1-(2-hydroxy-5-nonyl(branched)-phenyl)ethanone oxime

Endpoint summary

Description of key information

Based on the physicochemical properties and on the results of the toxicological evaluation, Ethanone, 1-(2-hydroxy-5-nonylphenyl)-, oxime, branched was shown to become systemic available following oral administration, most likely after micellular solubilisation prior to entering the systemic circulation, and is widely distributed. The major route of excretion will be the feces but excretion via the urine can also be considered as likely.
Uptake into the systemic circulation following dermal exposure can occur but is considered as very limited due to the very low water solubility and the high lipophilicity that limits the transfer rate across the different skin layers.
Based on the low vapour pressure and the very low water solubility, it is unlikely that relevant amounts of the substance will become systemically bioavailable via inhalation.
Although the physical-chemical properties would in principle indicate a possible potential for bioaccumulation, Ethanone, 1-(2-hydroxy-5-nonylphenyl)-, oxime, branched is not considered to bioaccumulate based on data obtained in a BCF study.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

1 Physical-Chemical Data on Ethanone, 1-(2-hydroxy-5-nonylphenyl)-, oxime, branched

Ethanone, 1-(2-hydroxy-5-nonylphenyl)-, oxime, branched is a liquid at standard ambient temperature and pressure.The molecular weight (Mw) of the substance lies between 220 and 291 g/mol. The melting point is < -20 °C at ambient pressure (1013 hPa).The substance has a vapour pressure of <0.015 hPa at 20 °C, which can be considered as very low.

The substance is highly insoluble in water (<0.1 mg/L).As the substance is highly insoluble in water, hydrolysis was not investigated. The partition coefficient log Pow was 4.8 and > 5.7.

 

2 Toxicokinetic analysis of Ethanone, 1-(2-hydroxy-5-nonylphenyl)-, oxime, branched

Absorption

Oral route:

With regards to its log Pow of 4.8 and >5.7, the substance is very lipophilic. Thus, the absorption within the gastrointestinal (Gl) tract may be limited by the inability to dissolve into GI fluids and to come into contact with the mucosal surface. However, it is known that the absorption of lipophilic substances may be enhanced, if they undergo micellular solubilisation by bile salts. Substances absorbed as micelles are known to enter the circulation via the lymphatic system.

With regards to toxicological data, in an acute oral toxicity study in rats (limit test) no mortality was observed at a dose level of 2000 mg/kg bw. Only unspecific signs of acute intoxication were noted. The LD₅₀value for Ethanone, 1-(2-hydroxy-5-nonylphenyl)-, oxime, branchedwas determined to be greater than 2000 mg/kg bw.

Results of a 14-day range finding study with Ethanone, 1-(2-hydroxy-5-nonylphenyl)-, oxime, branched where male and female rats received dose levels of 150, 450 and 750 (later reduced to 600 mg/kg bw/day) mg/kg bw/day confirmed bioavailability by the oral route showing effects on multiple organs (liver, prostate, seminal vesicles, adrenal glands, testes, epididymides, testes and ovaries) as well as some clinical parameters (decreased red blood cell (RBC) counts, decreased hematocrit and hemoglobin levels, increased creatinine levels).

Overall, with regards to its very low water solubility and the lipophilic character, the substance may undergo micellular solubilisation by bile salts prior entering the systemic circulation. Based on the results of the toxicological evaluation, absorption of Ethanone, 1-(2-hydroxy-5-nonylphenyl)-, oxime, branched into the systemic circulation following oral administration was demonstrated for higher dose levels.

Inhalation route:

The substance appears in the liquid form but based on the very low vapour pressure, inhalation exposure under normal use conditions is unlikely. Therefore, no acute inhalation study was performed.

Dermal route:

The physicochemical properties of Ethanone, 1-(2-hydroxy-5-nonylphenyl)-, oxime, branched do not favour dermal absorption. Although the substance is a liquid at room temperature, the very low water solubility and the high lipophilicity limits the transfer rate across the different skin layers.

A limit test with a Benzaldehyde, 5 -nonyl-2 -hydroxy, oxime dose of 2000 mg/kg bodyweight was performed. This read across test substance was applied unchanged under occlusive conditions for 24h to the skin of ten New Zealand White rabbits of both sexes, which were observed for 14 days post application. One rabbit was found dead on day 4. Body weights stagnated or increased, while no pathological abnormalities were present in all rabbits, except the dead rabbit. Thus, the rabbit acute dermal toxicity LD50 of the test substance was > 2000mg/kg bodyweight and is therefore considered practically non-toxic which confirms again that dermal absorption is low.

The topical application of the substance onto the skin of rabbits caused moderate to severe erythema and moderate oedema in all animals in a skin irritation/corrosion study according to OECD 404 guideline.Thus, there was some evidenceof tissue damage, which in turn could have favoured dermal absorption into the systemic circulation.

Furthermore, the read across substance Benzaldehyde, 5-nonyl-2-hydroxy, oxime, branched induced skin sensitization in a local lymph node assay (LLNA, OECD 429) but no evidence of systemic toxicity or local irritation were present. Therefore, some dermal absorption must have occurred although it could have been only a small fraction of the applied substance.

Overall, the physicochemical properties and the findings from the dermal toxicity, irritation and sensitisation studies indicated that low absorption into the systemic circulation can be expected after dermal application.

Distribution

Based on the signs of systemic toxicity of Ethanone, 1-(2-hydroxy-5-nonylphenyl)-, oxime, branched observed in the test with repeated administration, systemic availability and distribution within the body via the blood stream circulation following oral administration was demonstrated.

The physical-chemical properties would in principle indicate a possible potential for bioaccumulation. However, this was not confirmed in a bioaccumulation study in fish, conducted with the close homologue Benzaldehyde, 2-hydroxy-5-nonyl, oxime, branched (CAS 174333-80-3). The only structural difference between the source substance and the target substance is the lack of a methyl group at the oxime carbon atom of the source substance. In a standard test according to OECD guideline 305 a saturation plateau was reached within 6 days of exposure and the substance was rapidly eliminated below the detection limit within 4 days after termination of exposure. The bioconcentration factors of the tested concentrations of 7 and 35μg/l were approx. 138 and 159, respectively and thus, significantly below any level of concern for bioaccumulation. Based on the high structural similarity, which leads to similar behavior in the environment, this conclusion can also be considered true for Ethanone, 1-(2-hydroxy-5-nonylphenyl)-, oxime, branched (CAS 244235-47-0). This conclusion is supported by results of numerous publications showing similar low BCF values (167 - 740) of branched nonylphenol (CAS 84852-15-3) for different taxa (see respective dossier at ECHA database). Finally, there is no indication that mammals could behave differently than fish.

 

Metabolism

It can be assumed that Ethanone, 1-(2-hydroxy-5-nonylphenyl)-, oxime, branched is easily metabolized, possibly via a phase I oxidation step releasing 2-hydroxy-5-nonyl acetophenone, which could subsequently be glucuronidated or sulphated in a phase II metabolic step and excreted via the urine.

This assumption is considered reasonable as a similar metabolism has been observed for butanal oxime (Mathews et al., 1998). Butanal oxime is first converted to the corresponding aldehyde and is subsequently oxidised to the corresponding fatty acid, which enters the beta-oxidation pathway.

Acetophenone can directly be excreted via the urine without further metabolism (Nutley BP et al, 1994) but this pathway could be more easily entered if the hydroxy functionality is conjugated by a phase II metabolism step.

The formation of oximes is a known pathway of deamination in vivo (Beckett AH et al, 1971).

Since the water solubility of the Ethanone, 1-(2-hydroxy-5-nonylphenyl)-, oxime, branched is very low, storage or the plasma concentrations of the metabolites will also remain very low.

Excretion

With regards to the physical-chemical properties of Ethanone, 1-(2-hydroxy-5-nonylphenyl)-, oxime, branched limited GI absorption in the form of micelles can be considered as likely and the vast majority may be readily excreted via the feces. Any amount that enters the systemic circulation will be easily metabolized and finally the metabolites, in its glucuronidated or sulphated form, will be excreted either via bile or most likely asbenzoic acid derivativevia the urine.

 

3 Summary

Based on the physicochemical properties and on the results of the toxicological evaluation, Ethanone, 1-(2-hydroxy-5-nonylphenyl)-, oxime, branched was shown to become systemic available following oral administration, most likely after micellular solubilisation prior to entering the systemic circulation, and is widely distributed. The major route of excretion will be the feces but excretion via the urine can also be considered as likely.

Uptake into the systemic circulation following dermal exposure can occur but is considered as very limited due to the very low water solubility and the high lipophilicity that limits the transfer rate across the different skin layers.

Based on the low vapour pressure and the very low water solubility, it is unlikely that relevant amounts of the substance will become systemically bioavailable via inhalation.

Although the physical-chemical properties would in principle indicate a possible potential for bioaccumulation, Ethanone, 1-(2-hydroxy-5-nonylphenyl)-, oxime, branched is not considered to bioaccumulate based on data obtained in a BCF study.

 

4 References

Beckett AH, Van Dyk JM, Chissick HM, Gorrod JW (1971) Metabolism of amphetamines to oximes as a route to deamination, J. Pharm. Pharmacol., 23, 560

ECHA (2008), Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

Marquardt H., Schäfer S. (2004). Toxicology. Academic Press, San Diego, USA, 2nd Edition 688-689.

Mathews JM, Black SR, Burka LT (1998) Disposition of butanal oxime in rat following oral, intravenous and dermal administration, Xenobiotica, 28, 767 – 777

Mutschler E., Schäfer-Korting M. (2001) Arzneimittelwirkungen. Lehrbuch der Pharmakologie und Toxikologie.Wissenschaftliche Verlagsgesellschaft, Stuttgart.

Nutley BP, Farmer P and Caldwell J (1994) Metabolism of trans-cinnamic acid in the rat and the mouse and its variation with dose,Food and Chemical ToxicologyVolume 32, Issue 10, Pages 877-886

Renwick A.G. (1994) Toxicokinetics - pharmacokinetics in toxicology. In Hayes,A.W. (ed.) Principles and Methods of Toxicology. Raven Press, New York, p 103