α,α,6,6-tetramethylbicyclo[3.1.1]hept-2-ene-2-propionaldehyde

Endpoint summary

Description of key information

Pinyl Isobutyraldehyde is expected to be readily absorbed, orally and via inhalation but somewhat less via the dermal route, based on physico-chemical parameters. The substance also is expected to have some dermal absorption but this will be limited due to its log Kow of 5.4 and the dermal absorption will not exceed the oral route. As adverse effects were observed in the oral repeated dose study, route-to-route extrapolation will be performed to estimate the dermal and respiratory DNELs.

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

Toxicokinetic behaviour of Pinyl Isobutyraldehyde (CAS no. 33885-52-8)

Introduction

Pinyl Isobutyraldehyde (CAS no 33885-52-8)contains analpha pinene unit attached to the 2-position of isobutanal via its allylic 2-methyl group. The pinene unit is 2,6,6-trimethylbicyclo [3.1.1]hept-2-ene, a bicyclic monoterpene.The substance is a liquid with a molecular weight of 206.29 that does not preclude absorption. The substance has a low volatility of 3.4 Pa, a Log Kow 5.4, and its water solubility is 10.8 mg/L.

Absorption

Oral: The results of the repeated dose oral toxicity study (OECD TG 422) with Pinyl Isobutyraldehyde show that the substance is being absorbed by the gastro-intestinal tract following oral administration, since renal effects were observed in male rats.

Molecular weights below 500 are favourable for absorption by the GI tract. The relatively low molecular weight (206.29) and the moderate octanol/water partition coefficient (Log Kow 5.4) and water solubility (10.8 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. As no exact absorption data is available, the oral absorption of 50% will be used as a default value.

Dermal: Based on the substance having a molecular weight of 206.29 and the substance being a liquid, dermal absorption can occur. In view of its log Kow of 5.4 and water solubility this dermal absorption will not exceed the oral absorption because the values are outside the optimal range for dermal absorption ( < 100 molecular weight) and in the range of 1-4 log Kow; ECHA guidance, 7.12, Table R.7.12-3)). The skin absorption will not exceed oral absorption and 50% dermal absorption will be selected.

Respiratory: Absorption via the lungs is also indicated based on these physico-chemical properties, though exposure by inhalation of volatiles is thought minor as a result of the low vapour pressure. The octanol/water partition coefficient (5.4) indicates that inhalation absorption is possible. This is supported by the blood/air (BA) partition coefficient. 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 the substance the B/A partition coefficient would result in:

Log PBA = 6.96 – 1.04 Log (3.4) – 0.533 * 5.4 – 0.00495 * 206.29 = 2.51

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 being 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. As a conservative approach, an absorption percentage of 100% will be taken as a default value.

Metabolism

There are no mammalian data on the metabolism of the substance. During Phase I metabolism, aldehyde dehydrogenase oxidizes the aldehyde group to a carboxylic acid, which is predicted using OECD Toolbox (version 4.1) using simulated rate liver S9 metabolism and is presented in Fig. 1. Furthermore autoxidation was also predicted to occur for this substance, which would yield the acid form of the molecule. Based on information from the biodegradation and bioaccumulation study, the aldehyde group can also be reduced to an alcohol (see Fig. 1).

During phase 2 metabolism the metabolised molecules can be conjugated and as such transported to the kidneys.

 

Figure1According to the OECD Toolbox (4.1 and using simulated rat liver S9 metabolism) the aldehyde oxidised into an acid. In the biodegradation and bioaccumulation study the aldehyde can also be reduced into an alcohol.

 

Distribution

The moderate water solubility (10.8 mg/L) of the test substance may present some distribution in the body via the water channels. The log Kow (5.4) would suggest that the substance would pass through the biological cell membrane, and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. In view of the substance turning into an acid and excretion via the kidneys the log Kow is not a good parameter for bioaccumulation. A bioaccumulation study shows that the BCF is < 27 and based on this result Pinyl Isobutyraldehyde is also considered to not have a bioaccumulation potential in human. In this bioaccumulation study the alcohol derivative of Pinyl Isobutyraldehyde had a BCF of 32 and does not have a bioaccumulation potential either.

Excretion

In view of the anticipated higher water solubility of the metabolites the kidney is the main expected route of excretion. The repeated dose study in rats resulted in effects on the male kidneys. Tubular degeneration and tubular basophilia were observed. These renal effects are supportive of the kidneys as the main excretion route.

Discussion

Pinyl Isobutyraldehyde is expected to be readily absorbed, orally and via inhalation, based on the mammalian toxicological information and physico-chemical parameters. The substance also is expected to be absorbed dermally based on the physico-chemical properties. Though the molecular weight and the log Kow are slightly outside of the favourable range for dermal absorption, significant absorption is likely. As adverse effects were observed in the oral repeated dose study, route-to-route extrapolation will be performed to estimate the dermal and respiratory no effect levels.

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 absorption will be slower via the skin. Therefore it will be assumed that the oral absorption will be equal to 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%.

Oral to inhalation extrapolation: Though Pinyl Isobutyraldehyde is not a volatile substance, inhalation exposure is considered to be relevant. In the absence of bioavailability data it is most precautionary that 100% of the inhaled vapour becomes bioavailable. For the oral route, 50% absorption will be 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

Pinyl Isobutyraldehyde 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. 

 

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.