Citronellyl formate

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert statement

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert statement, no study available

Objective of study:

absorption

distribution

excretion

metabolism

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

Details on exposure:

not applicable

Duration and frequency of treatment / exposure:

not applicable

No. of animals per sex per dose / concentration:

not applicable

Positive control reference chemical:

not applicable

Details on study design:

not applicable

Details on dosing and sampling:

not applicable

Statistics:

not applicable

Details on absorption:

Oral route:
Generally, oral absorption is favoured for molecular weights below 500 g/mol. Furthermore, a high water solubility of more than 100 mg/L enables the substance to readily dissolve in the gastrointestinal fluids, allowing direct uptake into the systemic circulation through aqueous pores or via carriage of the molecules across membranes with the bulk passage of water. Citronellyl formate has a water solubility of 16.2 mg/L, therefore not favouring absorption, but the moderate log Pow value is favourable for passive diffusion. Taken together, the physiochemical properties indicate that citronellyl formate might become bioavailable following the oral route. This assumption is confirmed by the results of the acute toxicity study and the combined repeated oral dose toxicity study with the reproduction/ developmental toxicity screening test. Clinical signs and mortality were observed in both studies. The combined repeated oral dose toxicity study with the reproduction/ developmental toxicity screening test furthermore revealed developmental toxicity.

Inhalation route:
Due to the low vapour pressure of citronellyl formate it is unlikely that the substance will be available as a vapour, but if it is the case absorption via inhalation route is possible due to the water solubility and the moderate log Pow value, enabling uptake directly across the respiratory tract epithelium by passive diffusion.

Dermal route:
Dermal uptake is favoured for substances with a molecular weight < 100 g/mol and log Pow values between 1 and 4. The log Pow of citronellyl formate is 3.9 and therefore lies in the range of between -1 and 4. The molecular weight of the substance is above 100 g/mol, but < 500 g/mol and therefore still small enough to be absorbed by skin. In addition, the substances must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Absorption is anticipated to be moderate to high if water solubility is between 100 and 10000 mg/L. Citronellyl formate has a water solubility of 16.2 mg/L, therefore not supporting dermal absorption. This assumption is supported by the results of the acute dermal toxicity study. No deaths occurred and no untoward behavioral reactions were exhibited by any of the animals. Only pale red erythema, slight edema and dryness of the skin were observed.

Details on distribution in tissues:

As mentioned above, the physicochemical properties of citronellyl formate favour systemic absorption following oral and to a less extend inhalative and dermal uptake. Direct transport through aqueous pores is likely to be an entry route to the systemic circulation. In general, the smaller the molecule, the wider the distribution. Taken into account the log Pow and the water solubility, accumulation of citronellyl formate is unlikely. The available study data revealed no indications of the substance to cross the blood-brain barrier.

Details on excretion:

The metabolites of citronellyl formate are most likely excreted via urine due to their small molecular weight and their good water solubility.

Details on metabolites:

Metabolism mainly occurs in liver especially following oral intake. Citronellyl formate may be hydrolysed to citronellol and formic acid by carboxylesterases or esterases. Citronellol may undergo alcohol oxidation, omega-oxidation, hydration, or hydrogenation. Phase II reactions e.g. conjugation with glucuronic acid by glucuronyltransferases or conjugation with sulphuric acid by sulfotransferases may occur to enhance the hydrophilicity and to facilitate the elimination. Formic acid will be decomposed to CO2 in the C1 metabolism.

Conclusions:

Absorption via oral route is expected. Absorption via dermal and inhalation route is unlikely, but cannot be excluded. Bioaccumulation will not occur. After enzymatic conversion the metabolites will be mainly renally excreted.

Executive summary:

Based on physicochemical characteristics, particularly water solubility and octanol-water partition coefficient, absorption by the oral route is expected. This assumption was confirmed by the results of the acute toxicity study and the combined repeated oral dose toxicity study with the reproduction/ developmental toxicity screening test. Clinical signs and mortality were observed in both studies at high doses. Absorption via dermal and inhalation route is unlikely, but cannot be excluded. Bioaccumulation of citronellyl formate or its breakdown products will not occur. After enzymatic conversion the metabolites will be mainly renally excreted.

Description of key information

Based on physicochemical characteristics, particularly water solubility and octanol-water partition coefficient, absorption by the oral route is expected. This assumption was confirmed by the results of the acute toxicity study and the combined repeated oral dose toxicity study with the reproduction/ developmental toxicity screening test. Clinical signs and mortality were observed in both studiesat high doses.Absorption via dermal and inhalation route is unlikely, but cannot be excluded. Bioaccumulation of citronellyl formate or its breakdown products will not occur. After enzymatic conversion the metabolites will be mainly renally excreted.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Toxicokinetic Assessment

Citronellyl formate is a colourless to pale yellow liquid at room temperature with a molecular weight of 184.3 g/mol. The substance is soluble in water (16.2 mg/L at 20 °C). The log Pow of citronellyl formate was determined to be 3.9. Citronellyl formate has a vapour pressure of 4.0 Pa at 20 °C.

 

Absorption

Generally, oral absorption is favoured for molecular weights below 500 g/mol. Furthermore, a high water solubility of more than 100 mg/L enables the substance to readily dissolve in the gastrointestinal fluids, allowing direct uptake into the systemic circulation through aqueous pores or via carriage of the molecules across membranes with the bulk passage of water. Citronellyl formate has a water solubility of 16.2 mg/L, therefore not favouring absorption, but the moderate log Pow value is favourable for passive diffusion. Taken together, the physiochemical properties indicate that citronellyl formate might become bioavailable following the oral route. This assumption is confirmed by the results of the acute toxicity study and the combined repeated oral dose toxicity study with the reproduction/ developmental toxicity screening test. Clinical signs and mortality were observed in both studies. The combined repeated oral dose toxicity study with the reproduction/ developmental toxicity screening test furthermore revealed developmental toxicity.

Due to the low vapour pressure of citronellyl formate it is unlikely that the substance will be available as a vapour, but if it is the case absorption via inhalation route is possible due to the water solubility and the moderate log Pow value, enabling uptake directly across the respiratory tract epithelium by passive diffusion.

Dermal uptake is favoured for substances with a molecular weight < 100 g/mol and log Pow values between 1 and 4. The log Pow of citronellyl formate is 3.9 and therefore lies in the range of between -1 and 4. The molecular weight of the substance is above 100 g/mol, but < 500 g/mol and therefore still small enough to be absorbed by skin. In addition, the substances must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Absorption is anticipated to be moderate to high if water solubility is between 100 and 10000 mg/L. Citronellyl formate has a water solubility of 16.2 mg/L, therefore not supporting dermal absorption. This assumption is supported by the results of the acute dermal toxicity study. No deaths occurred and no untoward behavioral reactions were exhibited by any of the animals. Only pale red erythema, slight edema and dryness of the skin were observed.

 

Distribution

As mentioned above, the physicochemical properties of citronellyl formate favour systemic absorption following oral and to a less extend inhalative and dermal uptake.

Direct transport through aqueous pores is likely to be an entry route to the systemic circulation. In general, the smaller the molecule, the wider the distribution. Taken into account the log Pow and the water solubility, accumulation of citronellyl formate is unlikely. The available study data revealed no indications of the substance to cross the blood-brain barrier.

 

Metabolism

Metabolism mainly occurs in liver especially following oral intake. Citronellyl formate may be hydrolysed to citronellol and formic acidby carboxylesterases or esterases. Citronellol may undergo alcohol oxidation, omega-oxidation, hydration, or hydrogenation. Phase II reactions e.g. conjugation with glucuronic acid by glucuronyltransferases or conjugation with sulphuric acid by sulfotransferases may occur to enhance the hydrophilicity and to facilitate the elimination. Formic acid will be decomposed to CO₂ in the C1 metabolism.

 

Excretion

The metabolites of citronellyl formate are most likely excreted via urine due to their small molecular weight and their good water solubility.