Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 939-618-9 | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Link to relevant study record(s)
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 2ndC of the ethyl-group and two methyl groups at the 3rdC of the cyclohexyl ring. The minor constituent (8-18%) consist of a cycloheptyl ring with an ester group attached on the 1stC of the cycloheptyl ring, one methyl group on the 2ndC and two methyl groups on the 6thC 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.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.