Reaction Mass of (1R)-1-[(1S)-3,3-dimethylcyclohexyl]ethyl formate and (1R,2S)-2,6,6-trimethylcycloheptyl formate

Endpoint summary

Description of key information

No experimental toxico-kinetic data are available for assessing absorption, distribution, metabolisation and excretion of the substance. Based on effects seen in the human health toxicity studies and physico-chemical parameters CP Formate 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

Introduction

The main constituent (65-85%) of the test material CP Formate (Cas no 25225-08-5) consists of a cyclohexyl ring with an ethyl group at which an ester group is attached on the 2^ndC of the ethyl-group and two methyl groups at the 3^rdC of the cyclohexyl ring. The minor constituent (8-18%) consist of a cycloheptyl ring with an ester group attached on the 1^stC of the cycloheptyl ring, one methyl group on the 2^ndC and two methyl groups on the 6^thC of the cycloheptyl ring. The test material is a clear colourless liquid with a molecular weight of 184.3 g/mol that does not preclude absorption. The hydrolysis half-life of the test material is 22 days at pH7. The substance has a low volatility (vapour pressure of 13.4 Pa).

Absorption

Oral: The results of the repeat dose oral toxicity study on the analogue Applelide show that the substance is being absorbed by the gastro-intestinal tract following oral administration, because non-adverse effects including centrilobular hepatocyte enlargement in male and female rats and male rat specific alpha-hydrocarbon nephropathy were seen. The relatively low molecular weight and the moderate octanol/water partition coefficient (Log Kow 3.8) and water solubility (26.1 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 CP Formate 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 (184.3 g/Mol), log Kow (3.8) and water solubility (26.1), indicate that (some) dermal absorption is likely to occur. The optimal MW and log Kow for dermal absorption is < 100 g/Mol and in the range of 1-4, respectively (ECHA guidance, 7.12, Table R.7.12-3). The molecular weight of CP Formate is just outside 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 to be minor, because of its low volatility (13.4 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 CP Formate the B/A partition coefficient would result in:

Log P (BA) = 6.96 – (1.04 x 1.13) – (0.533 x 3.8) – (0.00495 x 184.3) = 2.85

This means that CP Formate has some 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 CP Formate being somewhat out of the applicability domain and the exact B/A may not be fully correct, it can be seen that when the substance is inhaled it will be absorbed partly.

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 hydrolysis and metabolisation the substance as such would not accumulate in the body fat.

Metabolism

There are no actual data on the metabolisation of CP Formate. However, the formate ester will be fully metabolised in the gut and in the liver (and in other organs, including skin and lung) into a cyclic-alcohol (1-(3,3-dimethylcyclohexyl)ethanol, CAS: 25225-09-6) and formic acid (e.g. Toxicological handbooks, Yamada et al., 2013, WHO, 2000, Belsito et al., 2008). The cyclohexyl-alcohol is expected to be more water soluble (estimated to be circa 1300 mg/l (EpiSuite) and even more so when conjugated with glucuronic acid. For a very similar structure compared to CP Formate the WHO concluded that only innocuous metabolites will be formed, which can be anticipated also for CP Formate. This analogue is 3,3,5 -Trimethylcyclohexyl acetate (CAS: 67859 -96 -5). The metabolite of CP Formate: formic acid is expected to be consumed in the Krebs cycle.

Excretion

The water solubility of the alcohol and its glucuronic metabolite indicates that CP Formate will mainly be excreted via the urine. The effects seen of the metabolite Applelide also indicate excretion via the urine because alpha-hydrocarbon nephropathy is seen. A minor fraction may be excreted via the bile and be reabsorbed or being excreted via the faeces. The fraction unabsorbed will be minor and will be excreted via the faeces.

Discussion

CP Formate 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 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 effects seen are related to systemic effects and therefore route to route extrapolation is applicable. The overriding principle will be used to avoid situations where the extrapolation of data would underestimate toxicity resulting from human exposure to a chemical by the route to route extrapolation. CP Formate is expected to be hydrolysed in the gut by micro-organisms because it is an ester. 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. 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 CP Formate is not a volatile liquid the inhalation exposure will be considered. CP Formate is not a skin and eye irritant 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

CP Formate 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

Belsito, D., Bickers, D., Bruze, M., Calow, P., Greim, H., Hanifin, J.M., Rogers, A.E., Saurat, J.H., Sipes, I.G., Tagami, H., 2008, A toxicologic and dermatologic assessment of cyclic acetates when used as fragrance ingredients,Food and Chemical Toxicology 46, Suppl 12:S1-27.

Buist, H.E., Wit-Bos de, L., Bouwman, T., Vaes, W.H.J., 2012, Predicting blood:air partition coefficient using basic physico-chemical properties, Regul. Toxicol. Pharmacol., 62, 23-28. 

GHRC, 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

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.

WHO, 2000, Evaluation of certain food additives, Technical Report Series 891, page 53/54,http://whqlibdoc.who.int/trs/WHO_TRS_891.pdf.

WHO, 2011, Safety evaluation of certain food additives, 73rd meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), http://whqlibdoc.who.int/publications/2011/9789241660648_eng.pdf

Yamada, T., Tanaka, Y., Hasegawa, R., Sakuratani, Y., Yamada, J., Kamata, E., Ono, A., Hirose., A., Yamazoe, Y., Mekenyan, O., Hayashi, M., 2013, A category approach to predicting the repeated-dose hepatotoxicity of allyl esters, Reg. Toxicol. Pharmacol, 65, 189-195.