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Endpoint:
basic toxicokinetics in vivo
Type of information:
other: Read Across from supporting substance
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented study, meets generally accepted scientific principles, acceptable for assessment.
Objective of study:
absorption
Qualifier:
no guideline followed
Principles of method if other than guideline:
The mechanism of the intestinal fat absorption has been studied with 14C labeled fat in rats with the intestinal lymph duct cannulated.
GLP compliance:
no
Radiolabelling:
yes
Remarks:
14C labeled fat
Species:
rat
Strain:
not specified
Sex:
not specified
Route of administration:
oral: gavage
Vehicle:
corn oil
Duration and frequency of treatment / exposure:
single oral exposure
(at least 18 hours after surgery)
Remarks:
Doses / Concentrations:
A) 0.5 mL corn oil + 2.5 mg active palmitic acid-1-14C
B) 0.5 mL corn oil transesterified with 2.5 mg active palmitic acid-1-14C
C) 0.5 mL hydrolysed corn oil + 2.5 mg active palmitic acid-1-14C
No. of animals per sex per dose:
5-6
Control animals:
no
Details on absorption:
24 hours after administration of the different fats the mean recovered activities in lymph were as following:

A) 0.5 mL corn oil + 2.5 mg active palmitic acid-1-14C: 57.0 %
B) 0.5 mL corn oil transesterified with 2.5 mg active palmitic acid-1-14C: 61.7 %
C) 0.5 mL hydrolysed corn oil + 2.5 mg active palmitic acid-1-14C: 62.3 %

In all three groups of experiments maximum recoveries were found after 24 hours, i.e. 80.9, 85.0 and 87.5 % of the activity given.
Free fatty acids administered alone or together with glycerides appear in the lymph in glycerides and phospholipids.
No free fatty acids or soaps appear in the lymph.
The intestinal wall supplies a quantitatively important part of phospholipids to the blood during fat absorption.
The recoveries in the lymph of the fat fed varied widely. Diarrhea occured in some animals especially after feeding hydrolysed corn oil.
Details on distribution in tissues:
Absorbed fat is mainly transported via lymphatic channels to the systemic circulation whether fed as glycerides or as fatty acids.
Details on metabolites:
A complete hydrolysis of the fat in the intestinal lumen might occur in the rat.

The proportions of neutral fat and phospholipids in the lymph were in all three cases about the same. 90% of the fatty acids were present in the neutral fat and the remaining 10 % in phospholipids. The neutral fat consisted chiefly of triglycerides; cholesterol and cholesterol esters representing only a minor part of this fraction. No free fatty acids or soaps appeared in the lymph.

The results indicated that glycerides might be completely hydrolysed in the intestinal lumen of the rat and then resynthesized in the intestinal wall.

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
Mean absorption rate of corn oil combined with palmitic acid was between 57 - 62 %.
Executive summary:

The mechanism of the intestinal fat absorption has been studied with C14 labelled fat in rats with the intestinal lymph duct cannulated.

It has been found that:

1.    Absorbed fat is mainly transported via lymphatic channels to the systemic circulation whether fed as glycerides or as free fatty acids

2.    Free fatty acids administered alone or together with the glycerides appear in the lymph in glycerides and phospholipids. No free fatty acids or soaps appear in the lymph.

3.    The intestinal wall supplies a quantitatively important part of phospholipids to the blood during fat absorption.

4.    A complete hydrolysis of the fat in the intestinal lumen might occur in the rat.

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
other: Read Across from supporting substance
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented publication meeting basic scientific principles
Objective of study:
metabolism
Qualifier:
no guideline followed
Principles of method if other than guideline:
The lipolytic activity of human gastric and duodenal juice against medium chain and long chain triglycerides was compared.
GLP compliance:
no
Species:
human
Route of administration:
other: in vitro testing
Metabolites identified:
yes
Details on metabolites:
Products of Lipolysis and Positional Specificity:
The specificity of pancreatic lipase for the 1 -ester bond in LCT has been demonstrated previously by establishing the formation of 2 -monoglycerides and fatty acid as end products of lipolysis. This procedure cannot be used for MCT because medium chain 2 -monoglycerides are either cleaved by pancreatic lipase or rapidly isomerized to the 1 -isomer which is rapidly hydrolyzed or both. Indeed, chromatographic examination of the products of hydrolysis of trioctanoin-14C showed only a small fraction of monoglyceride present.

Enzymatic Lipolysis by Gastric and Duodenal Juice:

All samples of gastric juice showed lipolytic activity against trioctanoin and triolein. Hydrolysis of emulsified trioctanoin was greater than of emulsified triolein. Hydrolysis of unemulsified trioctanoin was less and more variable. Duodenal juice was more active, even against unemulsified trioctanoin and triolein. Duodenal juice was more active against unemulsified substrate than gastric juice against emulsified substrate.

Table 1: Hydrolysis of trioctanoin and triolein*

 

Substrate and form

(μmoles)

Hydrolysis (%)

 

Trioctanoin

Triolein

Gastric juice

30, unemulsified

21

1

 

60, emulsified

33

16

Duodenal juice

30, unemulsified

40

34

 

45, emulsified

42

35

 

105, emulsified

45

36

*Gastric or duodenal juice (1 mL) was incubated (1 hour, continuous shaking, 37ºC) with 1 mL of buffer and unemulsified substrate or 1 mL of substrate emulsified in 10 mM sodium taurodeoxycholate, pH6.

pH Optimum

In the presence of bile acids, gastric lipolytic activity against trioctanoin had a broad pH optimum, between 4 and 7. The lipolytic activity of duodenal juice had a sharper pH optimum, between 6 and 8. The pH optimum was lower for short chain triglycerides, indicating that pH optimum values for lipases must be defined for a particular substrate.

Chain Length Specificity

Lipolysis rates increased with decreasing chain lengths for pure triglycerides.

Tributyrin was cleaved more rapidly than trihexanoin which in turn was cleaved more rapidly than trioctanoin (ratio of rates, 100:69:53). Because the pH optimum of gastric lipase is lower for short chain triglycerides than for MCT, trihexanoin and tributyrin were cleaved much more rapidly than, for example, trioctanoin at pH5.

Esterification and Fatty Acid Acceptors by Gastric and Duodenal Lipases

Gastric and duodenal lipases did not induce esterification of the fatty acid acceptor, glyceryl 2 -monooleyl ester, by octanoic acid over the pH range of 2 to 6. However, it was esterified by oleic acid in the presence of gastric juice, duodenal juice, or pancreatic fistula juice when bile acids were added. Esterification, calculated by disappearance of titratable fatty acid, was confirmed by TLC which showed the formation of compounds having the mobilities of a monoether monoester and a monoether diester. Control incubations without enzyme showed no loss of oleic acid or appearance of new lipids by TLC. To determine the amount of disubstituted and trisubstituted glyceryl derivatives which were formed, 14C-labeled glyceryl 2 -monooleyl ether was used and the products of the reaction were examined by zonal scanning. The glyceryl 2 -monooleyl ether was not cleaved during the incubation procedure. The amounts of ester bonds formed estimated by titration an by zonal scanning were in good agreement.

Table 2: Products of hydrolysis of trioctanoin by gastric juice*

 

Radioactivity distribution** (%)

Lipolysis

(%)

 

Monoglyceride

Diglyceride

Fatty acid

Triglyceride

Buffer (control)

0

0

0

100

0

Gastric juice

1 mL

3

26

26

44

34

3

28

24

43

33

4

28

25

43

36

4

28

25

43

36

Duodenal juice

 

 

 

 

 

0.4 mL

4

9

15

72

26

0.5 mL

4

14

20

62

40

*Glyceryl trioctanoate-1-14C was added to 1 mL of emulsified trioctanoin (60 μmoles) and incubated for 1 hour at 37ºC with buffer (blank) or gastric or duodenal juice. The reaction mixture was extracted and a 50 μL aliquot was analyzed by TLC and zonal scanning. A 3 mL aliquot was titrated to quantify fatty acids liberated.

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
Executive summary:

The lipolytic activity of human gastric and duodenal juice against medium chain and long chain triglycerides was compared. The work confirmed extensive literature showing that gastric juice contains lipolytic activity, that ingested triglyceride is hydrolyzed in the stomach, even after pancreatic diversion, that lipase may be demonstrated histochemically in gastric mucosa, and that gastric mucosal homogenates have lipolytic activity. Pancreatic lipase has some activity at the pH of gastric content, which is between pH6 and pH3 in normal subjects.

Endpoint:
basic toxicokinetics in vivo
Type of information:
other: Read Across from supporting substance
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented publication meeting basic scientific principles.
Objective of study:
absorption
Qualifier:
no guideline followed
Principles of method if other than guideline:
Triglycerides of known structure were fed to rats, and the distribution of the fatty acids in the triglycerides of the lymph was determined.
GLP compliance:
no
Radiolabelling:
yes
Remarks:
C14 labelled
Species:
rat
Strain:
not specified
Sex:
male
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
with 18.5% skim milk solids, 20% sucrose, 1.8% salt mix and 27.2% fat.
No. of animals per sex per dose:
3
Details on absorption:
The extent of absorption of palmitic acid depended on the form in which it was fed (rates between 52 an 96 %).
Absorption was greatest when palmitic acid was fed as β-palmitoyl diolein, and least when it was fed as the free acid.
Details on metabolites:
The results obtained showed that 85 to 90% of the fatty acids occupy the same position on the lymph triglyceride molecule as they did on the dietary triglyceride molecule before the processes of digestion and absorption.

Table 1:

Specific activity of lymph triglycerides as percentage of specific activity of fed lipids

Fat fed

%*

Oleic acid (2 moles) and 1 mole of palmitic-1-C14acid

64, 73, 71

Linoleic acid (2 moles) and 1 mole of palmitic-1-C14acid

58, 58, 63

Palmitate-oleate-oleate triglyceride

85, 85, 81

Oleate-palmitate-oleate triglyceride.

94, 96, 92

Oleic acid (2 moles) as triolein and 1 mole of palmitic-1-C14acid

59, 54, 54

Linoleic acid (2 moles) as trilinolein and 1 mole of palmitic-1-C14acid

52, 54, 53

*Each value is the percentage obtained in a single experiment

Conclusions:
Absorption rates were between 52 and 96 %, depending on the lipid fed.
Executive summary:

Rats were fed glyceryl α-[palmitate-1- C14] dioleate, glyceryl β-[palmitate-1- C14] dioleate, a mixture of oleic or linoleic acid and palmitic-1-C14acid, or a mixture of triolein or trilinolein and palmitic-1- C14acid. The position of the palmitic acid on the glycerol in the triglycerides of the lymph was determined.

When the mixtures of free acids were fed, the palmitic acid was essentially randomly distributed among all three positions of the lymph triglyceride molecules. From 85 to 90% of the palmitic acid in the dietary mixed triglycerides was found in its original position on the triglyceride molecule after the processes of digestion and absorption.

When the mixtures of triglyceride and free palmitic acid were fed, 22% of the palmitic acid in the lymph triglycerides was found to be esterified with the β position. The extent of absorption of palmitic acid depended on the form in which is was fed. Absorption was greatest when palmitic acid was fed as β-palmitoyl diolein and least when it was fed as the free acid.

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).

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
other: Read Across from supporting substance
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:
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).

Endpoint:
basic toxicokinetics in vivo
Type of information:
other: Read Across from supporting substance
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:
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).

Description of key information

There is no toxicokinetics information available on neopentyl glycol dipelargonate.

There are studies available on similar structures, which indicate that the bioaccumulation potential is likely to be low.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information