Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Based on the physicochemical properties and on the results of the toxicological evaluation, the substance was shown to become systemic available following oral administration, most likely after micellular solubilisation prior 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 limit 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, the substance 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

The substance is a liquid at standard ambient temperature and pressure. The molecular weight (Mw) of the substance is 305.46 g/mol (main constituent) and the molecular formula of the main constituent is C19H31NO2. The melting point is <-20 °C at ambient pressure (1013 hPa). The substance has a vapour pressure of <0.039 hPa at 20 °C, which can be considered as very low.

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

 

2 Toxicokinetic analysis

Absorption

Oral route:

With regards to its log Pow of >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 (OECD 401 equivalent) doses levels of 500, 890, 1580, 2810 and 5000 mg/kg bw were applied by gavage. Mortalities occurred dose-dependently at 890 mg/kg bw and above. Only unspecific signs of acute intoxication were noted. The LD50value for the substance was determined to be 1220 mg/kg bw.

The substance was repeatedly administered to rats via the oral route in a regular subchronic repeated dose toxicity study (OECD 408) under GLP conditions. Ten rats of both sexes received dose levels of either0, 15, 50 or 150 mg/kg bw/day for a period of 90 days. Clinical signs, food consumption, body weight, gross necropsy, ophthalmoscopy, clinical chemistry, hematology, urinalysis and histopathology were recorded as required by the guideline. Furthermore, a functional observation battery was included in the study. No treatment-related adverse effects were observed in male and female animals up the highest dose applied. Thus, the NOAEL of the test substance in this 90-day oral toxicity study was 150 mg/kg bw/day.

The possible impact of the substance on fertility, reproduction and development were examined in a reproduction/developmental toxicity screening test (OECD 421) under GLP conditions. Groups of each 10 male and 10 female rats received dose levels of 0, 30, 100 and 300 mg/kg bw/day orally by gavage. Both sexes were dosed during a 2-week premating and mating period. Thereafter, the males received the substance for three weeks after mating, while pregnant females with litters were dosed during the entire gestation period up to approximately 4 days of the lactation period. Non-pregnant females received the substance until 4 weeks of the post mating period had elapsed.

Signs of systemic toxicity in the parental animals occurred at 300 mg/kg bw/day in the form of a decrease in food consumption and body weight, altered red blood cell parameters and an increase in reticulocytes, indicative for a regenerative anemia as well as a functional liver impairment. The NOAEL for general systemic toxicity was 100 mg/kg bw/day.

Fertility in the male animals was dose-dependently affected at all dose levels as evidenced by a decrease in the number of sperm in the cauda epididymidis as well as a change in relative organ weights of seminal vesicles and pituitary glands at 30 mg/kg bw/day and above. A NOAEL for male fertility was not achieved. In females, fertility and reproductive performance were distinctly impaired at 100 mg/kg bw/day due to an increase in post-implantation loss, decreased number of delivered pups and morphological alterations in the ovaries. At 300 mg/kg bw/day numerous morphological alterations in the ovaries were noted and no mated female was pregnant. The NOAEL for female fertility was 30 mg/kg bw/day. Developmental toxicity occurred at 100 mg/kg bw/day in the form of a lower number of delivered pups and an increase in dead pups resulting in a reduced viability index. The NOAEL for developmental toxicity was 30 mg/kg bw/day.

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 the substance 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 the substance 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.

The assumption that low, if any dermal absorption occurs was further strengthened by the results obtained from dermal toxicity testing. In an acute dermal toxicity study (16 CFR 1500.40), the substance led to an inconsistent death pattern at dose levels of 10.000, 12.600, 15.870 and 20.000 mg/kg bw, which can be considered as very high and are clearly above the current limit dose of 2.000 mg/kg bw. No deaths were observed at 8.410 mg/kg bw. Clinical findings were noted at each of the very high dose levels but only unspecific signs of systemic toxicity occurred. The LD50of the test substance was >8.410 mg/kg bw but less than 10.000 mg/kg bw.

The topical application of the substance onto the skin of rabbits caused irritation as observed in a skin irritation/corrosion study (49CFR 173.240). Eschar formation was observed in all animals at the end of the treatment period. As the study design was not fully in line with the current OECD study protocol, another study with a close homologue (C9 side chain instead of C11-12 side chain) was performed (OECD 404) considering a weight of evidence approach. The irritative potential was confirmed as clear but fully reversible erythema and edema were observed in all rabbits. Thus, there was some evidence of tissue damage, which in turn could have favoured dermal absorption into the systemic circulation.

Furthermore, the close homologue 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 the substance observed in the test with repeated administration, systemic availability and distribution within the body via the blood stream circulation following oral administration was demonstrated for higher dose levels.

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), which has a branched C9 instead of a branched C11-12 side chain. 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 35 μg/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 the substance evaluated in this dossier. 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 the substance is easily metabolized, possibly via a phase I oxidation step releasing 2-hydroxy-5 -C12 -C12 benzaldehyde, which could subsequently be oxidized to the corresponding benzoic acid derivative.

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.

In addition, the major metabolites of cyclohexanone oxime are also monoglucuronides of the oxidation products, cis- and trans-cyclohexane-1,2-diol (Parmar and Burka, 1991).

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

Since the water solubility of the substance 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 the substance 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 as benzoic acid derivative via the urine.

 

3 Summary

Based on the physicochemical properties and on the results of the toxicological evaluation, the substance 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 limit 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, the substance 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.

Parmar D, Burka LT (1991) Metabolism and disposition of cyclohexanone oxime in male F-344 rats, Drug Metab.Dispos., 19, 1101-1107

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