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EC number: 815-461-0 | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Link to relevant study record(s)
- Endpoint:
- basic toxicokinetics
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Not specified
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Study produced using data from results undertaken following OECD and EU test guidelines performed by a GLP accredited laboratory.
- Objective of study:
- toxicokinetics
- Qualifier:
- no guideline required
- Principles of method if other than guideline:
- Summary based upon experimental results of the test substance.
- GLP compliance:
- no
- Radiolabelling:
- no
- Species:
- other: various
- Details on test animals or test system and environmental conditions:
- Various test animals used in the studies which have provided the results for the assessment.
- Route of administration:
- other: various
- Details on exposure:
- Various different exposures routes have been detailed in the assessment based on experiments performed using the test substance
- Duration and frequency of treatment / exposure:
- Various durations and frequency's have been used in the studies which have provided the results for the assessment.
- Remarks:
- Doses / Concentrations:
Various doses/concentrations have been used in the studies which have provided the results for the assessment. - No. of animals per sex per dose / concentration:
- Various numbers animals used in the studies which have provided the results for the assessment.
- Details on study design:
- Various different studies used which have provided the results for the assessment.
- Details on dosing and sampling:
- Various dosing and sampling methods used in the studies which have provided the results for the assessment.
- Conclusions:
- Interpretation of results (migrated information): low bioaccumulation potential based on study results
- Executive summary:
The pentaeryhritol family consists of 13 substances, which are all pentaeryhritol esters with linear and branched carboxylic acids C5-C10. All substances are clear colourless to light yellow liquids.
The acute oral and dermal toxicity tests with the different members of pentaeryhritol family showed the LD50 being high in all cases. For oral administration the LD50 ranged from > 01940 to >5000 mg/kg/day and for dermal administration the LD50 was higher than 2000 mg/kg body weight. The subacute toxicity test for 28 -days revealed a NOAEL ranging from 150 to 1000 mg/g/day. Therefore, an extensive toxicokinetic assessment is considered of limited value. Below, a summary of the anticipated toxicokinetic behaviour of the pentaeryhritol family is given.
The water solubility of the pentaeryhritol family is low (< 01 - < 0.5 mg/l), caused by the presence of the strongly apolar aliphatic chains. Since in general a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract, it is unlikely that the pentaeryhrilol family wil show a high systemic exposure after oral administration. However, in the presence of food and bile salts, the solubility will probably be increased and thus the systemic exposure might be higher. For compounds with a high partition coeffcient like the pentaeryhritol family also direct uptake via the lymph is sometimes observed. It is to be expected that the oral bioavailability, and thus the systemic exposure, of the pentaeryhritol family will be relatively low.
In the case absorption of the pentaeryhritol family occurs, extensive cleavage of the ester bonds is anticipated. The aliphatic chains will probably undergo extensive hydroxylation, followed by rapid sulfation or glucuronidation. The resulting metabolites will be extensively excreted via bile and/or urine.
The pentaeryhritol familywill show a high volume of distribution, because of the high lipophilcity of the compounds. They will be extensively distributed into peripheral tissue,especially fatty tissues. Accumulation in fatty tissues is therefore anticipated. The plasmaprotein binding is expected to be high.
Uptake via inhalation is unlikely because of the relatively large particles.
Since it is generally accepted that substances with log Po/w ranging from 0.1 to 6 penetrate the skin easily, it is to be expected that the pentaeryhritol family in general hardly penetrates theskin.
Based on the expected kinetic behaviour in the body, as described above, the members of the pentaeryhrilol family will hardly be absorbed after oral administration, mainly because of their low solubility. If absorption occurs, these compounds will be extensively metabolised in the liver or plasma and rapidly excreted via bile and/or urine. Therefore, accumulation in the body during prolonged exposure will be very low, although some retention in fatty tissues may occur.
Since the chemical structures of the members of the pentaeryhritol family are strongly comparable, and the physical, chemical, and toxicological data are in a narrow range, it is to be expected that the toxicokinetic behaviour of the different compounds will follow the same pattern.
- Endpoint:
- basic toxicokinetics, other
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 4 (not assignable)
- Rationale for reliability incl. deficiencies:
- other: only secondary data
- Reason / purpose for cross-reference:
- reference to same study
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Study well documented, meets generally accepted scientific principles, acceptable for assessment
- Objective of study:
- absorption
- 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
- 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 / concentration:
- 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.
- Conclusions:
- Mean absorption rate of corn oil combined with palmitic acid was between 57 - 62 %.
- Endpoint:
- basic toxicokinetics in vitro / ex vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Acceptable, well-documented publication meeting basic scientific principles
- Objective of study:
- metabolism
- 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
- Radiolabelling:
- yes
- Remarks:
- Glyceryl trioctanoate-1-14C
- Species:
- human
- Route of administration:
- other: in vitro testing
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Acceptable, well-documented publication meeting basic scientific principles.
- Objective of study:
- absorption
- Principles of method if other than guideline:
- The absorbability of the fatty acid moiety of the complete, oleate esters of alcohols containing from one to six hydroxyl groups was determined by the fat balance technique in adult rats. Similarly, the absorbability of sucrose octaoleate and sucrose monooleate was determined.
- GLP compliance:
- no
- Radiolabelling:
- no
- Species:
- rat
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: no data
- Age at study initiation: young adult
- Weight at study initiation: approx. 200 g
- Housing: Individually in cages with raised screen bottoms
- Diet (e.g. ad libitum): ad libitum - Route of administration:
- oral: feed
- Duration and frequency of treatment / exposure:
- 10 Days, diet ad libitum
- Remarks:
- Doses / Concentrations:
10% and 25 % of dietary fat - Details on absorption:
- The fatty acids of the compounds containing less than four ester groups, methyl oleate, ethylene glycol dioleate, glycerol trioleate, and sucrose monooleate, were almost completely absorbed. As the number of ester groups was increased - erythritol and pentaerythritol tetraoleate and xylitol pentaoleate - the absorbability decreased. The fatty acids of sorbitol hexaoleate and sucrose octaoleate were not absorbed. These differences in absorbability are related to the activity and specificity of the lipolytic enzymes in the lumen of the intestinal tract.
- Conclusions:
- Absorption rates were between 0 an 100 %, depending on the amount of ester groups present in the substance fed. Pentaerythritole tetraoleate had an absorption rate of 90% (10% of dietary fat) and 64% (25% of dietary fat), respectively. Erythritole tetraoleate had an absorption rate of 72% (25% of dietary fat).
- Endpoint:
- basic toxicokinetics
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 4 (not assignable)
- Rationale for reliability incl. deficiencies:
- other: Only secondary data Short review on metabolism from previous publications.
- Objective of study:
- metabolism
Referenceopen allclose all
Lipids are not only structural building blocks of cells and tissues but at the same time suppliers of C atoms for a number of biosynthetic pathways as well as carriers of essential fatty acids and fat-soluble vitamins. In addition, fatty acids are precursors of prostaglandins and other eicosanoids and therefore have important metabolic functions.
Fatty acids can be divided into three groups, saturated, monounsaturated, and polyunsaturated fatty acids.
Each class of fatty acids has a preferential specific role.
- Saturated fatty acids (medium or long-chain) are more devoted to energy supply, but one should not forget their specific structural role.
- The polyunsaturated fatty acids of the n–3 and n–6 families have very important structural and functional roles and ideally should not be utilized for energy purposes.
Table 1:
Role of different classes of fatty acids
Fatty acids |
Energy |
Structure |
Function |
Medium-chain saturated fatty acids |
+++ |
0 |
0 |
Long-chain fatty acids |
|
|
|
Saturated |
++ |
++ |
(+) |
Monounsaturated |
++ |
++ |
(+) |
Polyunsaturated |
|
|
|
Linoleic or n-6 family |
0 |
+++ |
+++ |
Linolenic or n-3 family |
0 |
+++ |
+++ |
0, +, ++, +++ : Emphasis of contribution, increasing in rank order
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.
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 and by zonal scanning were in good agreement.
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.
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.
Discussion:
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.
Test fat |
Percentage of dietary fat |
Absorbability [%] |
Methyl Oleate |
10 |
100 |
25 |
96 |
|
Ethylen Glycol Oleate |
10 |
100 |
25 |
92 |
|
Glycerol Trioleate |
100 |
(100) |
Erythritol Tetraoleate |
10 |
- |
25 |
72 |
|
Pentaerythritol Tetraoleate |
10 |
90 |
25 |
64 |
|
Xylol Pentaoleate |
10 |
50 |
25 |
24 |
|
Sorbitol hexaoleate |
10 |
0 |
25 |
0 |
|
Sucrose Octaoleate |
5 |
0 |
10 |
0 |
|
15 |
0 |
|
Sucrose Monooleate |
5 |
100 |
10 |
100 |
|
15 |
100 |
The metabolism of Medium chain triglycerides in the canine is a process whereby lipases from the buccal cavity and pancreas release the fatty acids in the gastrointestinal tract where they are absorbed. Unlike long chain triglycerides (LCT), where long chain fatty acids (LCFA) form micelles and are absorbed via the thoracic lymph duct, MCFA are most often transported directly to the liver through the portal vein and do not necessarily form micelles. Also, MCFA do not re-esterify into MCT across the intestinal mucosa. MCFA are transported into the hepatocytes through a carnitine-independent mechanism, and are metabolized into carbon dioxide, acetate, and ketones through b-oxidation and the citric acid cycle.
Description of key information
Assessment prepared using studies on test substance and structural analogues.
Key value for chemical safety assessment
- Bioaccumulation potential:
- low bioaccumulation potential
Additional information
The pentaeryhritol family consists of 13 substances, which are all pentaeryhritol esters with linear and branched carboxylic acids C5-C10. All substances are clear colourless to light yellow liquids.
The acute oral and dermal toxicity tests with the different members of pentaeryhritol family showed the LD50 being high in all cases. For oral administration the LD50 ranged from > 01940 to >5000 mg/kg/day and for dermal administration the LD50 was higher than 2000 mg/kg body weight. The subacute toxicity test for 28-days revealed a NOAEL ranging from 150 to 1000mg/g/day. Therefore, an extensive toxicokinetic assessment is considered of limited value. Below, a summary of the anticipated toxicokinetic behaviour of the pentaeryhritol family is given.
The water solubility of the pentaeryhritol family is low (< 01 - < 0.5 mg/l), caused by the presence of the strongly apolar aliphatic chains. Since in general a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract, it is unlikely that the pentaeryhrilol family wil show a high systemic exposure after oral administration. However, in the presence of food and bile salts, the solubility will probably be increased and thus the systemic exposure might be higher. For compounds with a high partition coeffcient like the pentaeryhritol family also direct uptake via the lymph is sometimes observed. It is to be expected that the oral bioavailability, and thus the systemic exposure, of the pentaeryhritol family will be relatively low.
In the case absorption of the pentaeryhritol family occurs, extensive cleavage of the ester bonds is anticipated. The aliphatic chains will probably undergo extensive hydroxylation, followed by rapid sulfation or glucuronidation. The resulting metabolites will be extensively excreted via bile and/or urine.
The pentaeryhritol familywill show a high volume of distribution, because of the high lipophilcity of the compounds. They will be extensively distributed into peripheral tissue,especially fatty tissues. Accumulation in fatty tissues is therefore anticipated. The plasmaprotein binding is expected to be high.
Uptake via inhalation is unlikely because of the relatively large particles.
Since it is generally accepted that substances with log Po/w ranging from 0.1 to 6 penetrate the skin easily, it is to be expected that the pentaeryhritol family in general hardly penetrates theskin.
Based on the expected kinetic behaviour in the body, as described above, the members of the pentaeryhrilol family will hardly be absorbed after oral administration, mainly because of their low solubility. If absorption occurs, these compounds will be extensively metabolised in the liver or plasma and rapidly excreted via bile and/or urine. Therefore, accumulation in the body during prolonged exposure will be very low, although some retention in fatty tissues may occur.
Since the chemical structures of the members of the pentaeryhritol family are strongly comparable, and the physical, chemical, and toxicological data are in a narrow range, it is to be expected that the toxicokinetic behaviour of the different compounds will follow the same pattern.
Justification for grouping of substances and read-across
The polyol esters category comprises of 51 aliphatic esters of polyfunctional alcohols containing two to six reactive hydroxyl groups and one to four fatty acid chains. The category contains mono constituent, multi-constituent and UVCB substances with fatty acid carbon chain lengths ranging from C5 - C28, which are mainly saturated but also mono unsaturated C16 and C18, polyunsaturated C18, branched C5 and C9,branched C14 – C22 building mono-, di-, tri-, and tetra esterswith an alcohol (i.e.polyol). Fatty acid esters are generally produced by chemical reaction of an alcohol (e.g. pentaerythritol, trimethylolpropane or neopentylglycol) with an organic acid (e.g. oleic acid) in the presence of an acid catalyst (Radzi et al., 2005). The esterification reaction is started by a transfer of a proton from the acid catalyst to the acid to form an alkyl oxonium ion. The acid is protonated on its carbonyl oxygen followed by a nucleophilic addition of a molecule of the alcohol to a carbonyl carbon of acid. An intermediate product is formed. This intermediate product loses a water molecule and a proton to give an ester (Liu et al, 2006; Lilja et al., 2005; Gubicza et al., 2000; Zhao, 2000).The final products of esterification of an alcohol and fatty acids are esters ranging from monoesters to tetra-esters.An indication of the general composition is given within the table below (members of the polyol esters category).
In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met. In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests", which includes the use of information from structurally related substances (grouping or read-across).
Keeping in line with the existing OECD category for polyol esters, the polyol ester substances regarded here are considered in one single category based primarily on structural and chemical similarities that result in “close commonalities” in physicochemical and toxicological properties (U.S. EPA, 2010) and having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006.
In order to facilitate the practicability of dealing with such an extensive category, its members were further arranged into three groups on the basis of the alcohol (polyol) moiety of the category members (pentaerythritol (PE), trimethylolpropane (TMP) or neopentylglycol (NPG)).This grouping may also be considered to follow the assumption that the degree of esterification may be associated with a varying rate of enzymatic hydrolysis of the ester bond. However, as the U.S. EPA states within their screening level hazard characterization, “although multiple linked polyols are in general subject to slower rates of enzymatic hydrolysis due to steric hindrance, it is nevertheless expected that they would be fully metabolized over a period of time and thus polyols can be treated and considered as one analogous category, whereby their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity, thus data can be used as read-across from one member to another to address any data gaps” (U.S. EPA, 2010).
The arrangement of polyol esters into three groups enables a clear overview of the similarity of structures and alcohol moiety and this was often used as an aid in finding the structural suitable or similar substance particularly with regard to the environmental effects, in terms of read-across.Nonetheless, all the experimental data confirm that the polyol esters have the same environmental fate and ecotoxicological properties (i.e. low water solubility, low mobility in soil, ready biodegradability, low persistence and low bioaccumulation potential), and no toxicological effects up to the limit of water solubility in aquatic toxicity tests. Likewiseall the category members show similar toxicological properties, and thus follow a similar toxicological profile.None of the category members caused acute oral, dermal or inhalation toxicity, or skin or eye irritation, or skin sensitisation. The polyol esters category members are of low toxicity after repeated exposure. They did not show a potential for toxicity to reproduction, fertility and development and no mutagenic or clastogenic potential was observed.
Members of the polyol esters category
[Please note that the substances given in this table were sorted according to alcohol groups (NPG, TMP, and PE), followed by the degree of esterification, then sorted by increasing chain length and finally by their molecular weight]
ID No. |
CAS |
EC name |
Fatty acid chain length |
Type of Alcohol |
Degree of esterifi-cation |
Molecular Formula |
Molecular weight |
||||||||
1 |
68855-18-5 (a) |
Heptanoic acid, ester with 2,2-dimethyl-1,3-propanediol |
C7 |
NPG |
Di |
C19H36O4 |
328.49 |
||||||||
2 |
31335-74-7 |
2,2-dimethyl-1,3-propanediyl dioctanoate |
C8 |
NPG |
Di |
C21H40O4 |
356.54 |
||||||||
3 |
85711-80-4 |
1,3-Propoanediol, 2,2-dimethyl-, C5-9 carboxylates |
C5-9 |
NPG |
Di |
C15H28O4 |
272.38 – 384.59 |
||||||||
4 |
70693-32-2 |
Decanoic acid, mixed esters with neopentyl glycol and octanoic acid |
C8-10 |
NPG |
Di |
C21H40O45 |
356.54 - 412.65 |
||||||||
5 |
former CAS 85186-86-3 |
Fatty acids, C8-10 (even numbered) and C16 and C18-unsatd., esters with Neopentylglycol |
C8-10 C16-18 C18uns. |
NPG |
Di |
C21H40O4 C25H48O4 C37H72O4 C41H80O4 C41H76O4 |
356.54 – 637.07 |
||||||||
6 |
85186-86-3 |
Fatty acids, C8-18 and C18-unsatd., esters with neopentyl glycol |
C8-18 C18:1 |
NPG |
Di |
C21H40O4 |
356.54 - 633.04 |
||||||||
7 |
85186-95-4 |
Fatty acids, C12-16, esters with neopentyl glycol |
C12-16 |
NPG |
Di |
C29H56O4 |
468.75 - 580.97 |
||||||||
8 |
91031-85-5 |
Fatty acids, coco, 2,2-dimethyl-1,3-propanediyl esters |
C12-14 |
NPG |
Di |
C29H56O4 |
468.75 - 524.86 |
||||||||
9 |
85116-81-0 |
Fatty acids C14-18 and C16-18 unsatd, esters with neopentyl glycol |
C16, C18:1 |
NPG |
Di |
C37H72O4 C41H76O4 |
580.98 - 637.07 |
||||||||
10 |
91031-27-5 |
Fatty acids, C6-18, 2,2-dimethyl-1,3-propanediyl esters |
C6-18 |
NPG |
Di |
C37H72O4 |
580.98 - 637.07 |
||||||||
11 |
42222-50-4 |
2,2-dimethyl-1,3-propanediyl dioleate |
C16-18, C18uns |
NPG |
Di |
C37H72O4 |
580.98 - 633.06 |
||||||||
12 |
67989-24-6 |
9-Octadecenoic acid (Z)-, ester with 2,2-dimethyl-1,3-propanediol |
C18:1 |
NPG |
Di |
C41H76O4 |
633.04 |
||||||||
13 |
85005-25-0 |
Neopentyl Glycol Diisostearate (Fatty acids, C14-18 and C18-unsatd., branched and linear, esters with neopentyl glycol) |
C18iso |
NPG |
Di |
C33H64O4 |
524.86 - 637.07 |
||||||||
14 |
78-16-0 |
2-ethyl-2-[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate |
C7 |
TMP |
Tri |
C27H50O6 |
470.68 |
||||||||
15 |
91050-88-3 |
Fatty acids, C6-18, triesters with trimethylolpropane |
C6-18 |
TMP |
Tri |
C24H44O6; C30H56O6; C36H68O6; C42H80O6; C48H82O6; C54H104O6 |
428.60 – 849.40 |
||||||||
16 |
97281-24-8 |
Fatty acids, C8-10, mixed esters with neopentyl glycol and trimethylolpropane |
C8-10 |
NPG and TMP |
Di/Tri |
C21H40O4 |
356.54 - 596.94 |
||||||||
17 |
189120-64-7 (c) |
Fatty acids, C7-8, triesters with trimethylolpropane |
C7-8 |
TMP |
Tri |
C27H50O6 |
470.68 – 512.78 |
||||||||
18 |
11138-60-6 (d) |
Fatty acids, 8-10 (even numbered), di- and triesters with propylidynetrimethanol |
C8-10 |
TMP |
Tri |
C30H56O6 |
512.78 - 596.94 |
||||||||
19 |
91050-89-4 |
Fatty acids, C8-10, triesters with trimethylolpropane |
C8-C10 |
TMP |
Tri |
C30H56O6 |
512.78 - 596.94 |
||||||||
20 |
85566-29-6 |
Fatty acids, coco, triester with trimethylolpropane, reaction product of coconutoil fatty acids and trimethylolpropane |
C12 C14 C16 |
TMP |
Tri |
C42 H80 O6 |
681.08 - 849.4 |
||||||||
21 |
(Formerly 85186-89-6) |
Fatty acids, C8-10(even), C14-18(even) and C16-18(even)-unsatd., triesters with trimethylolpropane |
C8 C10 C14 C16 C16 C18 C18:2 |
TMP |
Tri |
C30H56O6 C60H110O6 |
512.76 - 933.56 |
||||||||
22 |
403507-18-6 |
Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane |
C16-18, C18uns |
TMP |
Di / Tri |
C38H43O5 |
579.76 - 933.56 |
||||||||
23 |
68002-79-9 |
Fatty acids, C16-18 (even numbered) and C16-18 unsatd. (even numbered), triesters with trimethylolpropane |
C16-18, C18:1 |
TMP |
Tri |
C54H104O6 C60H110O6 C60H116O6 |
849.40 – 933.56 |
||||||||
24 |
(Formerly 85005-23-8) EC 931-531-4 |
Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropane |
C16 C18 C18uns |
TMP |
Di/Tri |
C54H104O6 C60H116O6 C60H116O6 |
849.40 – 933.56 |
||||||||
25 |
91050-90-7 |
Fatty acids, C16-18, triesters with trimethylolpropane |
C16-18 |
TMP |
Tri |
C54H104O6 |
849.40 - 933.56 |
||||||||
26 |
68002-78-8 |
Fatty acids, C16-18 and C18 unsatd., triesters with trimethylolpropane |
C16-18, C18uns |
TMP |
Tri |
C54H104O6 |
849.40 - 933.56 |
||||||||
27 |
(Formerly 57675-44-2) EC 931-461-4 |
Fatty acids, C16-18, even numbered and C18-unsatd. triesters with propylidynetrimethanol |
C16 C18 C18:1 |
TMP
|
Tri |
C54H104O6 |
361 - 932 |
||||||||
28 |
85186-92-1 |
Fatty acids, C16, C18 and C18-unsatd., mixed esters with neopentyl glycol and trimethylolpropane |
C16 C18 C18:1 |
TMP + NPG |
Di/Tri |
C37H68O4 C41H76O4 C54H104O6 C60H110O6 C60H116O6 |
577 - 927.5 |
||||||||
29 |
68541-50-4 |
2-ethyl-2-(((1-oxoisooctadecyl) oxy)methyl)-1,3-propanediyl bis (isoocta decanoate) |
C18iso |
TMP |
Tri |
C60H116O6 |
933.56 |
||||||||
30 |
15834-04-5 |
2,2-bis[[(1-oxopentyl)oxy]methyl] propane-1,3-diyl divalerate |
C5 |
PE |
Tetra |
C25H44O8 |
472.62 |
||||||||
31 |
85116-93-4 |
Fatty acids, C16-18 (even numbered), esters with pentaerythritol |
C16-18 |
PE |
Mono-Tetra |
C21H42O5 |
374.56 - 1201.99 |
||||||||
32 |
85711-45-1 |
Fatty acids, C16-18 and C18-unsatd., esters with pentaerythritol |
C16-18, C18:1 |
PE |
Mono-Tetra |
C21H42O5 |
374.56 – 1193.93 |
||||||||
33 |
25151-96-6 |
2,2-bis(hydroxymethyl)-1,3-propanediyl dioleate |
C18:1 |
PE |
Mono-Tri |
C41H76O6 |
665.04 – 929.48 |
||||||||
34 |
67762-53-2 |
Fatty acids, C5-9 tetraesters with pentaerythritol |
C5-9 |
PE |
Tetra |
C25H44O8 |
472.62 – 697.04 |
||||||||
35 |
(Formerly 68441-94-1) |
Reaction mass of Heptanoic acid 3-pentanoyloxy-2,2-bis-pentanoyloxymethyl-propyl ester, Heptanoic acid 2-heptanoyloxymethyl-3-pentanoyloxy-2-pentanoyloxymethyl-propyl ester and Heptanoic acid 3-heptanoyloxy-2-heptanoyloxymethyl-2-pentanoyloxymethyl-propyl ester |
C5, C7 |
PE |
Tetra |
C27H48O8 |
472.62 - 584.84 |
||||||||
36 |
(Formerly 68424-30-6) |
Tetraesters from esterification of pentaerythritol with pentanoic, heptanoic and isononanoic acids |
C5-9 |
PE |
Tetra |
C25H44O8 |
472.62 – 697.04 |
||||||||
37 |
146289-36-3 |
Pentaerythritol ester of pentanoic acids and isononanoic acid |
C5, C5iso, C9iso |
PE |
Tetra |
C25H44O8 |
472.62 – 697.04 |
||||||||
38 |
68424-31-7 (e) |
Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids |
C5-10 |
PE |
Tetra |
C25H44O8 |
472.62 – 753.14 |
||||||||
39 |
68424-31-7 (f) |
Tetra-esterification products of C5, C7, C8, C10 fatty acids with pentraerythritol |
C5 C7 C8 C10 |
PE |
Tetra |
C25H44O8 |
472.62 - 753.3 |
||||||||
40 |
68424-31-7 (g) |
Fatty acids, C7, C8, C10 and 2-ethylhexanoic acid, tetraesters with pentaerythritol |
C5 C7 C8 C10 |
PE |
Tetra |
C25H44O8 |
472.62 - 753.3 |
||||||||
41 |
71010-76-9 |
Decanoic acid, mixed esters with heptanoic acid, octanoic acid, pentaerythritol and valeric acid |
C5-10 |
PE |
Tetra |
C25H44O8 |
472.62 – 753.14 |
||||||||
42 |
68441-68-9 |
Decanoic acid, mixed esters with octanoic acid and pentaerythritol |
C8-10 |
PE |
Tetra |
C37H68O8 |
640.93 – 753.14 |
||||||||
43 |
85586-24-9 |
Fatty acids, C8-10, tetraesters with pentaerythritol |
C8-10 |
PE |
Tetra |
C37H68O8 |
640.93 – 753.14 |
||||||||
44 |
85049-33-8 |
Fatty acids, C8, C10, C12, C14, C16 esters with pentaerythritol, reaction product of coconut oil fatty acids, C8-C10 fatty acid mix and Pentaerythritol |
C8 C10 C12 C14 C16 |
PE |
Tetra |
C37H68O8 C43H80O8 C45H84O8 C47H88O8 C49H92O8 C51H96O8 C53H100O8 C55H104O8 C57H106O8 C61H116O8 C69H132O8 |
640.95 - 1089.80 |
||||||||
45 |
91050-82-7 |
Fatty acids, C16-18, tetraesters with pentaerythritol |
C16-18 |
PE |
Tetra |
C69H132O8 |
1089.7 -1201.99 |
||||||||
46 |
19321-40-5 |
Pentaerytritol tetraoleate |
C16:1 C18:1 C18:2 |
PE |
Tetra |
C69H124O8 |
1081.72 - 1193.93 |
||||||||
47 |
68604-44-4 |
Fatty acids, C16-18 and C18-unsatd., tetraesters with pentaerythritol |
C18, C18:1, C18:2 |
PE |
Tetra |
C69H132O8 |
1089.78 - 1201.99 |
||||||||
48 |
62125-22-8 |
2,2-bis[[(1-oxoisooctadecyl)oxy]methyl]-1,3-propanediyl bis(isooctadecanoate) |
C14-C22iso |
PE |
Tetra |
C61H116O8 |
977.57 – 1426.42 |
||||||||
49 |
68440-09-5 |
Fatty acids, lanolin, esters with pentaerythritol |
C10-28 |
PE |
Tetra |
C45H84O8 |
753.14 - 1819.16 |
||||||||
50 |
85536-35-2 |
Fatty acids, C5-9, mixed esters with dipentaerythritol and pentaerythritol |
C5-9 |
PE & DiPE |
Tetra |
C25H44O8 |
472.62 - 697.04; 758.98 - 1039.51 |
||||||||
51 |
189200-42-8 |
Fatty acids, C8-10 mixed esters with dipenaterythritol, isooctanoic acid, pentaerythritol and tripentaerythritol |
C8-10 C8iso |
PE & DiPE |
Tetra |
C37H68O8 |
640.93 – 1179.77 |
a) Category members subjected to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font
b) Substances that are either already registered under REACh, or not subject to the REACh Phase-in registration deadline of 31 May 2013, are indicated in normal font
c) As part of the original submission to the U.S. EPA CAS 189120-64-7 was only considered as a supporting chemical nevertheless it is now considered appropriately as a member of the TMP ester group due to its structural homology and similar toxicological properties (U.S. EPA, 2010)
d) Note: decanoic acid, ester with Fatty acids, 8-10 (even numbered), di- and triesters with propylidynetrimethanol (CAS 11138-60-6), was considered by the U.S. EPA not to fit into the above TMP ester group as it was determined to contain an unesterified hydroxyl group and thus would be structurally different from the other category members; however – according to the present specification - this is not the case.The substance CAS 11138-60-6 is specified with >80% triester of C8 and C10.(U.S. EPA, 2010)
e) CAS 68434-31-7 – Lead registrant
f) Separate registration of CAS 68434-31-7
g) Separate registration of CAS 68434-31-7 (2-ethylhexanoic acid)
Grouping of substances into the polyol esters category is based on:
(1) common functional groups: the substances of the category are characterized by ester bond(s) between an polyhydroxy alcohol (e.g., neopentylglycol (NPG), trimethylolpropane (TMP), pentaerythritol (PE)) and one to four carboxylic fatty acid chains. On the basis of the alcohol moiety the polyol esters category is organized into three groups: neopentylglycol, trimethylolpropane, pentaerythritol esters.The fatty acid chains comprise carbon chain lengths ranging from C5 to C28, mainly saturated but also mono unsaturated C16 and C18, polyunsaturated C18, branched C5 and C9, branched C14 – C22 are included into the category.
(2) common precursors and the likelihood of common breakdown products via biological processes, which result in structurally similar chemicals: the members of the category result from esterification of the alcohol with the respective fatty acid(s). Esterification is, under certain conditions, a reversible reaction. Hydrolysis of the ester bond results in the original reactants, alcohol and carboxylic acid. Thus, the alcohol and fatty acid moieties are simultaneously precursors and breakdown products of the category members.
After oral ingestion, polyol esters of the respective polyol and fatty acids will undergo stepwise chemical changes in the gastro-intestinal fluids as a result of enzymatic hydrolysis. In the gastrointestinal (GI) tract, metabolism prior to absorption via enzymes of the gut microflora may occur. In fact, after oral ingestion, fatty acid esters with glycerol (glycerides) are seen to be rapidly hydrolyzed by ubiquitously expressed esterases and the cleavage products are almost completely absorbed (Mattsson and Volpenhein, 1972a). In general, it is assumed that the hydrolysis rate varies depending on the fatty acid chain length and grade of esterification (Mattson and Volpenhein, 1969; Mattson and Volpenhein, 1972a,b). With regard to the polyol esters, a lower rate of enzymatic hydrolysis in the GI tract was observed for compounds with more than 3 ester groups (Mattson and Volpenhein, 1972a,b). In vitro hydrolysis rate of pentaerythritol esters was about 2000 times slower in comparison to glycerol esters (Mattson and Volpenhein, 1972a,b). Moreover, in vivo studies in rats demonstrated the incomplete absorption of the compounds containing more than three ester groups. This decrease became more pronounced as the number of ester groups increased, probably the results of different rates of hydrolysis in the intestinal lumen (Mattson and Volpenhein, 1972c).
Based on this, polyol esters are capable of being enzymatically hydrolysed to generate alcohol and the corresponding fatty acids. NPG, TMP and PE esters may show different rates of enzymatic hydrolysis depending on the number of ester bonds and the alcohol involved. Nevertheless, the metabolic fate of the substances is the same, as it is expected, that all of the polyol ester substances will be hydrolyzed over a period of time. The resulting products are subsequently absorbed into the bloodstream. The fatty acids, as potential cleavage products on the one hand, are stepwise degraded via beta–oxidation in the mitochondria. Even numbered fatty acids are degraded via beta-oxidation to carbon dioxide and acetyl-CoA, with release of biochemical energy. The metabolism of the uneven numbered fatty acids results in carbon dioxide and an activated C3-unit, which undergoes a conversion into succinyl-CoA before entering the citric acid cycle (Stryer, 1994). The alternative pathways of alpha- and omega-oxidation, can be found in the liver and the brain, respectively (CIR, 1987).
Polyols (NPG, TMP and PE) are - due to their physical-chemical properties (low molecular weight, low log Pow, and solubility in water) - easily absorbed and can either remain unchanged (i.e. those with more than three ester groups such as PE) or are expected to be further metabolized or conjugated (e.g. glucuronides, sulfates, etc.) into polar products that are excreted via urine (Gessner et al, 1960; Di Carlo et al., 1965).
(3) constant pattern in the changing of the potency of the properties across the category:
(a) Physico-chemical properties: The molecular weight of the category members ranges from 272.38 (C5 diester with NPG component of 1,3-propanediol, 2,2-dimethyl-, C5-9 carboxylates, CAS 85711-80-4) to 1819.16 g/mol (C28 tetraester with PE component of Fatty acids, lanolin, esters with pentaerythritol, CAS 68440-09-5). The physical appearance is related to the chain length of the fatty acid moiety, the degree of saturation and the degree of esterification. Thus, esters up to a fatty acid chain length of C14 are liquid (e.g. Fatty acids, coco, 2,2-dimethyl-1,3-propanediyl esters, CAS 91031-85-5), above a chain length of C16 esters are solids (e.g. Fatty acids, C16-18, triesters with trimethylolpropane, CAS 91050‑90‑7). Esters with unsaturated or branched longer chain fatty acids (C18:1, C18:2, C18iso) are liquid (Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane, CAS 403507-18-6). For all category members the vapour pressure is low (<0.001 Pa, calculated).The octanol/water partition coefficient (calculated) increases with increasing fatty acid chain length and degree of esterification, ranging from log Pow = 4.71 (C5 diester with NPG component) to log Pow >20 (e.g. C18 triester with TMP component) and above for long chain fatty acid polyesters.This trend is also applicable for log Koc (3.2 to 30.23), with increasing log Koc based on C-chain length. The water solubility for all category members is low (<1 mg/L or even lower); and
(b) Environmental fate and ecotoxicological properties: Considering the low water solubility and the potential for adsorption to organic soil and sediment particles, the main compartment for environmental distribution is expected to be the soil and sediment for all category members. Nevertheless, although they are expected to have a low mobility in soil, persistency in these compartments is not expected since the members of the category are readily biodegradable. Evaporation into air and the transport through the atmospheric compartment is not expected since the category members are not volatile based on the low vapour pressure. Moreover, bioaccumulation is assumed to be low based on available metabolism data. All available experimental data indicate that the members of the polyol esters category are not harmful to aquatic organism as no toxic effects were observed up to the limit of water solubility for any of the category members.
(c) Toxicological properties: The available data indicate that all the category members show similar toxicological properties. No category member showed acute oral, dermal or inhalation toxicity, no skin or eye irritation properties, no skin sensitization. The category members are of low toxicity after repeated oral exposure and are not mutagenic or clastogenic, they have not shown indications for reproduction toxicity or effects on intrauterine development.
The available data allows for an accurate hazard and risk assessment of the category and the category concept is applied for the assessment of environmental fate and environmental and human health hazards.Thus, where applicable, environmental and human health effects are predicted from adequate and reliable data of category members by interpolation to the target substances/member within the category in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, for each specific endpoint the structurally closest category member(s) is/are chosen for read-across, whilst taking regard to the requirements of adequacy and reliability of the available data. A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Section 13).
Basic toxicokinetics
There are no studies available in which the toxicokinetic behaviour ofPentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acidshas been investigated.
Therefore, in accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic behavior of the substancePentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acidswas conducted based on the relevant available information. This comprises a qualitative assessment of the available substance-specific data on physico-chemical and toxicological properties according to ‚Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance‘ (ECHA, 2012) and taking into account further available information on the polyol esters category from which data was used for read-across to cover data gaps.
The UVCB substancePentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acidsis an organic liquid. It is poorly water soluble (< 1 mg/L, Lumsden, 1999) with a molecular weight of 472.62 – 753.14 g/mol, a log Pow of 6.74 - > 10 (Müller, 2013) and a vapour pressure of < 0.0001 Pa at 20 °C (Dr. Knoell, 2009).
Absorption
Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2012).
Oral
The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 g/mol are favorable for oral absorption (ECHA, 2012). As the molecular weight ofPentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acidsis 472.62 – 753.14 g/mol, absorption of the molecule in the gastrointestinal tract is unlikely.
Absorption after oral administration is also unexpected when the “Lipinski Rule of Five” (Lipinski et al. (2001), Ghose et al. (1999)) is applied to the substance Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids as the log Pow value of 6.74 - > 10 is above the given range of ‑0.4 to 5.6.
The log Pow of 6.74 - > 10 of the substance Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids is favourable for absorption by micellar solubilisation, as this mechanism is of importance for highly lipophilic substances (log Pow > 4), which are poorly soluble in water (1 mg/L or less).
In the gastrointestinal (GI) tract, metabolism prior to absorption via enzymes of the microflora may occur. In fact, after oral ingestion, fatty acid esters with glycerol (glycerides) are rapidly hydrolysed by ubiquitously expressed esterases and the cleavage products are almost completely absorbed (Mattson and Volpenhein, 1972a). On the contrary, lower rate of enzymatic hydrolysis in the GI tract was observed for compounds with more than three ester groups (Mattson and Volpenhein, 1972a,b). In vitro hydrolysis rate of pentaerythritol ester was about 2000 times slower in comparison to glycerol esters (Mattson and Volpenhein, 1972a,b).
Moreover in vivo studies in rats demonstrated the incomplete absorption of the compounds containing more than three ester groups. This decrease became more pronounced as the number of ester groups increased, probably the results of different rates of hydrolysis in the intestinal lumen (Mattson and Volpenhein, 1972c).
The available data on oral toxicity of the structurally related substances Fatty acids, C5-10, esters with pentraerythritol (CAS 68424-31-7), Fatty acids, C16-18 (even numbered), esters with pentaerythritol (CAS 85116-93-4), and Fatty acids, C5-9 tetraesters with pentaerythritol (CAS 67762-53-2) are also considered for assessment of oral absorption. Acute oral toxicity studies were conducted at concentrations of 2000 and 15000 mg/kg bw in rats where no signs of systemic toxicity were seen (Robinson, 1991; Potokar, 1983; Zolyniene, 1999; D’Aleo, 1984). No systemic effects were observed in a 28-day repeated dose toxicity study with the structurally related substance Fatty acids, C5-10, esters with pentraerythritol (CAS 68424-31-7) up to and including the highest dose level of 1450 mg/kg bw/day for male rats and 1613 mg/kg bw/day for female rats (Brammer, 1993). Moreover, the structurally related substance Pentaerythritol ester of pentanoic acids , mixed esters with pentaerythritol, isopentanoic and isononanoic acid (CAS No. 146289-36-3) showed no systemic effects up the high-dose group (1000 mg/kg bw/day) in a 90-day repeated dose toxicity study (NOAEL ≥ 1000mg/kg bw/day; Müller, 1998). Therefore, if absorption of the intact parental compound or the respective metabolites occurred, this will result in a low order of systemic toxicity. These results suggest that Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids is of low systemic toxicity, either due to low toxicity potency or by a low absorption in combination with a low systemic toxicity.
In general, after oral ingestion, aliphatic esters of polyhydroxy alcohol (Polyol) and 1 – 6 fatty acids will undergo chemical changes in the gastro-intestinal fluids as a result of slow enzymatic hydrolysis. Pentaerythritol (PE, parental polyol) as well as the fatty acids will be formed, even if according to the available literature hydrolysis is not assumed to be rapid for pentaerythriol- and dipentaerythritol-ester and in general for polyol esters with more than three ester groups (multiple linked polyol esters) probably due to steric hindrance. The in-vitro hydrolysis rate of Pentaerythritol tetraoleate when compared with the hydrolysis rate of the triglyceride Glycerol trioleate was very slow (Mattson and Volpenhein, 1972). The physico-chemical characteristics of the cleavage products (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure, etc.) will be different from those of the parent substance before absorption into the blood takes place, and hence the predictions based upon the physico-chemical characteristics of the parent substance do no longer apply (ECHA, 2012). However, also for both cleavage products, it is anticipated that they will be absorbed in the gastro-intestinal tract.
The highly lipophilic fatty acids will be absorbed by micellar solubilisation (Ramirez et al., 2001). A study by Mattson and Nolen (1972) determined the absorbability of the fatty acid moiety of the complete oleate esters of alcohols containing from one to six hydroxyl groups. The fatty acids of the compounds containing less than four ester groups were almost completely absorbed. As the number of ester groups was increased (erythritol and pentaerythritol tetraoleate and xylitol pentaoleate) the absorbability of the fatty acids decreased but was still present.
The pentaerythritol, having a low molecular weight (136.15 g/mol) and being a highly water-soluble substance (25 g/L, OECD SIDS, 1998), will readily dissolve into the gastrointestinal fluids. After oral administration of 10 mg/kg C14-labled PE to mice, almost half of the administered dose was absorbed from the gastrointestinal tract within 15 minutes (DiCarlo et al., 1965).
In summary, the above discussed physical-chemical properties of Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids and relevant data from available literature on fatty acid esters with more than three ester bonds do not indicate rapid hydrolysis before absorption of Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids to the respective fatty acids and the polyol pentaerythritol.
On the basis of the above mentioned data, a low absorption of the parent substance is anticipated.
Dermal
The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 g/mol favors dermal absorption, above 500 g/mol the molecule may be too large (ECHA, 2012). As the molecular weight of Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids is 472.62 – 753.14 g/mol, a dermal absorption of the molecule is not likely.
If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2012). As Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids was not tested for skin irritation, read-across from Fatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7) (Robinson, 1991) was applied. As the read –across substance is not considered skin irritating in humans an enhanced penetration of the substance due to local skin damage can be excluded.
For substances with a log Pow above 4, the rate of dermal penetration is limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. For substances with a log Pow above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin, and the uptake into the stratum corneum itself is also slow. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis (ECHA, 2012). As the water solubility ofPentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acidsis less than 1 mg/L and log Pow is 6.74 - > 10, dermal uptake is likely to be very low.
The available data on dermal toxicity of the structurally related substances Decanoic acid, mixed esters with heptanoic acid, octanoic acid, pentaerythritol and valeric acid (CAS 71010-76-9) and Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) are also considered for assessment of dermal absorption.
An acute dermal toxicity study was available for Decanoic acid, mixed esters with heptanoic acid, octanoic acid, pentaerythritol and valeric acid (CAS 71010-76-9). At a concentration of 2000 mg/kg bw in rats no signs of systemic toxicity were seen (Mallory, 2006).
In the 90-day repeated dose toxicity study performed with the Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2), no toxicologically relevant effects were noted up to and including the highest dose level of 2000 mg/kg bw/day in male and female rats (Cruzan, 1988).
Overall, the calculated low dermal absorption potential, the low water solubility, the high molecular weight (> 100), the high log Pow values and the fact that the substance is not irritating to skin implies that dermal uptake of Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids in humans is considered to be very low.
Inhalation
Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids has a low vapour pressure of less than 0.0001 Pa at 20°C, thus being of low volatility. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours, gases, or mists is not expected to be significant.
However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the substance is sprayed. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract (ECHA, 2012).
Lipophilic compounds with a log Pow > 4, that are poorly soluble in water (1 mg/L or less) like Pentaerythritol tetraoleate can be taken up by micellar solubilisation. Esterases present in the lung lining fluid may also hydrolyse the substance, hence making the resulting alcohol and fatty acid available for respiratory absorption. Due to the high molecular weight of the substance, absorption is driven by enzymatic hydrolysis of the ester to the respective metabolites and subsequent absorption. However, as discussed above, hydrolysis of fatty acid esters with more than three ester bonds is considered to be slow (Mattson und Volpenhein, 1968, 1972a) and the possibility the test substance to be hydrolysed enzymatically to the respective metabolites and its relative absorption is considered to be low as well.
The available data on inhalation toxicity of the structurally related substances Fatty acids, C5-10, esters with pentraerythritol (CAS 68424-31-7) and Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) are also considered for assessment of inhalation absorption. An acute inhalation toxicity read-across study conducted with Fatty acids, C5-9, esters with pentaerythritol (CAS 68424-31-7; Parr-Dobrzansk, 1994) in rats show no effects of systemic toxicity. In the 90-day repeated dose toxicity study performed with the Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2), no toxicologically relevant effects were noted up to and including the highest dose level of 0.5 mg/L in male and female rats (Dulbey, 1992).
Therefore, respiratory absorption of Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids is considered not to be higher than absorption through the intestinal epithelium.
Overall, a systemic bioavailability of Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids in humans is considered possible after inhalation but is not expected to be higher than following oral exposure.
Accumulation
Generally highly lipophilic substances tend to concentrate in adipose tissue, and depending on the conditions of exposure may accumulate. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, it is generally the case that substances with high log Pow values have long biological half-lives. The high log Pow of 6.74 - > 10 implies that Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids may have the potential to accumulate in adipose tissue (ECHA, 2012).
However, as absorption of Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids is considered to be very low, the potential of bioaccumulation is very low as well.
Nevertheless, as further described in the section metabolism below, Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids will undergo to slow esterase-catalyzed hydrolysis, leading to the cleavage products pentaerythritol and fatty acids.
The log Pow of the first cleavage product pentaerythritol is < 0.3 and it is highly soluble in water (25 g/L) (OECD SIDS, 1998). Consequently, there is no potential for pentaerythritol to accumulate in adipose tissue. The other cleavage products, the fatty acids, can be stored as triglycerides in adipose tissue depots or be incorporated into cell membranes. At the same time, fatty acids are also required as a source of energy. Thus, stored fatty acids underlie a continuous turnover as they are permanently metabolized and excreted. Bioaccumulation of fatty acids only takes place, if their intake exceeds the caloric requirements of the organism.
Overall, the available information indicates that no significant bioaccumulation in adipose tissue of the parent substance and cleavage products is anticipated.
Distribution
Distribution within the body through the circulatory system depends on the molecular weight, the lipophilic character and water solubility of a substance. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA, 2012)
Furthermore, the concentration of a substance in blood or plasma and subsequently its distribution is dependent on the rates of absorption.
As discussed above, absorption ofPentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acidsis considered very low based on its physicochemical characterisation as poor water solubility and high molecular weight.
Nevertheless, esters of pentaerythritol and fatty acids will undergo chemical changes as a result of slow enzymatic hydrolysis, leading to the cleavage products pentaerythritol and the different fatty acids.
The fatty acids are also distributed in the organism and can be taken up by different tissues. They can be stored as triglycerides in adipose tissue depots or they can be incorporated into cell membranes (Masoro, 1977).
Overall, the available information indicates that the cleavage products, pentaerythritol and fatty acids can be distributed in the organism.
Metabolism
On the basis of the properties of the test substance a very low absorption of Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids is anticipated.
As discussed above, hydrolysis of an esterified alcohol with more than three ester groups is assumed to be slow. In in-vivo studies in rats, a decrease in absorption was observed with an increasing esterification grade. For example, for pentaerythritol tetraoleate an absorption rate of 64% and 90% was observed, when ingested at 25% and 10% of dietary fat, respectively, while an absorption rate of 100% was observed for glycerol trioleate when ingested at 100% of dietary fat (Mattson and Nolen, 1972). In addition, it has been shown in-vitro that the hydrolysis rate of pentaerythritol tetraoleate was about 2000 times lower when compared with the hydrolysis rate of the triglyceride Glycerol trioleate (Mattson and Volpenhein, 1972a).
Esters of fatty acids are hydrolysed to the corresponding alcohol and fatty acid by esterases (Fukami and Yokoi, 2012). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the organism: after oral ingestion, esters of alcohols and fatty acids undergo enzymatic hydrolysis already in the gastro-intestinal fluids. In contrast, substances which are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation unchanged before entering the liver where hydrolysis will basically take place. Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids will be hydrolysed to pentaerythritol and fatty acids, even though it was shown in-vitro that the hydrolysis rate of PE esters was lower when compared with the hydrolysis rate of the triglyceride Glycerol trioleate (Mattson and Volpenhein, 1972a).
The first cleavage products, Fatty acids, are stepwise metabolized by beta-oxidation, following the same pattern as other odd carbon number, straight-chain, aliphatic acids (Bingham et al 2001; HSDB, 2013). The metabolism of the uneven fatty acids results in carbon dioxide and an activated C3-unit, which undergoes a conversion into succinyl-CoA before entering the citric acid cycle (Stryer, 1996). The second cleavage product, pentaerythritol, is absorbed rapidly but excreted unchanged. DiCarlo et al. (1965) reported that C14-labeled PE, orally administered at 10 mg/kg to mice, was absorbed to 50% from the gastrointestinal tract within 15 minutes. 68% of the dose appeared as unchanged PE in the urine and faeces after 4 hours.
Excretion
On the basis of the low absorption of the test substance Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids is expected to be excreted via faeces.
However based on the hydrolysis described above, fatty acids and pentaerythritol as breakdown products will occur in the body. The fatty acid components will be metabolized for energy generation, stored as lipids in adipose tissue or used for further physiological properties e.g. incorporation into cell membranes (Lehninger, 1970; Stryer, 1996). Therefore, the fatty acid components are not expected to be excreted to a significant degree via the urine or faeces but excreted via exhaled air as CO2 or stored. The other cleavage product, pentaerythritol is not metabolized but excreted unchanged via urine. 10 mg/kg C14-labled PE orally administered to mice was absorbed from the gastrointestinal tract to almost 50% within 15 minutes. 68% of the dose was excreted via urine and faeces after 4 hours (DiCarlo et al., 1965). The amount found in faeces was assumed to arise from contamination with urine due to the setup of the metabolic cages. Additionally, Kutscher (1948) found 85-87% of unaltered PE in the urine of humans ingesting a radiolabeled PE.
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