Carboxylic acids, C5-9

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: review

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Only secondary literature (review)

Objective of study:

absorption

distribution

excretion

metabolism

Principles of method if other than guideline:

not applicable; review article

GLP compliance:

not specified

Radiolabelling:

no

Details on absorption:

The molecular weight of MCTs is smaller than the molecular size of long-chain triglycerides (LCTs) which facilitates the action of pancreatic lipase. Threfore, MCTs are hydrolysed faster and more completely than LCTs. The hydrolysis prodcuts are rapidly absorbed, mainly as free fatty acids

Details on distribution in tissues:

MC fatty acids are absorbed and trnsported to the liver via the portal vein in teh solubl eform of free fatty acids, bound to serum albumin.

Metabolites identified:

yes

Details on metabolites:

MC fatty acids cross the double mitochondrial membrane rapidly, and are acylated to the acyl-coA which undergo rapid ß-oxidation, with production of acetyl-CoA. Acetly-CoA can enter various anabolic (synthesis of fattay acids, cholesterol etc.) or catabolic (degradation) biochemical pathways. Oxidation in the Krebs cycle leads to the terminal metabolites, carbon dioxide and water.

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
MCTs are rapidly hydrolysed an liberate free fatty acids which are rapidly absorbed and transported to the liver where they are rapidly metabolised to acetyl-CoA (fatty acids with odd number of carbons give one terminal propionyl-CoA) that ma y enter anabolic or catabolic biochemical pathways.

Executive summary:

Medium chain fatty acid triglycerides (MCT) are rapidly hydrolysed to the free fatty acids and glycerol. The fatty acids are then rapidly transported to the liver where primarily mitochondrial metabolism takes place. Acetyl-CoA produced during ß-oxidation may be utilised for biosynthesis or for energy supply. The terminal metabolites are water and carbon dioxide (Bach and Babayan 1982; see also CLH reports (Austria, 2001 and 2012) on octanoic, nonanoic, and decanoic acids [see assessment reports in section 13], Papamandiaris et al. 1998; Traul et al. 2000 [section 13].

MCT are used in patients who need parenteral infusions, or in the treatment of obese because the caloric contents of MCT is less than that of dietary fats and oils. No adverse effects were seen in MCT safety studies even at high doses, nor in treated patients. The therapeutic effect (body weight reduction) was, however, found to be questionable (Papamandiaris et al. 1998).

Reference 2

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2000

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Handbook, secondary source

Objective of study:

metabolism

Principles of method if other than guideline:

no guideline required

GLP compliance:

not specified

Radiolabelling:

not specified

Species:

other: mammalian species

Strain:

not specified

Sex:

not specified

Route of administration:

other: no data

Vehicle:

not specified

Details on exposure:

no data

Duration and frequency of treatment / exposure:

no data

Remarks:

Doses / Concentrations:
no data

No. of animals per sex per dose / concentration:

no data

Control animals:

not specified

Metabolites identified:

not specified

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
The test substance is metabolised in the liver via ß-oxidation. There was no accumulation in tissues.

Executive summary:

Nonanoic acid is metabolized in the liver via beta-oxidation, producing ketone bodies. No chain elongation or tissue storage of the acid was observed in rats. Metabolism of the terminal propionic acid residue resulted in increased glucose and glycogen synthesis (Cragg, 2001).

Reference 3

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1970

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented publication which meets basic scientific principles

Objective of study:

metabolism

Principles of method if other than guideline:

no guideline required

GLP compliance:

not specified

Radiolabelling:

not specified

Species:

rat

Strain:

Wistar

Sex:

female

Route of administration:

other: in vitro perfused liver

Vehicle:

not specified

Duration and frequency of treatment / exposure:

single

Remarks:

Doses / Concentrations:
5 mM

No. of animals per sex per dose / concentration:

4 per group

Control animals:

yes, concurrent vehicle

Metabolites identified:

not specified

Liver perfusion with a 5 mM solution of the test substance increased the amount of ß-hydroxybutyrate, acetoacetate and glucose. acetoacetate. The formation of ketone bodies (sum of ß-hydroxybutyrate and acetoacetate) increased (and also the ratio of hydroxybutyrate to acetoacetate). The following table shows the corresponding mean values and standard deviations.

	ß-hydroxybutyrate (µmol/h/g)	Acetoacetate (µmol/h/g)	Total ketone bodies formation (µmol/h/g)	Glucose (µmol/h/g)
Control	19.6 ± 1.9	10.8 ± 0.9	30.4 ± 3.3	8.4 ± 1.6
5 mM	47.3 ± 7.6	32.8 ± 4.2	103 ± 12	16.8 ± 1.8

Conclusions:

Interpretation of results (migrated information): no data
The test substance produced biochemical alterations in the perfused rat liver.

Executive summary:

The perfusion of rat liver with a 5 mM solution of the test substance increased the amount of ß-hydroxybutyrate, acetoacetate and glucose. The formation of ketone bodies increased as well as the ratio of hydroxybutyrate to acetoacetate (Krebs, 1970).

Reference 4

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1998

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Review, secondary source

Objective of study:

metabolism

Principles of method if other than guideline:

no guideline required

GLP compliance:

not specified

Radiolabelling:

not specified

Species:

other: mammalian species

Strain:

not specified

Sex:

not specified

Route of administration:

oral: unspecified

Vehicle:

not specified

Duration and frequency of treatment / exposure:

no data

Remarks:

Doses / Concentrations:
no data

No. of animals per sex per dose / concentration:

no data

Control animals:

not specified

Details on absorption:

Like other linear aliphatic carboxylic acids, nonanoic acid can be assumed to be readily absorbed from the intestine.

Metabolites identified:

not specified

Like other linear aliphatic carboxylic acids, nonanoic acid can be assumed to be readily absorbed from the intestine.

As a common fatty acid, nonanoic acid will undergo biotransformation in 

established metabolic pathways (oxidation and tricarboxylic pathway). Degradation products will either be 

exhaled as CO2 or recycled within the intermediary metabolism.

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Nonanoic acid is readily absorbed after oral uptake, metabolised and excreted or used in intermediary metabolism.

Executive summary:

Like other linear aliphatic carboxylic acids, nonanoic acid can be assumed to be readily absorbed from the intestine.

As a common fatty acid, nonanoic acid will undergo biotransformation in 

established metabolic pathways (oxidation and tricarboxylic pathway). Degradation products will either be 

exhaled as CO2 or recycled within the intermediary metabolism (WHO, 1998).

Reference 5

Endpoint:

basic toxicokinetics

Type of information:

other: review

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Secondary literature (review, tables, book)

GLP compliance:

no

Radiolabelling:

no

Species:

other: several (review article)

1. Introduction

 

Fatty acids are aliphatic, saturated carbon acids with non-branched carbon chains. Pelargonic Acid is a fatty acid with nine carbons:

 

CH₃(CH₂)₇COOH.

 

As all fatty acids, Pelargonic Acid is present in nature and has been found in various plants as well as in a variety of animal fats and foods of animal origin. The absorption, distribution, metabolism and excretion characteristics are well known and described in medical and biochemical text books. A brief summary is given below. .

 

2. Absorption

 

Non-esterified short-chain fatty acids, like Pelargonic Acid, are rapidly absorbed from the lumen of the intestine directly into the portal blood stream. This entry is sodium-dependent and can take place against concentration gradient by a process of active transport (Bell et al. 1976).

 

Fats, however, are not able to pass as such the intestine brushborder cells. They must be emulsified by bile salts and then undergo lipolysis under the influence of pancreatic lipase (Bell et al. 1976). By the breakage of the triglyceride at the two primary positions, fatty acids and monoglycerides will be formed. They are able to form water soluble micelles, with the polar, hydrophilic hydroxyl- and carboxyl-groups facing outwards and the hydrophobic moieties directed inwards. In this form, the micelles passively transported into cells with the aid of bile acis, either by dissolving in the membrane or by pinocytosis.

Most fats are between 95 and 100% digestable. Longer-chain fatty acids are less well absorbed than shorter-chain fatty acids (Guthrie and Andrews 1975). In the case of Pelargonic Acid complete and rapid absorption can be expected. A profound description of the involved enzymatic processes is given by Orten and Neuhaus (1975).

 

3. Distribution

 

About 70% of the absorbed micelles are resynthesized immediately to form triglycerides (Guthrie and Andrews 1975), starting with the fatty acid activation to fatty acyl-CoA derivatives. These react with L-alpha-glycerophosphate to yield glyceride phosphates which then are hydrolyzed to form the corresponding glycerides. The enzymatic steps are described in detail by Orten and Neuhaus (1975).

 

Further transportation follows in at least three forms, as

-      chylomicrons (aggregates of triglycerides (80%), phospholipids (7%) and cholesterol (9%) which are “coated” with lipoproteins)

-      lipids associated with proteins as lipoproteins

-      non-esterified fatty acids (NEFA) loosely bound to albumin.

 

Chilomicrons and lipoproteins are predominantly are transported from the intracellular fluid into the lacteal and the lymphatics, and finally into the systemic blood stream (Orten and Neuhaus 1975).

 

Non-esterified fatty acids (NEFAs) are mainly transported through the portal blood system loosely bound to plasma albumin (Orten and Neuhaus 1975). While the amount of NEFAs in the plasma is very small (0.1-0.3 g/L in fasting adults), they apparently represent the mobile form for oxidation to meet energy needs. They have an exceedingly high turnover rate, with a half-life of only 2 to 3 minutes (Orten and Neuhaus 1975).

 

A large proportion of absorbed fat is carried to the liver, the chief site for its metabolic disposal. Triglycerides entering the liver as chilomicrons are hydrolyzed to their constituent fatty acids and glycerol. Both compounds may be utilized to form phospholipids and lipoproteins. The lipoproteins, which can contain 55 to 90% fat,  facilitate the transport of fat throughout the body where it is used as a source of energy or may be stored in the fat depots of each cell, or in special adipose cells, for future use (Guthrie and Andrews 1975). Fat is either oxidized - mainly in the liver and muscles - or is stored – mainly in the subcutaneous or retroperitoneal adipose tissues (Bell et al. 1972).

 

4. Metabolism

 

Fatty acids are utilized as a carbon source (biosynthesis of long-chain fatty acids, phospholipids and other lipids, amino acids, steroids etc.) and as a source of energy (oxidation to CO₂and acetyl CoA and further to CO₂and water). Biosynthesis and degradation occur by separate pathways and in different compartments. Biosynthesis is located in the cytoplasma and β-oxidation in mitochondria. Thus, both processes can occur simultaneously according to needs.

 

Acetyl-CoA from fatty acids (or from pyruvate) may be regarded as the main central metabolite of many various substance classes. A multienzyme complex (fatty acid synthetase) catalyzes long-chain saturated fatty acids from acetyl-CoA, malonyl-CoA and reduced nicotinamide-adenine-dinucleotide phosphate (NADPH) according to the following stoichometric biosynthesis, e.g. for palmitate:

 

CH₃CO – SCoA + 7HOOCCH₂CO – SCoA + 14NADPH + 14H⁺→ CH₃(CH₂)₁₄CO₂H + 7CO₂+ 14NADP⁺+ 8CoA + 6H₂O.

 

The stepwise following synthesis is described in detail (Orten and Neuhaus 1975, and by Thabrew and Ayling 2001). The authors give also details on the formation of other substance classes.

 

The oxidative degradation of fatty acids is a universal biochemical capability among living organisms. Fatty acids are the form in which fat is liberated from the depots. Albumin carries the fatty acids in the bloodstream to other tissues, like liver, heart, and kidneys (Zubay 1983). Intracellularly, fatty acid oxidation occurs principally in the mitochondria; ß-oxidation is the normal mechanism, in which two-carbon units are sequentially removed beginning from the carboxyl-terminal end (Orten and Neuhaus 1975). The pathway for the oxidation of fatty acids is illuistrated in Figure 1 of the attached document. The parent even-numbered fatty acid is activated by conversion to the fatty acyl-CoA, oxidized to the alpha, beta-unsaturated compound, hydrated, oxidized to the beta-keto derivative, and finally subjected to a thiolytic cleavage yielding acetyl-CoA and the fatty acyl-CoA containing two less carbon atoms, which, in turn, undergoes the same series of reactions (Mahler and Cordes 1971). Each of these steps is exhaustively described by the a.m. authors and by Bell et al. 1972. A detailed chapter on the enzymology of beta-oxidation is written by Zubay 1983.

 

Oxidation of fatty acids with an odd number of carbons: The sequence of reactions as summarized above for the oxidation of even-numbered fatty acids is also applicable to the oxidation of those with an odd number of carbon atoms. Consequently, straight-chain fatty acids with e.g. 9 carbons are oxidized by the normal ß-oxidation sequence and give rise to 3 acetyl-CoAs and 1 propionyl-CoA:

 

            CH₃CH₂C-CoA

 

The propionyl-CoA is converted to succinyl-CoA (as indicated in Fig. 2 of the attached document) which can be further metabolized in the tricarboxylic acid cycle, finally to yield CO₂and water. Two other pathways for the utilization of propionyl-CoA finally to form acetyl-CoA have been described by Mahler and Cordes 1971 and are also depicted in Fig 2.

 

 

5. Excretion

 

As a result of β-oxidation, which represents the by far major pathway for the metabolism of fatty acids, long-chain fatty acids are stepwise degraded to short-chain fatty acids and these to succinyl CoA resp. acetyl-CoA plus CO₂. These compounds are further oxidated via the citric acid cycle to CO₂ and water. No other ultimate excretion products than CO₂and water will be formed.

6. References: cf. attached document

 

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Pelargonic acid is an odd-numbered naturally occurring fatty acid. Abbsorption, distribution, metabolism and excretion is very similar across all fatty acids. ß-oxidation is the main metabolic pathway where odd-numbered fatty acids like pelargonic acid finally lead to propionyl-CoA. This is further metabolised to CO2 and water in the intermediary metabolism, similar to acetyl-CoA which results from the even-numbered fatty acids.

Executive summary:

Like all other naturally occurring fatty acids, pelargonic acid is utilized as food substrate for virtually all life forms including bacteria, fungi, algae, plants, animals and human beings. Fatty acids are required for teh organism's energy supply and biosynthesis of a variety of biomolecules including adipose and membrane lipids.

Absorption takes place through the cell membranes of the intestinal brush border cells of the jejunum, regardless of whether the fatty acid moiety is ingested as free fatty acid, as a salt or as a component of lipids. Short and intermediate chain fatty acids, like pelargonic acid, are absorbed directly and rapidly from the intestinal lumen into the portal circulation where they are bound to serum proteins and are transported to the liver and other tissues.

 

ß-oxidation in the mitochondria is the main metabolic pathway. Even-numbered fatty acids are degraded via ß-oxidation to CO₂ and acetyl-CoA, under the release of biochemical energy. Odd-numbered fatty acids like pelargonic acid are similarly decomposed to CO₂ and propionyl-CoA. The latter undergoes further degradation to succinyl-CoA resp. acetyl-CoA. These compounds are oxidized via the citric acid cycle to CO₂ and water. No other ultimate excretion products than CO₂ and water will be formed (GAB Consulting, 2003)

 

 

Description of key information

Fatty acids, main constituents of this UVCB substance, are typically unbranched, with different chain length. They are found in all living organism fulfilling three fundamental roles. Besides their function as part of molecules like phospholipids and glycolipids important for the cell-structure, they are often precursors of signalling molecules such as prostanoids in animals or phytohormones in plants. The third and best understood role of fatty acid is their role as an energy source, particularly in higher animals and plants. According the available data in the literature, fatty acids are almost completely absorbed after oral intake, whereas only limited dermal uptake has to be expected. The major metabolic pathway for linear fatty acids is the β-oxidation pathway for energy generation, while alternatives are the α- and ω-oxidation. Besides this, fatty acids are stored as lipids in adipose tissue, used as part of cellular membranes, as well as precursors for signalling molecules and even long chain fatty acids. It can be summarized:

Rapid absorption of free fatty acids from the gut following ingestion of either natural or synthetic (MCT) fats and oils or of free fatty acid or its salt.

Rapid and complete metabolism in the liver, with no other metabolites than carbon dioxide and water.

No bioaccumulation.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Additional information

Pelargonic acid, the main constituent of the target substance, is a naturally occurring fatty acid (see also the assessment of the Marin Municipal Water District in section 13), and pelargonic acid esters are used as a food flavoring substance (cf. WHO Technical Report No. 868 in section 13). Like all other naturally occurring fatty acids, pelargonic acid is utilized as food substrate for virtually all life forms including bacteria, fungi, algae, plants, animals and human beings (Zschintzsch, 2003). Fatty acids are required for the organism's energy supply and biosynthesis of a variety of biomolecules including adipose and membrane lipids.

 

In mammals and humans, absorption takes place through the cell membranes of the intestinal brush border cells of the jejunum, regardless of whether the fatty acid moiety is ingested as free fatty acid, as a salt or as a component of lipids. Short and intermediate chain fatty acids, like pelargonic acid, are absorbed directly and rapidly from the intestinal lumen into the portal circulation where they are bound to serum proteins and are transported to the liver and other tissues (Zschintzsch, 2003).

 

ß-oxidation in the mitochondria is the main metabolic pathway (Zschintzsch, 2003; Cragg, 2001; WHO, 1998). Even-numbered fatty acids are degraded via ß-oxidation to CO₂and acetyl-CoA, under the release of biochemical energy. Odd-numbered fatty acids like pelargonic acid are similarly decomposed to CO₂and propionyl-CoA. The latter undergoes further degradation to succinyl-CoA resp. acetyl-CoA. These compounds are oxidized via the citric acid cycle to CO₂and water. No other ultimate excretion products than CO₂and water will be formed. Thus, pelargonic acid or metabolites thereof are unlikely to accumulate (Zschintzsch, 2003).

 

Medium Chain fatty acid Triglycerides (MCT) represent another source of fatty acids. The fatty acid composition may vary from one MCT to the other MCT preparation. MCT are rapidly hydrolysed to the free fatty acids and glycerol. The fatty acids are then rapidly transported to the liver where primarily mitochondrial metabolism takes place. Acetyl-CoA produced during ß-oxidation may be utilised for biosynthesis or for energy supply. The terminal metabolites are water and carbon dioxide (Bach and Babayan 1982; see also CLH reports (Austria, 2001 and 2012) on octanoic, nonanoic, and decanoic acids [see assessment reports in section 13], Papamandiaris et al. 1998; Traul et al. 2000 [section 13].

MCT are used in patients who need parenteral infusions, or in the treatment of obese because the caloric contents of MCT is less than that of dietary fats and oils. No adverse effects were seen in MCT safety studies even at high doses, nor in treated patients. The therapeutic effect (body weight reduction) was, however, found to be questionable (Papamandiaris et al. 1998).