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Description of key information

No experimental toxicokinetic data are available for assessing adsorption, distribution, metabolisation and excretion of the substance. Based on effects seen in the human health toxicity studies and physico-chemical parameters Cashmeran 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

Cashmeran toxico-kinetic assessment

Introduction:The test material Cashmeran (Cas no. 3704-61-9) is a bicycle-ring, a hexylring with an alpha beta-conjugated ketone bond, which is part of the 2nd5-pentyl ring. On this 5-pentyl ring methyl groups are attached to each C atom. The substance is a liquid with a molecular weight of 206 that does not preclude absorption. The test material is not likely to hydrolyse and has a low volatility (1 Pa).

Absorption:Oral: The results of the 90-day repeat oral dose (gavage) and oral (dietary) reproductive toxicity show that the substance is being absorbed by the gastro-intestinal tract following oral administration because effects on especially kidneys were seen at the mid dose: 50 mg/kg bw. The relatively low molecular weight and the moderate octanol/water partition coefficient (Log Kow 4.2 and water solubility (49 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 Cashmeran is likely to be absorbed orally and therefore the oral absorption is expected to be > 50%. 

Skin: The substance is a skin and eye irritant and is a weak skin sensitizer which indicates that absorption occurs. Also based on the physico-chemical characteristics of the substance, being a liquid, its molecular weight (206), log Kow (4.2) and water solubility (49), 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 1-4, respectively (ECHA guidance, 7.12, Table R.7.12-3). Cashmeran is just outside this range optimal range and therefore the skin absorption is not expected to exceed 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 (1 Pa), the octanol/water partition coefficient (4.2), 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 Cashmeran the B/A partition coefficient would result in:

Log P (BA) = 6.96 – 1 x 0 – 0.533 x 4.2 – 0.00495 x 206 = 6.96 – 1.066 -1 = 4.9.

This means that Cashmeran has a high 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 Cashmeran 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 metabolisation the substance as such would limitedly accumulate in the body fat which is confirmed with the low bioaccumulation experimental data (BCF is 157)

Metabolism:The metabolisation of Cashmeran is assessed using OECD Toolbox 3 liver metabolism simulator. One of the metabolites is presented below (or in the IUCLID 7.1 attached file in the Endpoint summary) as an example in which an OH group is attached to one of the methyl groups of the 5-pentyl ring. Such an OH group maybe attached to every methyl group. An acid group may also be attached to the middle C-atom in the pentyl ring. These metabolites are expected to be more water soluble, have a lower Log Kow values and will therefore be more easily excreted. Some metabolisation expectation of Cashmeran can also be based on the BCF value of 157. This BCF is much lower than predicted for the parent substance using the standard model for neutral organics and assuming no biotransformation, that is BCF 1607 (e.g. Arnot and Gobas calculation in EpiSuite (BCFBAFv3.01 or 741 when based on the Veith model, 1979: log BCF = 0.85 logKow - 0.70).

 

 Fig. 1    (Can only be seen in the attached file in IUCLID section 7.1, Endpoint summary) The theoretical metabolisation of Cashmeran can occur via hydroxylation of the methyl groups of the pentyl ring and/or an acid group can be formed at C4 as predicted by the OECD Toolbox 3.0 liver metabolism simulator.

Excretion:Effects seen in the kidney of the rats indicate that the primary route of excretion is through the urine. Any unabsorbed substance will be excreted via the faeces.

Discussion:The substance is expected to be readily absorbed, orally and via inhalation, based on the human toxicological information and physico-chemical parameters. Cashmeran also is expected to be absorbed dermally due to the observed skin and eye irritation and skin sensitization properties. The MW and the log Kow are higher than the favourable range for dermal absorption but significant absorption is likely.

The IGHRC (2006) document of the HSE and 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. Cashmeran is not expected to be detoxified in the gut because it is hydrolytically stable. Though some first pass effect via the liver may occur the toxicity via 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. 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% (though likely to be lower).

Oral to inhalation extrapolation:Though Cashmeran is not a volatile liquid some inhalation exposure will be calculated. Cashmeran 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 the oral absorption 50% has been 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:Cashmeran 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 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