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EC number: 940-005-3 | 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
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics
- Type of information:
- other: Assessment of the toxicokinetic behaviour as can be derived from the available information
- Adequacy of study:
- weight of evidence
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 2 007
Materials and methods
- Principles of method if other than guideline:
- Review of reports summarized in the dataset
- GLP compliance:
- not specified
Test material
- Reference substance name:
- NLP polyols
- IUPAC Name:
- NLP polyols
Constituent 1
Results and discussion
Toxicokinetic / pharmacokinetic studies
- Details on absorption:
- Given the vapor pressure and the logP of the test substance (0.000295 Pa at 25°C, and >6.2, respectively), it is likely that inhalation of the vapor will be limited. In addition, the logP value of >6 indicates limited absorption across the skin, as stated in ECHA’s Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance, Table R.7.12-3.
It is likely that, following oral administration, the hydrolysis products derived from sucrose oligomers will rather be absorbed than the oligomers themselves. If the parent substance is absorbed, this would likely take place in the stomach. Shigeoka et al. (1984) have examined the absorption of esters of sucrose and fatty acids in vitro and in vivo (in rats). The results of this investigation suggest that hydrolysis to sucrose and fatty acid is needed for absorption.
Absorption decreases with increasing size of polyol, thus it is possible that, if any, only limited amounts of the smaller polyols may be absorbed orally, presumably by passive diffusion (Illing and Barratt, 2007).
It can be anticipated that propoxylated glycerol is well absorbed, similarly to nutritional triglycerides. Glycerol is presumably absorbed by facilitated diffusion during the absorption of dietary fats. Propane-1,2-diol oligomers are probably absorbed by passive diffusion. The short chain (1-6.5 mol) NLP polyols are likely to behave in a manner similar to fats of short chain fatty acids (i.e. those of C8 or less), which are not absorbed by facilitated diffusion. Mu and Hoy (2000) established that the accumulated lymphatic transport of triacylglycerols of medium chain fatty acids increased with increasing carbon length over the C8 to C10 to C12 (from ~7% to ~26% to ~82%) in rats. This implies that the NLP polyols of propoxylated glycerol, if absorbed, are likely to be absorbed by passive diffusion (Illing and Barratt, 2007).
Oleic acid and linoleic acid have low vapor pressures (<0.1 mbar and 16 mbar, respectively) and are practically insoluble in water, with log Pows of 7.64 and 7.05, respectively (Sangster, 1989). In the form of their glycerides, oleic acid and linoleic acid are natural constituents of plant and animal fats and are therefore subject to normal fatty acid metabolism. Like other free fatty acids, they are absorbed by the intestinal walls where they are converted to triglycerides. The triglycerides are transported in lipoproteins in serum or in chylomicrons in the lymphatic vessels and are stored in adipose tissue or metabolized. Like all fatty acids, oleic acid and linoleic acid are degraded metabolically via β-oxidation.
The species Disaccharide + (oleic acid/linoleic acid – H2O) + 10x PO can be anticipated to not be readily absorbed dermally due to its high molecular weight of approx. 1190 g/mol (ECHA guidance, Chapter R.7c, Table R.7.12-3). Hydrolysis products can be expected to be absorbed orally and find their way into endogenous pathways of fatty acid and carbohydrate metabolism.
Sources:
Shigeoka, T, Izawa, O, Kitazawa, K, Yamamuchi, F, Murata, T (1984). Studies in the fate of sucrose esters in rats. Food Chem Toxicol 22, 409-414.
Illing, H.P.A., and Barratt, M.D. (2007). Grouping of NLP ‘Polyols’ and their toxicokinetics assessments. Prepared for European Diisocyanate and Polyols Producers Association. (ISOPA, unpublished report).
Miller, K W, Lawson, K D, Tallmadge, D H et al (1995). Disposition of ingested Olestra in the Fischer 344 rat. Fundamental Appl Toxicol 24(2), 229-237.
Mu, H, Hoy, C E (2000). Effects of different medium chain fatty acids on intestinal absorption of structured triacylglycerols. Lipids 35, 83-89.
Sangster, J., J. (1989). Octanol-Water Partition Coefficients of Simple Organic Compounds. Phys. Chem. Ref. Data, 18(3), 1111 - Details on distribution in tissues:
- Given the logP value of the test substance, it is likely that any absorbed compounds will be distributed into cells (ECHA guidance, Chapter R.7c, Table R.7.12-3).
- Details on excretion:
- In the unlikely event that unmetabolized higher molecular weight material is absorbed, it is likely to be excreted in bile. In rats, the molecular weight threshold for biliary excretion is around 350, in humans it is about 500 (Illing, 1989). The material most likely to be absorbed is likely to be hydrolyzed and the products appear in urine, except when the end point of metabolism is carbon dioxide. Carbon dioxide will be exhaled (Illing and Barratt, 2007).
Sources:
Illing, H P A (1989). Afterword. In ‘Xenobiotic metabolism and disposition: The design of studies on novel compounds’, edited by H P A Illing. Boca Raton: CRC Press pp83-85.
Illing, H.P.A., and Barratt, M.D. (2007). Grouping of NLP ‘Polyols’ and their toxicokinetics assessments. Prepared for European Diisocyanate and Polyols Producers Association. (ISOPA, unpublished report).
Metabolite characterisation studies
- Details on metabolites:
- Based on information from the propane-1,2-diol and trimer, the propane-1,2-diol moiety of the propoxylated sucrose, if absorbed, could be further conjugated (with glucuronic acid or sulphate) or hydrolyzed in a stepwise manner (Illing and Barratt, 2007).
The three-carbon elements are likely to be taken into intermediary metabolism.
If hydrolysis occurs, it eventually yields sucrose, glycerol or free fatty acids. Sucrose can be hydrolyzed to its component monosaccharides, whereas fatty acids will be degraded via β-oxidation. The sugar as well as the fatty acids will eventually enter endogenous carbohydrate metabolism and be degraded to the ultimate end product carbon dioxide.
Glycerol produced from hydrolysis is likely to enter endogenous metabolism and, following conversion to pyruvate, either enter the citric acid cycle under aerobic conditions or be converted to lactic acid under anaerobic conditions. Lactic acid may enter gluconeogenesis (Illing and Barratt, 2007).
Source:
Illing, H.P.A., and Barratt, M.D. (2007). Grouping of NLP ‘Polyols’ and their toxicokinetics assessments. Prepared for European Diisocyanate and Polyols Producers Association. (ISOPA, unpublished report)
Any other information on results incl. tables
There are no experimental studies on the toxicokinetics of the
test substance, Reaction product of Saccharose, Glycerine, biodiesel
propoxylated. Illing and Barratt (2007) have extensively discussed a
number of NLP polyols with regard to grouping and toxicokinetics
assessment. In accordance with this report, sucrose, glycerol,
oleic/linoleic acid (the core substances) and propane-1,2-diol and
oligomers (the propoxylated side chains) can be considered possible
models for the toxicokinetic behavior and the toxicity of the test
substance. In the following, they key information from Illing and
Barratt’s report is provided, together with supporting information from
other sources (as indicated):
Sucrose is unlikely to be absorbed by passive diffusion. However,
if absorption by passive diffusion occurred, it would take place in the
stomach and upper intestine where the alcohol groups are unionized.
Sucrose is hydrolyzed in the brush border of the intestine to its
monosaccharides, fructose and glucose. These two sugars are absorbed by
active transport. Propane-1,2-diol and its oligomer
[(methylethylene)bis(oxy)]dipropanol (and, presumably also
oxydipropanol) are absorbed when administered orally, probably by
passive diffusion. Essentially, the NLP polyol (propoxylated sucrose) is
non-toxic.
For the calculations of bioavailability the composition of the
commercial NLP polyol (propoxylated sucrose) was obtained and LogP
values were calculated using the incremental fragment method of Suzuki
and Kudo (1990). The propoxy-groups have an important effect on the
toxicity by modulating any toxicity arising from the core substance. The
substitution of a hydroxyl group on a core compound by a propoxyl-group
increases its logP value by 0.24 units and its molecular weight by 58
Daltons. The combined effect of these changes is to reduce the
bioavailability by a factor of 1.53 (calculated using the Potts and Guy
equation). Thus the molecular weight changes are more significant than
the logP changes in determining the bioavailability. The relative
bioavailabilities are indicated in the following table. The contribution
to toxicity of each individual component to the overall toxicity of a
virtual mixture of all the listed components was calculated by
multiplying the bioavailability of each component by its mole fraction.
Molecule |
Molecularweight |
WeightFraction(%) |
Molefraction |
Relativebioavailability |
%Contributiontotoxicity |
Sucrose+3PO |
534 |
0.56 |
0.012 |
1 |
8.93 |
Sucrose+4PO |
592 |
1.13 |
0.023 |
0.65 |
11.17 |
Sucrose+5PO |
650 |
2.95 |
0.053 |
0.47 |
18.84 |
Sucrose+6PO |
708 |
4.8 |
0.08 |
0.28 |
16.68 |
Sucrose+7PO |
766 |
7.13 |
0.11 |
0.18 |
14.97 |
Sucrose+8PO |
824 |
8.87 |
0.127 |
0.12 |
11.32 |
Sucrose+9PO |
882 |
10.77 |
0.144 |
0.078 |
8.34 |
Sucrose+10PO |
940 |
9.05 |
0.113 |
0.051 |
4.32 |
Sucrose+11PO |
998 |
10.2 |
0.12 |
0.033 |
2.98 |
Sucrose+12PO |
1056 |
7.01 |
0.078 |
0.022 |
1.27 |
Sucrose+13PO |
1114 |
6.1 |
0.064 |
0.01 |
0.67 |
Sucrose+14PO |
1172 |
5.04 |
0.051 |
0.009 |
0.37 |
Sucrose+15PO |
1230 |
2.73 |
0.026 |
0.006 |
0.15 |
The value in bold (logP [calculated] –0.70) indicates the component representing the “mean toxicity” for the NLP polyol.
The representative single entity for the toxicity of this NLP polyol is sucrose with 5 propoxy-groups attached. QSAR comparisons for the bioavailability of propoxylated sucrose are based on the molecules present in the commercial NLP polyol. The SAR predictions indicate the relative bioavailability falls off rapidly, such that the bioavailability of sucrose + 5PO is less than half of that of sucrose + 3PO. The logP for sucrose is considerably less than that for propane-1,2-diol, thus it is likely that sucrose + 3PO is less well absorbed than the propane-1,2-diol trimer. Given this, the amounts absorbed of the propoxylated sucrose representing the mean toxicity of commercial propoxylated sucrose are likely to be small (<5%). Thus it is likely that the propoxylated sucrose NLP polyol is not well absorbed.
Lipinski et al (1997) have proposed the so-called ‘rule-of-five’ for identifying chemicals that would have poor absorption. This rule states that poor absorption is likely when any two of the following conditions are satisfied:
a) molecular weight >500;
b) log P >5.0;
c) number of hydrogen bond donors >5;
d) the number of hydrogen bond acceptors >10.
Oligomers of sucrose with seven or more propoxy units (MW 766 or higher) and containing more than five hydrogen bond donating hydroxyl groups are unlikely to be absorbed to any great extent. The QSAR calculations are consistent with the literature information on related substances.
Glycerol is solely a core substance (initiator). However, it is structurally related to propane-1,2-diol (both are C3), and there are similarities in the metabolism of fatty acid esters of both substances in the intestine.
The information on the toxicokinetics of glycerol, propoxylated, 1-6.5 mol (the NLP polyol), and higher oligomers/polymers is based on the information for glycerol (JECFA, 2002), for triglycerides (fats) and for propane-1,2-diol and oligomers. Additional information is derived from studies on the absorption of hydrocarbons (Abro and Fishbein, 1970; Miller et al., 1996). There is some further information in Patty (Cavendar and Sowinski, 2001) which has also been incorporated into this assessment. In addition, some predictions can be made from the physicochemical and toxicological information on the oligomers.
At the molecular weight range of the NLP polyol, the postulated mechanism for absorption is passive diffusion. However, it should be noted that there is an additional mechanism - facilitated diffusion - that may apply to material currently categorized as polymer.
For the calculations of bioavailability, logP values of the commercial NLP polyol were calculated using the incremental fragment method of Suzuki and Kudo (1990), corresponding to the method described for sucrose above. The relative bioavailabilities are indicated in the following table.
Molecule |
Mn |
Weight fraction(%) |
Mole fraction |
Relative bioavailability |
% Contribution to toxicity |
Glycerol |
92 |
0 |
0 |
1 |
0 |
Glycerol+1PO |
150 |
6.37 |
0.108 |
0.654 |
19.94 |
Glycerol+2PO |
208 |
25.58 |
0.314 |
0.478 |
42.4 |
Glycerol+3PO |
266 |
35.79 |
0.343 |
0.28 |
27.11 |
Glycerol+4PO |
324 |
20.84 |
0.164 |
0.183 |
8.47 |
Glycerol+5PO |
382 |
6.58 |
0.044 |
0.12 |
1.5 |
Glycerol+6PO |
440 |
3.37 |
0.02 |
0.078 |
0.45 |
Glycerol+7PO |
498 |
1.48 |
0.008 |
0.051 |
0.11 |
The value in bold (logP [calculated –0.92) indicates the component representing the mean toxicity for the NLP polyol.
Glycerol propoxylated with 2 propoxy-units is equivalent to the trimer of propane-1,2-diol, but is likely to have a lower logP. The trimer of propane-1,2-diol is known to be well absorbed. QSAR comparisons for the bioavailability ofpropoxylated glycerol are based on the glycerol molecule and the propane-1,2-diol molecule. Glycerol, propane-1,2-diol and the trimer of propane-1,2-diol are well absorbed. Hence glycerol + 2PO is probably well absorbed.
Oleic acid and linoleic acid
As extensively described by Illing &
Barratt, the relative bioavailability of a core substance gradually
decreases with an increasing degree of propoxylation. Also, increasing
molecular weight leads to a decrease in bioavailability. Consequently,
the propoxylated derivatives of oleic and linoleic acid as well as their
reaction products with sucrose can be anticipated to be less
bioavailable than the free fatty acids.
Comprehensive evaluations of the available data on oleic and linoleic
acid indicate low systemic toxicity and no relevant local effects to
skin and eyes (MAK value documentation, 2002; Patty’s Toxicology,
1994/2001;Anonymous, 1987; Briggs, B., et al., 1976).The safety of oleic
acid and linoleic acid is further underlined by the fact that the FDA
generally considers both substances as safe for the use in food and in
the manufacture of food components (21CFR172.860), and as safe as a
nutrient and/or dietary supplement (21 CFR 182.5065), respectively.
In conclusion, the two fatty acids, their propoxylated derivatives and
their reaction products with sucrose can be anticipated to be
essentially non-toxic.
Sources:
Illing, H.P.A., and Barratt, M.D. (2007, revised 2009). Grouping of NLP ‘Polyols’ and their toxicokinetics assessments. Prepared for European Diisocyanate and Polyols Producers Association. (ISOPA, unpublished report) (Report attached to chapter 13 of the IUCLID)
Illing,
H.P.A., and Barratt, M.D. (2009). Proposals for further testing for the
NLP ‘Polyols’. Prepared for European Diisocyanate and Polyols Producers
Association. (ISOPA, unpublished report) (Report attached to chapter 13
of the IUCLID)
Suzuki, T, Kudo, Y (1990). Automatic log P estimation based on combined additive modelling methods. J Computer-Aided Molecular Design, 1455-198.
Lipinski, C A, Lombardo, F, Dominy, B W, Feeney, P J (1997). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Delivery Rev 23, 3-25.
JECFA (2002). Safety evaluation of certain food additives and contaminants, evaluation 1036, Aliphatic acyclic diols, triols and related substances, WHO Food Additives Series 48, Geneva (available athttp://www.inchem.org)
Abro, P W, Fishbein, L (1970). Absorption of aliphatic hydrocarbons by rats. Biochim Biophys Acta 219, 437-446.
Cavendar F and Sowinski E J (2002). Glycols in Patty’s Toxicology, fifth edition, edited by E Bingham, B Cohrssen and CH Powell, Vol 7 pp 1-72, John Wiley, 2002
2012. Oleic acid [MAK Value Documentation, 2002]. The MAK Collection for Occupational Health and Safety. 246–266
Katz, G.V., and Guest, D., Aliphatic Carboxylic Acids, Patty’s Industrial Hygiene and Toxicology, 4th/6thedition, Volume 2, Part E, 1994/2001
Anonymous, Final Report on the Safety Assessment of Oleic Acid, Lauric Acid, Palmitic Acid, Myristic Acid and Stearic Acid, J Am Coll Toxicol, 6 (3), 1987
Briggs, B., Doyle, R. L., and Young, J.A., Safety studies on a series of fatty acids, Am Ind Hyg Ass J, 37(4): 251, 1976
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