1-Propanol, 2-methyl-3-[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]-

Endpoint summary

Description of key information

No experimental toxico-kinetic data are available for Bornafix. The toxico-kinetic behaviour is predicted from its physico-chemical properties, theoretical metabolic assessment and the effects found during the repeated dose toxicity testing. Bornafix is expected to be readily absorbed via the oral and inhalation route and somewhat lower via the dermal route. Using the precautionary principles the final absorption percentages are: 50% oral, 50% dermal 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

Bornafix toxico-kinetic assessment (EC no 416-210-4, Cas no 128119-70-0)

Introduction: The test material has a hexyl-ring with a 1-carbon bow and on this carbon two methyl groups are attached. In addition there is an alkyl chain including an ether bond, a methyl group and a primary alcohol at the end (Fig. 1). The substance is a viscous liquid as presented in several test reports. Its melting point is -25°C and it has a molecular weight of 226 that does not preclude absorption. The test material is not likely to hydrolyse under physiological conditions because it has no hydrolysable groups in its chemical structure and has a low volatility (0.67 Pa).

Absorption: Oral: The results of the 28-day repeat oral dose (gavage) and oral (dietary) reproscreen toxicity show that the substance is being absorbed by the gastro-intestinal tract following oral administration because adverse effects on liver weight are seen at the high dose of 1000 mg/kg bw in the repeated dose toxicity test in male and female rats and in males treated with 252 mg/kg bw in the reproscreen study. Furthermore, body weight gain and food consumption was affected in the females in the reproscreen study exposed to 264-395 mg/kg bw. The relatively low molecular weight and the moderate octanol/water partition coefficient (Log Kow 3.86) and water solubility (57.8 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 the substance is likely to be absorbed orally and therefore the oral absorption is expected to be > 50%.

Skin: The substance is not a skin irritant or a skin sensitizer but based on the physico-chemical characteristics of the substance, being a liquid, its molecular weight (226), log Kow (3.86) and water solubility (57.8 mg/l), (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). The substance is just outside this range 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. Though the inhalation exposure route is thought minor, because of its low volatility (0.67 Pa) and its viscosity, the log Kow (3.86) and water solubility 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 B/A model for humans using the most important and readily available parameters:

Log P (BA) = 6.96 – 1.04 Log (VP) – 0.533 (Log) Kow – 0.00495 MW.

For Bornafix the B/A partition coefficient would result in:

Log P (BA) = 6.96 +0.18 - (1.04 x - 0.174) – 2.06 (0.533 x 3.86) – 1.12 (0.00495 x 226) = 3.96

This means that the substance 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 Bornafix 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 could 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 the expected metabolisation the substance as such would limitedly accumulate in the body fat.

Metabolism: Theoretically Bornafix is expected to metabolise as is presented in Fig. 1. EFSA paper (2008) presents information on the metabolization of Myrtanol and related substances further supporting the metabolization into the carboxylic acid of the primary alcohol.

 

Fig. 1     The metabolisation of Bornafix is expected to result in additional alcohol attached to the methyl groups (via hydroxylation) and/or an acid group can be formed at the primary alcohol as predicted by the OECD Toolbox 3.0 liver metabolism simulator. The primary alcohol can also be glucuronidated during Phase II metabolism.

 

The Phase I metabolization is predicted with the OECD Toolbox 4.5 and the Phase 2 with Xenosite (Annex 1). These metabolites are expected to be more water soluble, have lower Log Kow values and will therefore be more easily excreted.

Excretion: Effects seen in the kidney of the rats indicate that one route of excretion is through the urine. 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 is expected to be absorbed dermally due to the observed skin sensitization 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 available 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 not expected to be detoxified in the gut because it is hydrolytically stable. Though some first pass effect via the liver may occur the toxicity via the dermal route will not be underestimated because absorption will be 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% (though likely to be lower).

Oral to inhalation extrapolation: Though the substance is not a volatile liquid some inhalation exposure will be calculated. The substance is not corrosive to skin and eye and the systemic effects 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: Bornafix 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, 2008, Primary saturated or unsaturated alicyclic alcohol, aldehyde, and esters from chemical group 7, Flavouring Groug Evaluation 12, Revision 1 (FGE.12Rev1), Scientific Opinion of the panel on food additives, flavouring, processing aids and materials in contact with food (AFC): https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2008.791, site visited April, 2022.

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

Xenosite: Glucuronidation predictor; https://swami.wustl.edu/xenosite/, site visited April, 2022

 

 

Annex 1

The first figure is the probability scale that the glucuronidation is occurring. The red colouring on the Bornafix moleculs shows that it is very likely that the substance will be glucuronidated.

 

 

• Citations:


• Na Le Dang, Tyler B. Hughes, Varun Krishnamurthy, S. Joshua Swamidass, A simple model predicts UGT-mediated metabolism, Bioinformatics, Volume 32, Issue 20, 15 October 2016, Pages 3183–3189, https://doi.org/10.1093/bioinformatics/btw350