Cyclohexadecen-1-one

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

Expert Statement

Type of information:

other: Expert Statement

Adequacy of study:

key study

Study period:

2019-02-14

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert statement, no other study available

Principles of method if other than guideline:

Expert Statement

GLP compliance:

no

Details on absorption:

Inhalation
The low water solubility (<1 mg/L) and high lipophilicity (log Pow = 6.5) indicate that the substance may be retained in the mucus and indicates a potential for accumulation. However, due to the low volatility (vapour pressure = 0.0092 Pa) and the susceptibility to convert to the molten state in view of the very low melting point (= 25°C) tendency, the potential for inhalation of dust or vapours is only marginal.

Oral
The test item has a low water solubility (<1 mg/L) and is highly lipophilic, and therefore may not readily dissolve in gastrointestinal fluid and absorption by passive diffusion will be very limited. Furthermore, no toxicity was observed in the acute oral toxicity study and in the subchronic oral toxicity study up to 1000 mg/kg bw. Systemic absorption does not seem to be a preferential route of entry into the body.

Dermal
Due to the low water solubility (<1 mg/L) and a logPow of 5.8, dermal uptake is likely to be low. Since the substance is a skin irritant, damage to the skin surface may enhance penetration. However, the lack of toxicity in the acute dermal toxicity study up to a dose of 2000 mg/kg bw may be seen as an indication that this is not a preferential route of entry into the body.

Details on distribution in tissues:

During the 28-day oral toxicity study in the rat only marginal changes in cholesterol levels and liver weights were observed, which indicate that the liver can be considered as target organ. However, the histopathological examination revealed no changes on cellular level. The results of the examinations indicate that following the repeated administration of high doses sufficient amounts are resorbed, as indicated by the marginal reaction of the liver. Apart from that, no signs of systemic toxicity could be observed.

Details on excretion:

The available data do not allow the prediction of an expected metabolism or excretion of the substance.

Details on metabolites:

It can be assumed that P450-enzymes are substantially involved in the metabolism of the test item, since in the chromosome aberration test with human lymphocytes clear toxic effects were observed after 4 h and 22h treatment with 49 µg/mL and above in the absence of S9 mix, whereas no cytotoxic effects could be observed after 4h treatment up to the highest applied concentration in the presence of S9 mix. The available data do not allow the prediction of an expected metabolism or excretion of the substance. Metabolism by Phase I enzymes, such as CYP450 enzymes, usually aims to enhance hydrophilicity of the substance by for example hydroxylation. Thus, the test item is not considered of concern in regards to bioaccumulation, since it is anticipated that it is metabolised to more hydrophilic metabolites in the organism.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Toxicokinetic Assessment

Substance composition

The test item consists to ~ 90 % of a mixture of the main isomers of Cyclohexadecenone, being an aliphatic keton with one alkene group at position 7 or 8, besides some minor structurally related impurities. Therefore, all components can be regarded as alicyclic hydrocarbons.  

Summary of toxicological profile

Acute toxicity: 

Acute oral toxicity in rats was assessed after a single oral application of 2000 mg/kg bw. No mortality occurred. Hunched posture, tremor and piloerection were noted after the single application lasting for up to 2 days. Based on an acute dermal toxicity study in rats at a limit dose of 2000 mg/kg bw, the test substance did not show any signs of toxicity after single dermal application.  

Irritation and sensitisation: 

The tests for skin irritation produced signs of irritation, but no signs of any systemic toxicological effects. The test item is classified and labelled as irritant to the skin. No signs of irritation were observed in the eye irritation test. Therefore, the test item does not require classification according to CLP. No signs of sensitisation or any systemic toxicological effects were observed in the skin sensitisation test. 

Repeated dose toxicity: 

In a 28-d oral toxicity study in the rat (doses: 0, 100, 300 and 1,000 mg/kg bw/d by gavage; vehicle: hydroxypropylmethyl cellulose), no mortality was noted. Salivation was the only effect observed at the two highest doses tested (300 and 1000 mg/kg bw), starting 3 min after administration and lasting for 30 min. No clinical or histopathological signs related to the test substance, influence on body weight, food and drinking consumption, the eye and optic region were noted. Marginal changes observed (increase in cholesterol levels and liver weight with no histopathological correlation) are considered to be non-specific metabolic adaptation caused by the high workload on the liver with the test item. The NOAEL was derived to be >1000 mg/kg bw.  

In a study performed according to the OECD test guideline No. 408 and in compliance with GLP, the read across source substance Globalide (Oxacyclohexadecen-2-one, CAS No 111879-80-2) diluted in carboxymethylcellulose was administered by gavage to rats at 0, 50, 250 or 1000 mg/kg bw/day for 90 days. Additional satellite animals were included in the control and high dose group to evaluate the reversibility or persistence of any toxic effects after a post-treatment period of 28 days. There were no treatment-related deaths during the study. Two males treated with 1000 mg/kg bw/day were found dead during the treatment period one each on Days 34 and 85 almost certainly following a mal-dose. A 250 mg/kg bw/day female was killed in extremis on Day 49 after a large mass developed around its abdominal region. No clinically observable signs of toxicity were detected during the study. No adverse effect on bodyweight development, on dietary intake, on water consumption was detected during the study. No treatment-related effects were observed during ophtalmoscopic examination. Haematology, clinical chemistry and urinalysis were normal. At necropsy, no treatmentrelated macroscopic or microscopic lesions were noticed, organ weight were within normal ranges.

In a developmental toxicity study conducted according to the OECD guideline No. 414 and in compliance with GLP, the test material diluted in carboxymethyl cellulose was administered to 24 females Sprague- Dawley CD rats/dose by gavage at dose levels of 0, 50, 250 or 1000 g/kg bw/d from day 5 of gestation through day 19 of gestation. Individual clinical observations, bodyweight and food consumption were recorded during the study. The females were killed on Day 20 of gestation, examined macroscopically and the uterine contents examined. The number of corpora lutea, implantation number, position and type, foetal and placental weights, foetal sex, and external appearance were recorded. All live foetuses were preserved, processed and subsequently examined for skeletal or visceral anomalies. At all dose levels up to and including 1000 mg/kg bw/d there were no significant treatment related effects on adult bodyweight gain and food consumption during gestation. There were no clinical signs of reaction to test material administration and no significant macroscopic findings at post mortem examination. At caesarian necropsy, there were no significant treatment-related effects on any of the parameters examined. At all dose levels up to and including 1000 mg/kg bw/d there were no significant treatment related effects upon foetal viability, growth and development. There was no effect upon the type or incidence of visceral or skeletal anomalies observed. The oral administration of the test material at dose levels up to 1000 mg/kg bw/d, to pregnant rats from Day 5 to 19 of gestation resulted in no significant systemic effects on the adults. There were no significant effects on any of the uterine parameters examined. There were no significant effects upon offspring viability, growth or development. The No Observed Adverse Effect Level (NOAEL) for adult toxicity and developmental toxicity was ≥ 1000 mg /kg bw/d. Under the test conditions, the test material is not classified according to the annex VI of the Regulation (EC) No. 1272/2008 (CLP) and of the Directive 67/548/EEC. This study is acceptable and satisfies the requirement for developmental toxicity endpoint.

Genotoxicity:
The test item was shown to be not mutagenic or clastogenic in bacterial and mammalian cell systems. 

Absorption

Inhalation route:

The low water solubility (<1 mg/L) and high lipophilicity (log Pow = 6.5) indicate that the substance may be retained in the mucus and indicates a potential for accumulation. However, due to the low volatility (vapour pressure = 0.0092 Pa) and the susceptibility to convert to the molten state in view of the very low melting point (= 25°C) tendency, the potential for inhalation of dust or vapours is only marginal.

Oral route:

The test item has a low water solubility (<1 mg/L) and is highly lipophilic, and therefore may not readily dissolve in gastrointestinal fluid and absorption by passive diffusion will be very limited. Furthermore, no toxicity was observed in the acute oral toxicity study and in the subchronic oral toxicity study up to 1000 mg/kg bw. Systemic absorption does not seem to be a preferential route of entry into the body.  

Dermal route:

Due to the low water solubility (<1 mg/L) and a logPow of 6.5, dermal uptake is likely to be low. Since the substance is a skin irritant, damage to the skin surface may enhance penetration. However, the lack of toxicity in the acute dermal toxicity study up to a dose of 2000 mg/kg bw may be seen as an indication that this is not a preferential route of entry into the body.  

Distribution

During the 28-day oral toxicity study in the rat only marginal changes in cholesterol levels and liver weights were observed, which indicate that the liver can be considered as target organ. However, the histopathological examination revealed no changes on cellular level.  The results of the examinations indicate that following the repeated administration of high doses sufficient amounts are resorbed, as indicated by the marginal reaction of the liver. Apart from that, no signs of systemic toxicity could be observed.

Metabolism
It can be assumed that P450-enzymes are substantially involved in the metabolism of the test item, since in the chromosome aberration test with human lymphocytes clear toxic effects were observed after 4 h and 22h treatment with 49 µg/mL and above in the absence of S9 mix, whereas no cytotoxic effects could be observed after 4h treatment up to the highest applied concentration in the presence of S9 mix. Metabolism by Phase I enzymes, such as CYP450 enzymes, usually aims to enhance hydrophilicity of the substance by for example hydroxylation. Thus, the test item is not considered of concern in regards to bioaccumulation, since it is anticipated that it is metabolised to more hydrophilic metabolites in the organism.

Excretion

The available data do not allow the prediction of an expected metabolism or excretion of the substance.