Cyclopentadecanone

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

other: toxicokinetic assessment based on all available information

Adequacy of study:

key study

Study period:

March 2018

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: expert statement based on analysis of all available information

Objective of study:

absorption

distribution

excretion

metabolism

Qualifier:

no guideline required

Principles of method if other than guideline:

Expert statement based on the analysis of all available information on the substance, including physico-chemical properties and the results of toxicological studies.

GLP compliance:

no

Radiolabelling:

no

Species:

other: not applicable, toxicokinetic assessment

Type:

absorption

Results:

For risk assessment purposes, 100% absorption will be considered for oral and respiratory exposure; 50% absorption will be considered for dermal route.

Type:

distribution

Results:

The substance is metabolized in the liver and can be distributed through the body.

Type:

metabolism

Results:

The substance is likely to be metabolized in the liver.

Type:

excretion

Results:

The substance is likely to be excreted via urine.

Details on absorption:

The results of the available 28-day study with the reproductive and developmental toxicity screening suggest that the substance can be absorbed by oral route. Adverse toxicological effects were observed following the substance administration by gavage. For risk assessment purposes, 100% oral absorption will be considered in the lack of other data. The substance has a high log Kow (range 3.3-5.6, the main constituent has most probably the log Kow of 5.6), but its molecular weight is below the cut-off value of 500 g/mol. However, the substance is not irritating and not sensitizing, and its very low solubility and high log Pow suggests that it will not partition readily from stratum corneum into the epidermis. Therefore the value of 100% is considered to be overly conservative, and in the absence of other data the value of 50% will be used for dermal absorption. Cyclopentanone is a paste with a low vapour pressure (< 0.4 Pa, value probably overestimated, as it was obtained from the melting point study), thus respiratory exposure to the substance is considered to be very unlikely. However, as a worst case approach, 100% respiratory absorption will be considered in the risk assessment.

Details on distribution in tissues:

Based on the results of the available 28-day study with reproductive and developmental toxicity screening, in which adverse effects on the liver and kidneys were seen, following oral absorption the substance is transported to liver where it is probably metabolized and is subsequently excreted into urine via kidneys. As toxicological effects were observed in several organs and tissues, it is possible that the metabolites are distributed through the body after entering the systemic cirtulation. Based on physico-chemical properties of the substance, i.e. high log Kow, some degree of accumulation of the non-metabolized substance in adipose tissue cannot be excluded.

Details on excretion:

Based on the results of the available 28-day study with reproductive and developmental toxicity screening, in which adverse effects on kidneys were observed, the substance is probably removed by kidneys and is subsequently excreted in urine.

Metabolites identified:

no

Details on metabolites:

Based on Toxtree v 2.6.13 prediction for CYP450-mediated metabolism, the primary site for metabolic conversion is an aliphatic hydroxylation of the CH2 group in the alpha-position of the ketone group, while the secondary site is the aliphatic hydroxylation at C8 and C9 carbon atoms. It is possible that the generated hydroxyl groups are subsequently glucuronidated in the liver, which will increase the water solubility.

Conclusions:

The toxicokinetic assessment for cyclopentadecanone was performed based on all available data. For risk assessment purposes, 100% absorption is considered for oral and respiratory routes of exposure, and 50% absorption is considered for dermal route. Based on the results of the available 28-day toxicity study, following oral absorption the substance is probably transported to liver, where it undergoes metabolization, with subsequent excretion into urine via kidneys. Based on physico-chemical properties of the substance, some degree of accumulation in adipose tissue cannot be excluded.

Executive summary:

The toxicokinetic assessment for cyclopentadecanone was performed based on all available data. The results of the available 28-day study with the reproductive and developmental toxicity screening suggest that the substance can be absorbed by oral route. Adverse toxicological effects were observed following the substance administration by gavage. For risk assessment purposes, 100% oral absorption will be considered in the lack of other data. The substance has a high log Kow (range 3.3-5.9, the main constituent has most probably the log Kow of 5.6), but its molecular weight is below the cut-off value of 500 g/mol. However, based on the very low solubility of the substance and its high log Pow, the value of 50% will be used for dermal absorption. Cyclopentadecanone is a paste with a low vapour pressure (< 0.4 Pa, value probably overestimated, as it was obtained from the melting point study), thus respiratory exposure to the substance is considered to be very unlikely. However, as a worst case approach, 100% respiratory absorption will be considered in the risk assessment. Based on the results of the available 28-day study with reproductive and developmental toxicity screening, in which adverse effects on the liver and kidneys were seen, following oral absorption the substance is transported to liver where it is probably metabolized and is subsequently excreted into urine via kidneys. Based on Toxtree v 2.6.13 prediction for CYP450-mediated metabolism, the primary site for metabolic conversion is an aliphatic hydroxylation of the CH₂group in the alpha-position of the ketone group, while the secondary site is the aliphatic hydroxylation at C8 and C9 carbon atoms. As toxicological effects were observed in several organs and tissues, it is possible that the substance and/or its metabolites are distributed through the body after entering the systemic cirtulation. Based on physico-chemical properties of the substance, i.e. high log Kow, some degree of accumulation of the non-metabolized substance in adipose tissue cannot be excluded.

Description of key information

The toxicokinetic assessment for cyclopentadecanone was performed based on all available data. For risk assessment purposes, 100% absorption is considered for oral and respiratory routes of exposure, and 50% absorption is considered for dermal route. Based on the results of the available 28-day toxicity study, following oral absorption the substance is probably transported to liver, where it undergoes metabolization, with subsequent excretion into urine via kidneys. Based on physico-chemical properties of the substance, some degree of accumulation of the non-metabolized substance in adipose tissue cannot be excluded.

Key value for chemical safety assessment

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

The toxicokinetic assessment for cyclopentadecanone was performed based on all available data. The results of the available 28-day study with the reproductive and developmental toxicity screening suggest that the substance can be absorbed by oral route. Adverse toxicological effects were observed following the substance administration by gavage. For risk assessment purposes, 100% oral absorption will be considered in the lack of other data. The substance has a high log Kow (range 3.3-5.9, the main constituent has most probably the log Kow of 5.6), but its molecular weight is below the cut-off value of 500 g/mol. However, based on the very low solubility of the substance and its high log Pow, the value of 50% will be used for dermal absorption. Cyclopentadecanone is a paste with a low vapour pressure (< 0.4 Pa, value probably overestimated, as it was obtained from the melting point study), thus respiratory exposure to the substance is considered to be very unlikely. However, as a worst case approach, 100% respiratory absorption will be considered in the risk assessment. Based on the results of the available 28-day study with reproductive and developmental toxicity screening, in which adverse effects on the liver and kidneys were seen, following oral absorption the substance is transported to liver where it is probably metabolized and is subsequently excreted into urine via kidneys. Based on Toxtree v 2.6.13 prediction for CYP450-mediated metabolism, the primary site for metabolic conversion is an aliphatic hydroxylation of the CH₂ group in the alpha-position of the ketone group, while the secondary site is the aliphatic hydroxylation at C8 and C9 carbon atoms. As toxicological effects were observed in several organs and tissues, it is possible that the substance and/or its metabolites are distributed through the body after entering the systemic cirtulation. Based on physico-chemical properties of the substance, i.e. high log Kow, some degree of accumulation of the non-metabolized substance in adipose tissue cannot be excluded.