3-(p-methoxyphenyl)-2-methylpropionaldehyde

Endpoint summary

Description of key information

No experimental toxico-kinetic data are available for assessing adsorption, distribution, metabolism and excretion of the substance. Based on an expert statement 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. There is no bioaccumulation risk identified.

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 Canthoxal

Introduction

Canthoxal (CAS#5462-06-6) is a methoxybenzene moiety substituted with a 2-methyl-3-propanal group on the para-position. The substance is a clear liquid with a molecular weight of 178.23 g/mol with a melting below -20 °C, a boiling point of 263 °C, a water solubility of 1085.7 mg/L, a vapour pressure 0.3 Pa, a Log Kow of 2.3 and viscosity of 9.43 mPa.s

Absorption

Oral route: In an acute oral toxicity study doses of 1.73, 2.47, 3.51, 4.2 and 5.0 g/kg bw resulted in mortality in 0/10, 0/10, 4/10, 4/10 and 9/10 animals, respectively. These toxicological responses indicate that the substance is, at least partially, absorbed via the oral route. In addition, in the available sub-acute repeated dose toxicity study with reproduction/developmental toxicity screening test (OECD 422) systemic effects were observed in the animals exposed continually via a mixture to the diet. In addition, based on the relatively low molecular weight (178.23 g/mol), the moderate log Kow (2.3) and relatively high water solubility (1085.7 mg/L) 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 the substance is likely to be absorbed orally and therefore the oral absorption is expected to be over 50%.

Dermal route: In the available study on dermal acute toxicity no animals died after exposure to 5000 mg/kg. However, systemic effects including diarrhoea or decreased faeces, alopecia, ptosis and slight weight loss indicate that the substance is at least partially absorbed via the dermal route. Based on the physico-chemical characteristics of the substance, being a liquid, its relatively low molecular weight (178.23 g/mol), moderate log Kow (2.3) and high water solubility (1085.7 mg/L), dermal absorption can be expected. 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 within the optimal range for log Kow and is above the optimal range for molecular weight. However, the molecular is far below 500 g/mol, above which dermal uptake would be unlikely. Therefore the skin absorption is not expected to exceed the oral absorption.

Inhalation route:Absorption via the lungs is also indicated based on the physico-chemical properties. Though the inhalation exposure is thought to be minor because of the low volatility of the substance (vapour pressure of 0.3 Pa), the Log Kow and water solubility indicate, as for oral uptake, 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 Canthoxal the B/A partition coefficient would result in:

Log (PBA) = 6.96 – (1.04 x -0.52) – (0.533 x 2.3) – (0.00495 x 178.23) = 5.4

 

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 the substance is out of the applicability domain and the exact B/A may not be fully correct, it is suggested that the substance will be readily absorbed via the inhalation route. 

 

Distribution

The relatively high water solubility and low molecular weight allow distribution via the water channels. In addition, the log Kow (2.3) suggests that the substance is able to pass through biological cell membranes and does not indicate bioaccumulation risk. The organ specific effects observed in the sub-acute repeated dose toxicity study with reproduction/developmental toxicity screening test (OECD 422) indicate that the substance is able to reach the spleen, liver and adrenal gland, which supports the expected wide distribution through the body.

 

Metabolism

No experimental data on the metabolism of the substance is available.Metabolic simulations (rat liver S9) usingOECD QSAR Toolbox (version 4.2) and O’Brien et al. (2005) predicts the following : a) Oxidation of the aldehyde into an acid is a key pathway; b) reduction of the aldehyde is less likely in an oxygen rich environment; c) De-methylation of the ether group; d) hydroxylation of the benzylic ring resulting in an extra OH on the ring.

 

Figure 1:The molecular structure of Canthoxal (upper figure) and theoretical metabolites using OECD Toolbox , O’Brien et al. (2005)

 

Excretion

The resulting metabolites are relatively hydrophilic and may be excreted as such. Also further phase II reactions may take place such as conjugation/glucuronidation on the introduced carboxylic acid moiety or sulfation of the benzylic alcohol groups which further enhances excretion of the substance.

 

Based on the relatively low molecular weight and the relatively high water solubility of the substance and predicted metabolites, excretion via theurinary tract is mainly anticipated.

 

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 experimental toxicological information and physico-chemical parameters of the substance.

Dermal absorption is also anticipated based on the physico-chemical properties and systemic effects observed in the dermal acute toxicity study. 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: The substance is absorbed orally and oxidative metabolism in the liver is anticipated. Since dermal absorption will be slower and the substance will also pass the liver during systemic circulation, it is assumed that the oral absorption will equal dermal absorption as a conservative approach.

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:Although the substance is not volatile, exposure via inhalation 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 is worst case 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., Shangari, N., 2005, Aldehyde sources, metabolism, molecular toxicity mechanisms and possible effects on human health, Critical Rev. Toxicol., 35,609-662