight 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 Cedramber being somewhat out of the applicability domain and the exact B/A portioning may not be fully correct, it can be seen that the substance will be readily absorbed via the inhalation route.

Distribution

The low 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. Hydrolysis is not expected based on the absence of hydrolysible groups in the molecular structure of Cedramber. However metabolisation of the substance in the liver is likely and therefore bioaccumulation is expected to be limited.

Metabolism

There are no experimental data on the metabolisation of Cedramber. The substance is expected to be de-methylated at the ether bond and hydroxylated at the methyl-groups on the ring (alcohol, aldehyde or acid groups may be formed, according to OECD Toolbox (3.3.5.17, 2016) in the liver by cytochrome P450 enzymes.

 

Figure 1. Schematic view of the predicted metabolisation of Cedramber by OECD Toolbox (3.3.5.17). The upper structure presents the O-de-methylation and the lower structure presents one of the the methyl hydroxylation sites.

Excretion

The primary route of excretion is expected to be through the urine due to the non-adverse alpha-hydrocarbon nephropathy effects seen in the kidney in the repeated dose study. Any unabsorbed substance will be excreted via the faeces.

Bioaccumulation: Based on the anticipated metabolism the substance will present a low or moderate bioaccumulation potential.

Discussion

Cedramber 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 less absorbed dermally based on the physico-chemical propertiesu. The MW and the log Kow are higher than the favourable range for dermal absorption.

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 characterization.

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 absorption will be slower via the skin. 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% (though likely to be lower).

Oral to inhalation extrapolation: Though Cedramber is not a volatile substance the inhalation exposure will be considered. 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:Cedramber 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 basic physico-chemical properties, Regul. Toxicol. Pharmacol., 62, 23-28. 

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