3,7-dimethylocta-2,6-dienyl acetate

Endpoint summary

Description of key information

Based on physico-chemical parameters, Neryl acetate multi is expected to be readily absorbed via the oral and inhalation route and somewhat (s)lower via the dermal route. For risk assessment purposes the final absorption percentages derived are: 50, 50 and 100% absorption via the oral, dermal and inhalation absorption, respectively.

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

The toxico-kinetic behaviour of Neryl acetate multi

 

Introduction

Neryl acetate multi is a multi-constituent of Neryl acetate and Geranyl acetate, which are the Z and E-isomers (cis and trans) of each other; its generic CAS No. is 16409-44-2. This substance is a liquid with a molecular weight of 196 for all constituents, water solubility (WS) of 28.8 mg/L and a log Kow of 4.6 that does not preclude absorption. The test material has an hydrolysable ester group. The substance has a vapour pressure of 2.12 Pa.

Absorption

Oral: The relatively low molecular weight (196 for its constituents) and the moderate octanol/water partition coefficient (Log Kow 4.6) 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 Neryl acetate multi is likely to be absorbed orally and therefore the oral absorption is expected to be> > 50%.

Skin: Based on the physico-chemical characteristics of the substance, being a liquid, its molecular weight (196), log Kow (4.6) and water solubility (28.8 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 to +4, respectively (ECHA guidance, 7.12, Table R.7.12-3). In view of these characteristics being out of the optimum range it is anticipated that dermal absorption will not exceed oral absorption.

Lungs: Absorption via the lungs is also indicated based on these physico-chemical properties. Though the inhalation exposure route is thought minor, because of its low volatility (2.12 Pa), the octanol/water partition coefficient (4.6), indicates that inhalation absorption is possible.

 

The blood/air (B/A) partition coefficient (log (PBA)) is another coefficient indicating lung absorption. Buist et al. (2012) have developed a 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 Neryl acetate multi the B/A partition coefficient would result in:

Log (PBA) = 6.96 – (1.04 x 0.326) – (0.533 x 4.6) – (0.00495 x 198) = 3.2

 

This means that the substance has a tendency to go from air into the blood. It should, however, be noted that this regression is only valid for substances which have a vapour pressure > 100 Pa. Despite the fact that substance is out of the applicability domain and the exact B/A may consequently not be fully correct, it is suggested that the substance will be readily absorbed via the inhalation route and will be close to 100%.

Distribution:

The moderate to low water solubility (28.8 mg/l) of the substance indicates that some distribution in the body via the water channels may occur. The log Kow suggests that the substance passes through the biological cell membrane. Due to the expected metabolism the substance as such does not accumulate significantly in the body fat.

Metabolism

There are actual experimental metabolism data on one of Neryl acetate multi constituents. For Geranyl acetate (Extra, solely trans isomer), the stability and degradation is studied in vitro in plasma, liver S9 fraction of rats, gastric juice simulant and intestinal-fluid simulant including pancreas lipase (Fabian, 2013, see IUCLID record 7.1.1). This Geranyl acetate was hydrolysed within 0.5 hour almost completely in rat plasma, liver S9 fraction of rats and intestinal fluid simulant, as demonstrated by the decrease of Geranyl acetate extra and formation of the hydrolysis product Geraniol. In gastric fluid simulant the degradation was about 50% after 2 hours (see section IUCLID 7.1.1). The Neryl acetate constituent will be hydrolysed at a comparable rate into the respective alcohol and acetic acid because Neryl acetate and Geranyl acetate are Z- and E-isomers of each other.

Fig. 1 The first metabolic step for Neryl and Geranyl acetate the cleavage of the ester, resulting in Nerol or Geraniol and acetic acid.

Excretion

Neryl acetate multi will be excreted via its alcohol metabolites and their pathways. Any unabsorbed substance will be excreted via the faeces.

Discussion

Neryl acetate multi is expected to be readily absorbed, orally and via inhalation, based on the human physico-chemical parameters. The substance also is expected to be absorbed dermally based on the physico-chemical properties. The MW and log Kow values exceed the favourable range for dermal absorption and therefore dermal absorption unlikely exceeds oral absorption.

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. Therefore for the oral route and dermal route 50% oral absorption will be used.

Oral to inhalation extrapolation

Though Neryl acetate multi is not a volatile liquid, inhalation exposure will be considered. The substance is not corrosive for skin and eye and therefore the systemic effect will prevail over the effects at the site of contact. For inhalation absorption 100% will be used for route to route extrapolation.

Conclusion

Neryl acetate multi is expected to be readily absorbed. The IGHRC guidelines will be followed and for the oral and dermal absorption 50% and for inhalation 100% absorption will be used.

 

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