Acetic acid, anhydride, reaction products with 1,5,10-trimethyl-1,5,9-cyclododecatriene

Endpoint summary

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 the substance 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

Short 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 the substance 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.

 

Toxico-kinetic behaviour of substance Trimofix O

Introduction

Trimofix O (Cas no 144020-22-4) is an organic UVCB substance called Reaction products of acetic anhydride and of 1,5,10-trimethyl 1,5,9-cyclodecatriene. One constituent has a cyclododecadiene ring with two methyl groups, an acetyl and a methylene group attached to it and has exocyclic double bond (structure no 1). The second one has a cyclododecatriene ring with three methyl groups and an acetyl group attached to the ring. The 3rd constituent is similar to the 2nd one but has a conjugated bond with the acetyl group (see Fig. 1). Trimofix O is clear liquid with a molecular weight of 246 that does not preclude absorption. The substance has a volatility of 0.06 Pa at 25°C, water solubility of 4.8 mg/L at 20°C and a Log Kow of 5.55 (at 25°C and 7 ≥ pH ≤ 7.3). According to Belsito et al. (2013) Trimofix O belongs to the diverse group unsaturated alkyl cyclic ketones in which either the alkyl or cyclic portion of the molecule has at least one double bond.

Absorption, oral: The results of the repeat dose oral toxicity of Trimofix O show that the substance is being absorbed by the gastro-intestinal tract following oral administration, because increased liver weights were seen. The relatively low molecular weight and the high octanol/water partition coefficient (Log Kow 5.5) and water solubility (4.8 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 the substance is likely to be absorbed orally and therefore the oral absorption is expected to be > 50%.

Absorption, skin: Based on the physico-chemical characteristics of the substance, being a liquid, its molecular weight (246), log Kow (5.55) and water solubility (4.8 mg/L), indicate that (some) dermal absorption is likely to occur. The molecular weight lies outside the optimum of < 100 as well as its log Kow (ECHA guidance, 7.12, Table R.7.12-3). (log Kow 1-4), The substance is considered to be not irritating to skin and is classified as a skin sensitiser, which indicates that (some) dermal absorption occurs.

Absorption, lungs: Absorption via the lungs is also indicated based on physico-chemical properties. Though the inhalation exposure route is thought minor, because its low volatility (0.06 Pa), the octanol/water partition coefficient (5.55), 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 Trimofix the B/A partition coefficient would result in:

Log P (BA) = 6.96 – 1.04 (-1.22) – 0.533 x 5.55 – 0.00495 x 246 = 4.04

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 suggest that the substance would pass through the biological cell membrane. The absence of bioaccumulation in fish indicates that the substance will not bioaccumulate and is metabolised significantly. 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 the substance. The OECD Toolbox (4.4.1) predicts over 50 metabolites. According to Belsito et al. 2013 structurally complex molecules with multiple functionalities, such as the ACK fragrance ingredients, rarely undergo a single primary metabolism pathway. During phase 1 the predominant primary metabolic pathway is the reduction of the ketone by alcohol dehydrogenases and the hydroxylation of the double bonds.). During Phase II the alcohols will be conjugated with glucuronic acid and excreted (Belsito, 2013).

Excretion: The metabolic profile and molecular weight indicate that a 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. The substance also is expected to be absorbed dermally based on the physic-chemical 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. 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.

Oral to inhalation extrapolation

Though the substance is not a volatile liquid the inhalation exposure will be considered. The substance is not 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

The substance is expected to be readily absorbed via the oral, dermal and inhalation 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

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.

IGHRC, 2006, Guidelines on route to route extrapolation of toxicity data when assessing health risks of chemicals, http://www.iehconsulting.co.uk/IEH_Consulting/IEHCPubs/IGHRC/cr12.pdf 

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.