6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-propionaldehyde

Endpoint summary

Description of key information

No experimental toxico-kinetic data are available for assessing adsorption, distribution, metabolism and excretion of the substance apart from dermal absorption study. Pino Acetald is expected to be readily absorbed via the oral and inhalation routes and less by 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

Toxico-kinetic information on Pino Acetald

Introduction

Pino Acetald (generic CAS# 33885-51-7) is a mono-constituent substance. Pino Acetald has a molecular weight of 178.75 g/mol. It is a liquid with a melting point of <-20°C, a boiling point of 243.9°C, a water solubility of 61 mg/L, a vapour pressure of 4.4 Pa and a log Kow of 4.3.

Absorption

Oral route: In an oral (gavage) combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (OECD 422), systemic effects were observed in exposed animals. These effects indicate that Pino Acetald is absorbed via the oral route. The molecular weight below 500 g/mol (178.75 g/mol) indicates that Pino Acetald is easily absorbed. The log Kow is only just out of the favourable range for absorption (-1 to 4). All this information indicates that Pino Acetald is likely to be absorbed orally. The oral absorption is assumed to be >>50%.

Inhalation route: Absorption via the lungs is also indicated based on physico-chemical properties. Though the inhalation exposure route is thought minor, because of its low volatility (4.4 Pa), the octanol/water partition coefficient (Log Kow 4.3), 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 (VP) – 0.533 (Log) Kow – 0.00495 MW.

For Pino Acetald the B/A partition coefficient would result in:

Log P (BA) = 6.96 - 1.04 Log (4.4) - 0.533 x 4.3 - 0.00495 x 178.75 = 6.96 + 0.669 - 2.292 - 0.885 = 4.5

This means that the substance has a high 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 Pino Acetald being somewhat out of the applicability domain and the exact B/A may not be fully correct, it can be assumed that the substance will be absorbed via the inhalation route and will be close to 100%.

Dermal route: Based on the physico-chemical characteristics of the substance, being a liquid, its molecular weight (178.75), log Kow (4.3) and water solubility (61 mg/L), indicate that (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). These parameters of Pino Acetald are just outside optimal range and therefore the skin absorption is not expected to exceed oral absorption.

Distribution

The log Kow of 4.3 (lipophilic) would suggest that the substance would readily pass through the biological membranes. The high Log Kow of Pino Acetald (log Kow>4) suggests a potential for the substance to accumulate in the adipose tissue of individuals that are frequently exposed, however, upon cessation of exposure the concentration in the body would be expected to decline. The predicted metabolism of the substance would limit the accumulation in the body fat.

Metabolism

There are no experimental data on the metabolism of Pino Acetald. The aldehyde functionality at the head side of this substance can oxidise into an acid or reduced into an alcohol. The straight alkyl chain will be beta-oxidised resulting in the formation of 6,6-Dimethylbicyclo(3.1.1)hept-2-ene-2-carboxylic acid (CAS: 19250-17-0), also called Myrtenic acid. Furthermore, based on the modelling performed by Xenosite UGT v.1, the aldehyde is likely to be the sites for UGT-mediated glucuronidation.

The possible metabolic pathway is presented below

 

 

Figure 1: Theoretical metabolites of Pino Acetald.

Excretion

Pino Acetald is likely to be excreted via the urine as hydrophilic metabolites. As a glucuronide the substance is likely to be excreted via kidneys because the molecular weight is < 500 (https://www.sciencedirect.com/topics/medicine-and-dentistry/glucuronide), excretion via bile is therefore less likely as well as enterohepatic circulation.

Discussion

The substance is expected to be readily absorbed, orally and via inhalation (although the exposure is expected to be low based on the low vapour pressure), based on the human toxicological information and physico-chemical parameters. The substance is also expected to be absorbed dermally to a certain extent based on its 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 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 toxicity of 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 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.

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.

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.

Xenosite UGT v.1  2021; https://swami.wustl.edu/xenosite/p/ugt