Reaction mass of 3-O-acetyl-1,5-anhydro-4-butyl-2,4-dideoxy-2-methyl-D-xylitol and (2R,3S)-2-methyloctane-1,3-diyl diacetate

Endpoint summary

Description of key information

Jessemal 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

The toxico-kinetic behaviour of Jessemal (CAS no 38285-49-3 major and67634-09-7 minor)

Toxico-kinetic behaviour of Jessemal

Introduction

The substance consists mainly of two sub-groups of constituents, 50% Tetrahydropyran acetate -like constituents (e.g. 38385-49-3) and 40% Branched alkyl diacetates-type(which have also an acetate group at the site of the O in the ring e.g.67634-09-7).Jessemal is a liquid with a molecular weight of 214 or 244, a water solubility (WS) of 714.1 mg/L and a selected log Kow of 3.5 all indicating absorption. The test material has acetate(s) as hydrolysable group(s). The substance has a low volatility of 0.38 Pa.

Absorption

Oral:The results of the repeat dose oral toxicity of Jessemal show that the substance is being absorbed by the gastro-intestinal tract following oral administration, because some slight hyperplasia in the bile ducts was seen. The relatively low molecular weight and the moderate octanol/water partition coefficient (Log Kow 3.5) favours 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 Jessemal 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 (214 or 244), log Kow (3.5) and water solubility (714.1 mg/L), indicate that 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) and therefore the Jessemal physico-chemical properties are outside this range and therefore the skin absorption is not expected to 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 (0.38 Pa), the octanol/water partition coefficient (3.5), 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 Jessemal the B/A partition coefficient would result in: Log (PBA) = 6.96 – 1.04 (Log 0.43=-0.37) – (0.533 x 3.5=1.87) – (0.00495 x 214=0.106) = 5.36

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 water solubility of the test substance indicates that some distribution in the body via the water channels can occur. The log Kow would suggest that the substance would pass through the biological cell membrane. Due to the expected acetate metabolisation the substance as such would not accumulate significantly in the body fat.

Metabolism

The first metabolic step is the cleavage of the acetic ester bond as depicted in Fig. 1. Acetic ester cleavage is a normal process in the body as is presented in Toxicological handbooks, Belsitio et al. (2008) and Wu et al. (2010). The alkyl chain can possibly be used for beta-oxidation also generating acetic acid. This acidity may have caused the minimal to slight hyperplasia in the bile ducts.

Fig. 1     First metabolic pathway of Jessemal’s Tetrahydropyran acetate type and Branched alkyl diacetate-type, which results in the respective secondary alcohols and acetic acid.

 

Excretion

Because of the moderate water solubility and the relatively low molecular weight, Jessemal and its metabolites are expected to be excreted mainly via urine, and possibly also via the bile. Any unabsorbed substance will be excreted via the faeces.

Discussion

Jessemal is expected to be readily absorbed, orally and via inhalation, based on the effects seen in the repeated dose toxicity study and physico-chemical parameters. The substance also is expected to be absorbed dermally based on its physico-chemical properties. The MW is higher than the cut off value but the log Kow is in the favourable range for dermal absorption and therefore significant dermal absorption is likely.

The IGHRC (2006) document of the HSE - also mentioned in the ECHA guidance Chapter 8 - will be followed to derive the final absorption values for the risk characterisation.

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. For risk assessment purposes the oral absorption will be considered 50% (though likely to be higher) and the dermal absorption will be considered also 50% (unlikely exceeding the oral route).

Oral to inhalation extrapolation: Though Jessemal is not a volatile liquid inhalation exposure will be considered. Jessemal 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 inhalation absorption 100% will be used for route to route extrapolation, because this will be precautionary for the inhalation route.

Conclusion

Jessemal is expected to be readily absorbed via the oral and inhalation route and somewhat (s)lower via the dermal route based on toxicity seen in the repeated dose toxicity study 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

Belsito, D., Bickers, D., Bruze, M., Calow, P., Dagli, M.L., Fryer, A.D., Greim, H., Miyachi, Y., Saurat, J.H., Sipes, I.G., 2013, A toxicological and dermatological assessment of alkyl cyclic ketones when used as fragrance ingredients, Food and Chemical Toxicology 62, S1-S44.

 

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

 

Wu, S., Blackburn, K., Amburgery, J., Jaworska, J., Federle, T., 2010, A framework for using structural, reactivity, metabolic and physico-chemical similarity to evaluate the suitability of analogs for SAR-based toxicological assessments, Regul. Toxicol. Pharmacol., 56, 67-81.