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Description of key information

No experimental toxico-kinetic data are available for assessing adsorption, distribution, metabolism and excretion of the substance. Based on effects seen in the human health toxicity studies and physico-chemical parameters Fleuramone is expected to be readily absorbed via the oral and inhalation route and dermal absorption is expected to be somewhat lower, finally resulting in absorption percentages: 50% oral absorption, 50% dermal absorption and 100% inhalation absorption which is in line with the default values in the ECHA guidance.

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 Fleuramone (CAS nr. 137-03-1)

Introduction

The test material Fleuramone (Cas no 137-03-1) is a 2-Heptylcyclopentanone. It is a liquid with a molecular weight of 182.31, water solubility (WS) of 20.63 mg/L and a log Kow of 3.8 that does not preclude absorption. The test material has no hydrolysable groups. The substance has a low vapour pressure of 2.38 Pa.

Absorption

Oral:The results of the repeat dose oral toxicity of Fleuramone show that the substance is being absorbed by the gastro-intestinal tract following oral administration, because non-adverse effects were seen on liver and kidney in the rat that indicated that the substance was processed. In addition, in mice mortality and clinical signs were seen at 1000 mg/kg bw in an in vivo micronucleus test (OECD TG 474). The relatively low molecular weight and the moderate octanol/water partition coefficient (Log Kow 3.8) 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 Fleuramoneis likely to be absorbed orally and therefore the oral absorption is expected to be much higher than 50%.

Skin: The results of the acute dermal rabbit test show that Fleuramone can be dermally absorbed. Based on the physico-chemical characteristics of the substance, being a liquid, its molecular weight (182.31), log Kow (3.8) and water solubility (20.63 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). Based on the physico-chemical properties of Fleuramone the dermal absorption is expected to be somewhat lower than the oral absorption and therefore expected to be < 50%.

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 (2.38 Pa), the octanol/water partition coefficient (3.8), 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 the substance the B/A partition coefficient would result in:

Log P (BA) = 6.96 – 1.04 (0.377) – 0.533 *3.8 – 0.00495*182.31 = 3.64

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 somewhat 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 and will be close to 100%.

Distribution

The moderate water solubility of the test substance would limit distribution in the body via the water channels. The log Kow would suggest that the substance would pass through the biological cell membrane. Due to the expected metabolism the substance as such would not accumulate in the body fat. 

Metabolism

There are no actual data on the metabolism of Fleuramone. The anticipated primary metabolism can be the reduction of the ketone group to the alcohol and hydroxylation of the ring. Considering P450 metabolism, the following steps are predicted by ToxTree (v 2.6.6); aliphatic hydroxylation of C5 of ring (C1 has the ketone group): C2 (on the opposite side of the alkyl chain), C3 or C4 of this 4 ring (see Fig. 1). The alkyl tail of this substance is expected to be firstly omega-oxidised to convert the tail into a carboxylic acid. Thereafter the alkyl chain is cut by beta-oxidation into 3x2C2, resulting in a pentyl –ring-acid and acetic acid.

The ketone group and the fatty backbone of Fleuramone likely fit into the alpha2-globuline pocket (Borghoff et al., 1991) and will be transported into the kidneys as can be derived from the increase of alpha2u-globulin in males in plasma and the hyaline droplets found in the kidneys.

The anticipated Phase 2 metabolism includes possible conjugation of the oxidized C-atom on the ring (Belsito et al, 2013) and/or the reduced ketone group.

  Phase 1 metabolisation of Fleuramone based empirical information and gathered in OECD Toolbox and Toxtree

 

Excretion

Because of the moderate water solubility and the relatively low molecular weight, Fleuramone and its acidic metabolites are expected to be excreted mainly via urine in view of the non-adverse kidney effects seen. The alpha2-globulin increase in males further supports this anticipated transport of the (metabolite) to the kidneys. Any unabsorbed substance will be excreted via the faeces.

Discussion

Fleuramone is expected to be readily absorbed, orally and via inhalation, based on the human toxicological information and physico-chemical parameters, resulting in minimally 50% oral absorption and 100% inhalation absorption. The MW and the log Kow are higher than the favourable range for dermal absorption and therefore for dermal absorption the maximum of 50% is used, which is in line with the ECHA derived default values.

Conclusion

Fleuramone is expected to be readily absorbed via the oral and inhalation route and somewhat less for the dermal route. Therefore the final conclusions are: 50% oral absorption, 50% dermal absorption and 100% inhalation absorption.

 

References

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

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.

Borghoff, S.J., Miller, A.B., Bowen, J.P. and Swenberg, J.A., 1991, Characteristics of chemical binding to alph2u-globulin in vitro-Evaluation structure-acitivity relationships, Toxicol. Appl.Pharmacol. , 107, 228-238.