1-hydroxyoctan-2-one

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

other: Assessment of toxicokinetic behaviour based on literature data, knowledge of functional group metabolism pathways and phys-chem properties of 1-hydroxyoctan-2-one

Adequacy of study:

key study

Study period:

2018

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

GLP compliance:

no

Metabolites identified:

yes

Details on metabolites:

Existing literature data concerning biotransformation pathways for aliphatic ketones and hydroxyketones (EFSA, 2014; WHO 2011a; WHO 2011b), show the potential metabolic reactions involved in the biotransformation of 1-hydroxyoctan-2-one are:
 
(i) Reduction of the ketone functional group to yield the corresponding diol (caprylyl glycol) with subsequent excretion in urine or bile as conjugate of glucuronic acid;
 
(ii) Oxidation of the terminal hydroxyl group to yield α-ketocarboxylic acid (an intermediary metabolite) which may undergo oxidative decarboxylation to yield carbon dioxide and an aliphatic carboxylic acid which may be completely metabolised via fatty acids and the krebs cycle.

Conclusions:

In general, aliphatic secondary alcohols and ketones (functional groups present in the registered substance 1-hydroxyoctan-2-one) are expected to be rapidly absorbed in the gastrointestinal tract (EFSA, 2014). Specifically, significant absorption and systemic availability of 1-hydroxyoctan-2-one or metabolites after oral administration can be concluded from its moderately high water solubility (9.2 g/L at 20°C), low octanol-water partition coefficient (Log Kow = 1.68) and its relatively low molecular weight (144.2 g/mol). These three physicochemical properties also favour dermal uptake, although the systemic availability of 1-hydroxyoctan-2-one after dermal uptake is considered to be lower than after gastro-intestinal absorption following exposure via the oral route.

Executive summary:

No specific experimental study data is available on the absorption, distribution, metabolism and/or excretion (ADME) profile of 1-hydroxyoctan-2-one. However, the toxicokinetic behaviour of the substancein vivocan be estimated using physic-chemical properties of the substance combined with data on structurally analogous compounds.

 

In general, aliphatic secondary alcohols and ketones are expected to be rapidly absorbed in the gastrointestinal tract (EFSA, 2014). Specifically, significant absorption and systemic availability of 1-hydroxyoctan-2-one or metabolites after oral administration can be concluded from its moderately high water solubility (9.2 g/L at 20°C), low octanol-water partition coefficient (Log Kow = 1.68) and its relatively low molecular weight (144.2 g/mol). These three physicochemical properties also favour dermal uptake, although the systemic availability of 1-hydroxyoctan-2-one after dermal uptake is considered to be lower than after gastro-intestinal absorption following exposure via the oral route.

 

Although the low octanol-water partition coefficient (log Kow) and the moderately high water solubility, indicate absorption directly across the respiratory tract epithelium by passive diffusion, the risk of exposure by the inhalation route for 1-hydroxyoctan-2-one is considered to be low, because of its relatively low vapour pressure (27 Pa at 20°C).

 

Existing literature data concerning biotransformation pathways for aliphatic ketones and hydroxyketones (EFSA, 2014; WHO 2011a; WHO 2011b), show the potential metabolic reactions involved in the biotransformation of 1-hydroxyoctan-2-one are:

 

(i) Reduction of the ketone functional group to yield the corresponding diol (caprylyl glycol) with subsequent excretion in urine or bile as conjugate of glucuronic acid;

 

(ii) Oxidation of the terminal hydroxyl group to yield α-ketocarboxylic acid (an intermediary metabolite) which may undergo oxidative decarboxylation to yield carbon dioxide and an aliphatic carboxylic acid which may be completely metabolised via fatty acids and the krebs cycle.

 

According to the available literature, reduction of the ketone group in aliphatic α-hydroxyketones (i.e. metabolic transformation route (i) above) is favoured at elevatedin vivoconcentrations, especially for longer chain length ketones (EFSA, 2014).

 

An overview of the possible biotransformation pathways involved in the metabolism of 1-hydroxyoctan-2-one is provided in the attached Figure 1.

 

It is noted that α-hydroxy ketones (i.e.1-hydroxyoctan-2-one)exist in equilibrium with α-hydroxy aldehydes (i.e. 2-hydroxyoctanal) via enediol keto-enol tautomerism. However the inductive effect caused by the adjacent hydroxyl group intensifies electrophilicity of the α-carbon and increases the rate of enolization and conversion of aldehyde into the more stable keto form which predominates (Vaismaa, 2009). The α-hydroxyl also makes the aldehyde carbon highly reactive, which have been exploited in natural processes. Due to this high reactivity it can be reasonably anticipated that even if the aldehyde form of 1-hydroxyoctan-2-one (i.e. 2-hydroxyoctanal) were to existin vivo, it would be expected (but not proven experimentally) to be subject to oxidation and conversion toα-ketocarboxylic acid (via α-hydroxycarboxylicacid) as shown in the attached Figure 1.

 

In view of its high water solubility, a Log octanol-water partition coefficient (Log Kow) value of 1.68 and anticipated susceptibility to undergo rapid metabolism and elimination processesin vivo, the potential for bioaccumulation of 1-hydroxyoctan-2-one is not considered to be of concern.

References:

EFSA ANS Panel (EFSA Panel on Food Additives and Nutrient Sources added to Food), Mortensen A, Aguilar F, Crebelli R, Di Domenico A, Dusemund B, Frutos MJ, Galtier P, Gott D, Gundert‐Remy U, Leblanc J‐C, Lindtner O, Moldeus P, Mosesso P, Parent‐Massin D, Oskarsson A, Stankovic I, Waalkens‐Berendsen I, Woutersen RA, Wright M, Younes M, Boon P, Chrysafidis D, Gürtler R, Tobback P, Gergelova P, Rincon AM and Lambré C, 2017. Scientific Opinion on the re‐evaluation of fatty acids (E 570) as a food additive. EFSA Journal 2017;15(5):4785, 48 pp.https://doi.org/10.2903/j.efsa.2017.4785

 

EFSA CEF Panel (EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids), 2014. Scientific Opinion on Flavouring Group Evaluation 11, Revision 3 (FGE.11Rev3): Aliphatic dialcohols, diketones, and hydroxyketones from chemical groups 8 and 10. EFSA Journal 2014;12(11):3888, 60 pp.http://www.efsa.europa.eu/en/efsajournal/pub/3888

 

Vaismaa M. (2009). Development of Benign Synthesis of Some Terminal α-Hydroxy Ketones and Aldehydes. Faculty of Science, Department of Chemistry, University of Oulu, P.O. Box 3000, FI-90014 University of Oulu, Finland Acta Univ. Oul. A 532, 2009.http://jultika.oulu.fi/files/isbn9789514291753.pdf

 

WHO (2011a). WHO Food Additives Series: 64. Safety evaluation of certain food additives and contaminants. Prepared by the Seventy-third meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA).

http://apps.who.int/iris/bitstream/handle/10665/44521/9789241660648_eng.pdf?sequence=1&ua=1

WHO (2011b). Evaluation of certain food additives and contaminants. Seventy-third report of the Joint FAO/WHO Expert Committee on Food Additives. Geneva, 8–17 June 2010. WHO Technical Report Series, No 960. WHO, Geneva, Switzerland.

http://apps.who.int/iris/bitstream/handle/10665/44515/WHO_TRS_960_eng.pdf

Description of key information

No specific experimental study data is available on the absorption, distribution, metabolism and/or excretion (ADME) profile of 1-hydroxyoctan-2-one. However, the toxicokinetic behaviour of the substancein vivocan be estimated using physic-chemical properties of the substance combined with data on structurally analogous compounds.

 

In general, aliphatic secondary alcohols and ketones are expected to be rapidly absorbed in the gastrointestinal tract (EFSA, 2014). Specifically, significant absorption and systemic availability of 1-hydroxyoctan-2-one or metabolites after oral administration can be concluded from its moderately high water solubility (9.2 g/L at 20°C), low octanol-water partition coefficient (Log Kow = 1.68) and its relatively low molecular weight (144.2 g/mol). These three physicochemical properties also favour dermal uptake, although the systemic availability of 1-hydroxyoctan-2-one after dermal uptake is considered to be lower than after gastro-intestinal absorption following exposure via the oral route.

 

Although the low octanol-water partition coefficient (log Kow) and the moderately high water solubility, indicate absorption directly across the respiratory tract epithelium by passive diffusion, the risk of exposure by the inhalation route for 1-hydroxyoctan-2-one is considered to be low, because of its relatively low vapour pressure (27 Pa at 20°C).

 

Existing literature data concerning biotransformation pathways for aliphatic ketones and hydroxyketones (EFSA, 2014; WHO 2011a; WHO 2011b), show the potential metabolic reactions involved in the biotransformation of 1-hydroxyoctan-2-one are:

 

(i) Reduction of the ketone functional group to yield the corresponding diol (caprylyl glycol) with subsequent excretion in urine or bile as conjugate of glucuronic acid;

 

(ii) Oxidation of the terminal hydroxyl group to yield α-ketocarboxylic acid (an intermediary metabolite) which may undergo oxidative decarboxylation to yield carbon dioxide and an aliphatic carboxylic acid which may be completely metabolised via fatty acids and the krebs cycle.

 

According to the available literature, reduction of the ketone group in aliphatic α-hydroxyketones (i.e. metabolic transformation route (i) above) is favoured at elevatedin vivoconcentrations, especially for longer chain length ketones (EFSA, 2014).

 

An overview of the possible biotransformation pathways involved in the metabolism of 1-hydroxyoctan-2-one is provided in the attached Figure 1.

 

It is noted that α-hydroxy ketones (i.e.1-hydroxyoctan-2-one)exist in equilibrium with α-hydroxy aldehydes (i.e. 2-hydroxyoctanal) via enediol keto-enol tautomerism. However the inductive effect caused by the adjacent hydroxyl group intensifies electrophilicity of the α-carbon and increases the rate of enolization and conversion of aldehyde into the more stable keto form which predominates (Vaismaa, 2009). The α-hydroxyl also makes the aldehyde carbon highly reactive, which have been exploited in natural processes. Due to this high reactivity it can be reasonably anticipated that even if the aldehyde form of 1-hydroxyoctan-2-one (i.e. 2-hydroxyoctanal) were to existin vivo, it would be expected (but not proven experimentally) to be subject to oxidation and conversion toα-ketocarboxylic acid (via α-hydroxycarboxylicacid) as shown in the attached Figure 1.

 

In view of its high water solubility, a Log octanol-water partition coefficient (Log Kow) value of 1.68 and anticipated susceptibility to undergo rapid metabolism and elimination processesin vivo, the potential for bioaccumulation of 1-hydroxyoctan-2-one is not considered to be of concern.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential