Reaction mass of 1-(3,3-dimethylcyclohex-1-en-1-yl)pent-4-en-1-one and 1-(5,5-dimethylcyclohex-1-en-1-yl)pent-4-en-1-one

Endpoint summary

Description of key information

No experimental toxico-kinetic 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 Galbascone 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:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Introduction

The test material Galbascone (Cas no 56973-85-4) is a pent-4-en-1-one attached to the double bond of a 5,5-dimethyl-1-cyclohexenyl resulting in an alpha,beta unsaturated ketone. It is a liquid with a molecular weight of 192, water solubility (WS) of 88.9 mg/L and a log Kow of 4.5 that does not preclude absorption. The test material has no hydrolysable groups. The substance has a low volatility of 1.14 Pa.

Absorption

Oral:The results of the repeat dose oral toxicity of Galbascone show that the substance is being absorbed by the gastro-intestinal tract following oral administration, because effects were seen on body weight, liver, kidney and urinary bladder. The relatively low molecular weight and the moderate octanol/water partition coefficient (Log Kow 4.5) and water solubility (88.9 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 Galbasconeis 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 (192), log Kow (4.5) and water solubility (88.9 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). According to the ECHA guidance, a default value of 100% skin absorption is generally used unless molecular mass is above 500 and log P is outside the range -1 to +4, in which case a value of 10% skin absorption is chosen. Based on the physico-chemical properties of Galbascone (the log Kow > 4), the skin absorption is 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 (1.14 Pa), the octanol/water partition coefficient (4.5), indicates that inhalation absorption is possible.

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 not accumulate in the body fat.

Metabolism

There are no actual data on the metabolisation of Galbascone. Possible primary and secondary steps of metabolism are (Belsito et al, 2013):

-primary metabolism

• Reduction of the ketone group to a secondary alcohol
• Hydroxylation/oxygenation of the cyclohexene ring
• Oxidation of the angular methyl groups -
• Reduction of the double bond in the exocyclic alkenyl side chain or cyclic portion of the molecule to form dihydro derivatives
• Epoxidation of isolated (non-conjugated) double bounds of exocyclic alkyl chains and subsequent reaction with epoxide hydrolases or glutathione transferase

-secondary metabolism

• Conjugation of the hydroxylated metabolites
• Conjugation of epoxide metabolites.

Excretion

Because of the moderate water solubility and the relatively low molecular weight, Galbascone 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

Galbascone is expected to be readily absorbed, orally and via inhalation, based on the human toxicological information and physico-chemical parameters. The substance also is expected to be absorbed dermally based on the physico-chemical properties. The MW is below the limit value and the log Kow is higher than the favourable range for dermal absorption and therefore significant 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. Some first pass effect via the liver may also occur. 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% (though likely to be lower).

Oral to inhalation extrapolation

Though Galbascone is not a volatile liquid inhalation exposure will be considered. Galbascone 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

Galbascone 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.