Reaction mass of 1-(2,6,6-trimethylcyclohex-2-en-1-yl)hepta-1,6-dien-3-one and 1-(2,6,6-trimethylcyclohex-1-en-1-yl)hepta-1,6-dien-3-one

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 mainly 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:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Toxico-kinetic information on Hexalon

Introduction

The test material Hexalon (CAS #79-78-7) is a trimethyl-cyclohexene with an alkyl chain to it. The alkyl chain has an alpha-beta conjugated ketone bond and has an allyl bond at the end of the chain (see section 1 on identity). Hexalon is a liquid with a melting point of < -20 °C and a boiling point of 301.1 °C under atmospheric pressure. The substance has a molecular weight of 232 g/mol and a water solubility of 79.0 mg/L at 24°C. Hexalon has a Log Kow of 5.5 at 24°C and a vapour pressure of 0.08 Pa at 24°C. The substance contains no hydrolysable groups and no hydrolysis is anticipated. Experimental information on hydrolysis is not available.

Absorption

Oral route: There is an acute oral study in mice showing an LD50 of 9500 mg/kg bw indicating some oral absorption. Oral absorption is also anticipated based on the effects seen in a repeated dose toxicity test with the analogue Galbascone (alpha-hydrocarbon nephropathy and bladder effects). The relatively low molecular weight (232 g/mol) and the moderate octanol/water partition coefficient (Log Kow 5.5) and water solubility (79.0 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 Hexalon is likely to be absorbed orally and therefore the oral absorption is expected to be > 50%.

Dermal route: Based on the physico-chemical characteristics of the substance, being a liquid, its molecular weight (232), log Kow (5.5) and water solubility (79.0 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). Hexalon is outside optimal range and therefore the skin absorption is expected to be <=50%.

Inhalation route: 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 (0.08 Pa), the octanol/water partition coefficient (5.5), 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 Hexalon the B/A partition coefficient would result in:

Log P (BA) = 6.96 – 1.04 x -1.097 – 0.533 x 5.5 – 0.00495 x 232 = 4.021

 

This means that Hexalon 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 Hexalon being out of the applicability domain and the exact B/A partitioning may not be fully correct, it can be seen that the substance will be absorbed via the inhalation route and anticipated to be > 50%.

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 and the in vitro BCF study the substance would not accumulate in the body fat.

Metabolism: No studies regarding the metabolism of Hexalon are available however supporting literature is available to identify possible metabolic pathways of Hexalon. According to JECFA (1999) Hexalon can be predicted to be metabolised to innocuous products, which was confirmed by EFSA in 2014. Belsito et al. (2007) states that “the available evidence indicates that the ionones and rose ketones are extensively metabolized in vivo by pathways involving: oxidation, reduction and conjugation. These metabolites do not raise issues of toxicological concern”.

Potential metabolic products are presented in Fig. 1. Metabolites derived with the OECD Toolbox are presented in Fig. 2

 

Fig. 1 Hexalon and the potential sites of attack for Phase 1 metabolism

 

Fig. 2   Theoretical metabolites from the Rat liver S9 metabolism simulator (OECD Toolbox , 3.3.5.17): epoxidation (1) or hydroxylation/oxidation (3 and 4) of the double bond and reduction of the ketone group (2)

Phase 1 metabolites can be formed based on: Reduction of the ketone group to a secondary alcohol;

Hydroxylation/oxygenation of the cyclohexene ring; Oxidation of the angular methyl groups; reduction of the double bonds in the exocyclic alkenyl side chain or cyclic portion of the molecule to form dihydro derivatives; Epoxidation of isolated (non-conjugated) double bounds of exocyclic chain and subsequent reaction with epoxide hydrolases or glutathione transferase. Phase II metabolism can include conjugation of the hydroxylated metabolites and/or epoxide metabolites.

Excretion:  The urine is one of the excretion pathways of Hexalon’s metabolites based on the anticipated effects in the kidney and bladder. These are anticipated because these effects were seen in the in the repeated dose study with the analogue Galbascone. Any unabsorbed substance will be excreted via the faeces.

Discussion

Hexalon is expected to be readily absorbed, orally, via inhalation and via the skin, based on physico-chemical parameters. 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 substance is absorbed orally and is likely metabolized in the liver (see metabolism paragraph). The absorption will be slower via the skin and the substance will also pass the liver. It will be assumed that the oral absorption will equal dermal absorption. The toxicity of the dermal route will therefore not be underestimated. 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 Hexalon 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 inhalation absorption 100% will be used for route to route extrapolation, because this will be precautionary for the inhalation route.

 

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. 

 

D. Belsito, D. Bickers, M. Bruze, P. Calow, H. Greim, J.M. Hanifin , A.E. Rogers, J.H. Saurat, I.G. Sipes, H. Tagami., 2007. toxicologic and dermatologic assessment of ionones when used as fragrance ingredientsFood and Chemical Toxicology 45 (2007) S130–S167.

 

European Food Safety Authority (EFSA); Scientific Opinion on Flavouring Group Evaluation 210, Revision 1 (FGE.210Rev1): Consideration of genotoxic potential for α,β-unsaturated alicyclic ketones and precursors from chemical subgroup 2.4 of FGE.19. EFSA Journal 2014;12(2):3587

 

IGHRC, 2006, Guidelines on route to route extrapolation of toxicity data when assessing health risks of chemicals

 

JECFA, 1999. Safety Evaluation of Certain Food Additives. WHO Food Additive Series 42: Ionones and structurally Related Substances. Prepared by the Fifty-first Meeting of the Joint FAO/WHO Expert Committee on Food Additives, pp. 335–352.

 

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.