Dimethylcyclohex-3-ene-1-carbaldehyde

Endpoint summary

Description of key information

No experimental toxico-kinetic data are available for assessing adsorption, distribution, metabolism and excretion of the substance. Vertoliff 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 Vertoliff

Introduction

Vertoliff (generic CAS# 27939-60-2) is a multi-constituent consisting of two isomers which are di-methyl-cyclohexene structures with an aldehyde function. The methyl groups are either located on the ortho- and para-position (major constituent) or the ortho- and meta-position (minor constituent) relative to the aldehyde functional group. Vertoliff has a molecular weight of 138.21 g/mol, is a liquid, a water solubility of 381.8 mg/L, a vapour pressure of 66.1 Pa and a log Kow of 3.1.

The toxico-kinetic information is derived from a 28-day repeated dose oral (gavage) toxicity test (OECD TG 407) and a reproduction/ developmental toxicity screening test (OECD TG 421).

Absorption

Oral route: In the two performed repeated dose toxicity studies systemic effects were observed in exposed animals. The effects on liver and kidney show that Vertoliff is absorbed via the oral route. Based on the relatively low molecular weight (138.21 g/mol), the moderate log Kow (3.1) and moderate water solubility (381.8 mg/L) full absorption through the gut is expected. According to Martinez and Amidon (2002) the optimal log Kow for oral absorption falls within a range of 2-7. This information indicates that Vertoliff is likely to be absorbed orally and therefore the oral absorption is expected to be > 50%.

Dermal route: No experimental dermal systemic toxicity data is available for Vertoliff. Based on the physico-chemical characteristics of the substance, being a liquid, its relatively low molecular weight (138.21 g/mol), moderate log Kow (3.1) and moderate water solubility (381.8 mg/L), some dermal absorption is likely to occur. The optimal molecular weight 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 or within this range, respectively and therefore the skin absorption is not expected to exceed oral absorption.

Inhalation route: Absorption via the lungs is also indicated based on these physico-chemical properties. Though inhalation exposure is thought to be minor because of the fairly low volatility of the substance (vapour pressure of 66.1 Pa), the octanol/water partition coefficient (3.1) indicates 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 BA 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 Vertoliff the B/A partition coefficient would result in:

Log (PBA) = 6.96 – (1.04 x 1.82) – (0.533 x 3.1) – (0.00495 x 138.21) = 2.73

 

This means that Vertoliff 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 Vertoliff being just out of the applicability domain and the exact B/A may not be fully correct, it can be seen that the substance will be readily absorbed via the inhalation route and will be close to 100%.

This log PBA equation can also be considered a substitute for the Log Koa prediction, which is 5.1 (EpiSuite prediction). Both equations estimate the tendency of the substance being exhaled versus being bioaccumulated. The log PBA equation indicates that the substance is more easily exhaled and less bioaccumulated compared to the Koa. The PBA equation is a more relevant equation using mammals (rat and humans) for the accumulation of the substance in the body for air-breathing organisms. Therefore no accumulation in air-breathing organisms is anticipated based on the parent alone.

Distribution

The moderate water solubility and low molecular weight allow distribution via the water channels. In addition, the log Kow (3.1) suggests that the substance is able to pass through biological cell membranes and does not indicate bioaccumulation potential.

Metabolism

No experimental data on the metabolism of Vertoliff is available. Aldehydes are prone to oxidation, reduction (Phase 1 metabolism)  and hydroxylation (on the latter see ECHA guidance on Henry C (Table R.7.1-17). A fast conversion of the aldehyde moiety to a carboxylic acid function (oxidation) is expected. In addition, reduction can result in a hydroxy metabolite (Figure 2).

Both the carboxyl and hydroxy group in the resulting metabolites are targets for subsequent conjugation reactions (Phase 2 metabolism). For acids this can be glycine conjugates and for alcohols glucuronic conjugates (O’Brien et al., 2005: section a. aldehyde oxidation enzymes). Beside the aldehyde group also the double bond with the methyl group is prone to oxidation.

 

 

Figure 1: Anticipated major metabolic pathways illustrated for the main constituent of Vertoliff: during Phase 1 oxidation or reduction of the aldehyde can occur, after which in Phase 2 conjugation will smoothen the excretion to the kidneys.

 

Excretion

The metabolic conversion of Vertoliff results in carboxylic acid and/or alcohol metabolites. After conjugation these will excreted via the urinary route as is confirmed with effects in the kidneys in the OECD TG 421.

Discussion

The substance is expected to be readily absorbed, orally and via inhalation (although the exposure is expected to be limited based on its vapour pressure), based on the human toxicological information and physico-chemical parameters. The substance is also expected to be absorbed dermally based on the physico-chemical properties. The molecular weight and the log Kow are within or close to the favourable range for dermal absorption and significant absorption is therefore likely. 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: Vertoliff is absorbed orally and metabolism in the liver is anticipated (see metabolism paragraph). Since 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 also be considered 50% (though likely to be lower).

Oral to inhalation extrapolation: Though Vertoliff is limitedly volatile 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 partion coefficient using basis 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, http://ieh.cranfield.ac.uk/ighrc/cr12[1].pdf

 

O’Brien P.J., Siraki A.G. and Shangari N., 2005, Aldehyde sources, metabolism, molecular toxicity mechanisms and possible effects on human health. Crit. Rev in Tox 35: 609-662 2005.