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Basic toxicokinetics

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 substance Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol (CAS 93334-10-2) was conducted to the extent that can be derived from the relevant available information on physicochemical and toxicological characteristics. A study investigating hydrolysis of sorbitan stearate in vitro is available (Krantz, 1951) in addition to in vivo data on hydrolysis, excretion and distribution after oral ingestion of radiolabeled test substance (Wick, 1953, Elder, 1985).

Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol represents an UVCB substance. Due to their chemical structure, all components belong to the family of Sorbitan fatty acid esters. The test substance is a liquid with a molecular weight range of 410.59 – 975.51 g/mol, low water solubility (< 0.1 g/L at 25 °C) and an octanol/water partition coefficient (log Pow) > 4. Moreover, the substance is non-volatile with a vapour pressure <0.0001 Pa at room temperature.

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 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 are favorable for oral absorption (ECHA, 2008). As the molecular weight of components of Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol ranges from 410.59 – 975.51 g/mol, absorption in the gastrointestinal tract is considered as possible for the sorbitol, sorbitan and dianhydroglucitol monoesters. Absorption of di- and triesters is considered unlikely in the gastrointestinal tract due to their increasing molecular size (molecular weights > 500 g/mol).

A log Pow > 4 and the poor water solubility suggest that the components of Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol are favourable for absorption by micelullar solubilisation, as this mechanism is of importance for highly lipophilic substances (log Pow >4), poorly soluble in water (1 mg/L or less).

 

After oral ingestion, the components of the test substance are expected to undergo enzymatic hydrolysis in the gastro-intestinal fluids. In general, hydrolysis of Sorbitan fatty acid esters occurs within a maximum of 48h for mono-, di- and tri-ester but decreases with the degree of esterification so that no hydrolysis of hexa-ester occurs (Krantz, 1951, Mattson and Nolen, 1972, Treon, 1967, Wick, 1953). The physico-chemical characteristics of the cleavage products (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure, etc.) differ 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, for the cleavage products, it is anticipated that they will be absorbed in the gastro-intestinal tract: The highly lipophilic fatty acid will be absorbed by micellar solubilisation (Ramirez et al., 2001), whereas the alcohol residues (D-glucitol, sorbitol and/or sorbitan), being highly water-soluble substances, will dissolve into the gastrointestinal fluids and slowly be absorbed with a subsequent metabolism in the liver (Senti 1986, Touster 1975). Depending on the pH, mostly the isomeric chain isomer D-glucitol will be present in the gastrointestinal tract.

Overall, a systemic bioavailability of the constituents of Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol is considered unlikely after oral ingestion whereas absorption of the respective cleavage products is considered likely in humans.

 

Dermal

The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 favours dermal absorption, above 500 the molecule may be too large (ECHA, 2012). With a molecular weight range of 410.59 – 975.51 g/mol, dermal absorption of the mono-esters contained in the test substance cannot be excluded whereas dermal absorption of the di- and tri-esters is considered unlikely.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2012). As Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol is not considered as skin irritating in humans, an enhanced penetration of the substance due to local skin damage can be excluded. Moreover, based on QSAR predictions, dermal absorption values ranging from 1.04 E-5 to 3.54 E-13 mg/cm²/event were calculated (Dermwin v 2.02, Epiweb 4.1), indicating a negligible potential for dermal absorption (please refer to Table 1).

 

Table 1: Dermal absorption values for the components of Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol (calculated with Dermwin v 2.02, Epiweb 4.1)

 

Component

Molecular formula

Dermal absorption value [mg/cm²/event]

esters with 1.4:3.6-dianhydroglucitol (mono-ester)

C24H42O5 (m)

3.82 E-5

esters with 1.4:3.6-dianhydroglucitol (di-ester)

C42H74O6 (di)

1.39 E-9

ester with sorbitan (mono-ester)

C24H44O6 (m)

1.05 E-5

ester with sorbitan (di-ester)

C42H76O7 (di)

9.25 E-10

ester with sorbitan (tri-ester)

C60H108O8 (tri)

3.54 E-13

esters with Sorbitol (mono-ester)

C24H46O7 (m)

1.04 E-5

esters with Sorbitol (di-ester)

C42H78O8 (di)

1.38 E-9

esters with Sorbitol (tri-ester)

C60H110O9 (tri)

1.21 E-13

 

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). Due to a log Pow > 4, dermal uptake of components of Fatty acids, rape-oil, mixed esters with 1.4:3.6-dianhydro-d-glucitol, sorbitan and sorbitol is considered to be very low.

Overall, the calculated low dermal absorption potential, the low water solubility, the high molecular weight (>100),the high log Pow value (>4) and the fact that the test substance is not irritating to skin implies that dermal uptake of components of the test substance in humans is considered as very limited.

 

Inhalation

Fatty acids, rape-oil, mixed esters with 1.4:3.6-dianhydro-d-glucitol, sorbitan and sorbitol has a low vapour pressure of <0.0001 Pa at 25 °C thus being of low volatility. Therefore, inhalation exposure and thus availability for respiratory absorption of components of the test substance is expected to be low.

However, the test substance and hence its components 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 Fatty acids, rape-oil, mixed esters with 1.4:3.6-dianhydro-d-glucitol, sorbitan and sorbitol can be taken up by micellar solubilisation.

Overall, a systemic bioavailability of components of Fatty acids, rape-oil, mixed esters with 1.4:3.6-dianhydro-d-glucitol, sorbitan and sorbitol in humans cannot be excluded after inhalation of aerosols with aerodynamic diameters below 15 µm.

Accumulation

Highly lipophilic substances tend in general 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 > 4 implies that Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol and its components may have the potential to accumulate in adipose tissue (ECHA, 2012).

However, as further described in the section metabolism below, components of Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol will undergo esterase-catalysed hydrolysis, leading to the cleavage products of the respective alcohol moiety, mostly the open chain isomer D-glucitol and the respective fatty acids.

The log Pow of the first cleavage product, D-glucitol, is -2.2 (International Chemical Safety Cards), indicating a high solubility in water. Consequently, there is no potential for D-glucitol to accumulate in adipose tissue. The second cleavage product, 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 of the parent substance in adipose tissue is expected.

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 its 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).

Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol will undergo chemical changes as a result of enzymatic hydrolysis, leading to release of the alcohol moiety, which will mainly be present as the open chain isomer D-glucitol and the respective fatty acids.

D-glucitol, a small (MW 182.2 g/mol), polar water-soluble substance (log Pow -2.2 (International Chemical Safety Cards))

, will be distributed in aqueous fluids by diffusion through aqueous channels and pores and oxidized by L-iditol dehydrogenase to fructose which is subsequently metabolized by the fructose metabolic pathway (Touster 1975).

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).

Experimental data from rats exposed to 0.5-6.5 g/kg bw radiolabeled Sorbitan stearate showed 3-7% of the administered labeled polyol and 10-41% of the stearate label in liver, kidney and intestine as well as in the carcass. The highest amounts were found in the intestine followed by liver and kidney. The stearate label was recovered to a higher extent than the polyol label. Furthermore, the recovered amounts of polyol and stearate were higher when the test substance was administered as oily emulsion in comparison to an aqueous emulsion (Wick, 1953). The identified distribution pattern is supported by the repeated dose toxicity studies in which organ enlargement and changes at gross and histopathology were only observed in the aboved mentioned organs, indicating that the test substance and/or its metabolites reach the internal organs. In view of the log Pow, a general accumulation of the test substance in fat tissue may normally be unlikely with repeated intermittent exposure, but may accumulate if exposure is continuous. Accumulation and deposition in body fat of rats was studied after repeated oral administration of 100 mg labeled Sorbitan stearate /kg bw via food for 28 days (Elder 1985). After sacrifice, fractionation of the carcass fats revealed only 0.35 to 0.49 % of the administered radioactivity in crude fat, 0.15 to 0.32 % into fatty acids, 0.01 to 0.07 % into glycerol, and a residue that did not sublime. Hence, from this study it was found, that repeated administration did not result in an accumulation of the test substance in body fat stores (Wick 1953).

Overall, the available information indicates that the cleavage products, D-glucitol and fatty acids distribute in the organism.

Metabolism

Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol belongs to Sorbitan fatty acid esters. Esters are known to hydrolyse into carboxylic acids and alcohols by esterases (Fukami and Yokoi, 2012). Therefore it is expected that the individual components of the test substance hydrolyse to the alcohol, mostly D-glucitol depending on the pH, and the respective fatty acids under physiological conditions. Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the organism: After oral ingestion, Sorbitan fatty acid esters will undergo chemical changes already in the gastro-intestinal fluids as a result of enzymatic hydrolysis. In contrast, substances which are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before entering the liver where hydrolysis will basically take place.

The first cleavage product, the fatty acid, is stepwise degraded by beta-oxidation based on enzymatic removal of C2 units in the matrix of the mitochondria in most vertebrate tissues. The C2 units are cleaved as acyl-CoA, the entry molecule for the citric acid cycle. For the complete catabolism of unsaturated fatty acids such as oleic acid, an additional isomerization reaction step is required. The alpha- and omega-oxidation, alternative pathways for oxidation, can be found in the liver and the brain, respectively (CIR, 1987).

For the alcohol residue D-glucitol it was found, that it is relatively slowly absorbed from the gastro-intestinal tract compared with glucose and that it can be metabolized by the intestinal microflora (Senti, 1986). Once absorbed, D-glucitol is primarily metabolized in the liver. The first step involves oxidation by L-iditol dehydrogenase to fructose which is metabolized by the fructose metabolic pathway (Touster, 1975). D-glucitol does not enter tissues other than the liver and does not directly influence the metabolism of endogenous D-glucitol in other tissues (Allison, 1979).

Experimental investigations with Sorbitan stearate revealed hydrolysis in vitro (Krantz, 1951) as well as in vivo (Wick, 1953, Elder, 1985). Incubation with pancreatic lipase for 24 h at 37 °C resulted in a release of fatty acids from the test substance reaching 5.4%.In the same study 21.4% fatty acids were liberated from corn oil, which was used as positive control. After oral administration of 0.5 – 6.5 g radiolabeled test substance /kg bw dissolved in corn oil to rats, 90% of the test substance was hydrolyzed to stearic acid and anhydrides of D-glucitol (Wick, 1953). The resulting anhydrid was poorly absorbed and excreted into the urine before they could be completely oxidized to CO2 (see “Excretion”). In contrast, administration as water solution revealed hydrolyses of only 50% Sorbitan stearate.

Excretion

Characteristics favourable for urinary excretion are low molecular weight (below 300 in the rat), good water solubility, and ionization of the molecule at the pH of urine. In the rat, molecules that are excreted in the bile are amphipathic (containing both polar and nonpolar regions), hydrophobic/strongly polar and have a high molecular weight. In general, for organic cations with a molecular weight below 300 it is unlikely that more than 5-10% will be excreted in the bile, for organic anions this cut off may be lower. Substances excreted in the bile may potentially undergo enterohepatic circulation. Little is known about the determinants of biliary excretion in humans. Highly lipophilic substances that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with skin cells (ECHA, 2012).

Due to the high molecular weight and the low solubility in water, excretion of parental components of Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol via the urine is unlikely after oral administration.

After oral ingestion, Sorbitan fatty acid esters will undergo stepwise chemical changes in the gastro-intestinal fluids as a result of enzymatic hydrolysis. As 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 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 readily absorbed by micelullar solubilisation und undergo beta-oxidation or will be stored in fat tissue (Ramirez et al., 2001).The alcohol residues, being a highly water-soluble substance, will dissolve into the gastrointestinal fluids and slowly be absorbed with a subsequent metabolism to fructose in the liver by L-iditol dehydrogenase (Senti, 1986, Touster, 1975). Amounts of non-metabolized alcohol residues will mainly be excreted via urine, due the low molecular weight and the high water solubilty of the substance. Amounts of both cleavage products that are not absorbed, will be excreted via faeces. High amounts of D-glucitol in the intestine trigger diarrhea (Peters, 1958) and de facto, diarrhea was observed in nearly all acute oral toxicity and repeated dose toxicity studies with Sorbitan fatty acid esters.

For Sorbitan stearate, a significant fraction of the administered 14C-radiolabeled parent substance was found in the expired CO2 (Wick, 1953). Feeding of the polyol labeled ester resulted in recovery rates of 14-24% of the administered radioactive labeled dose. A recovery of 7-33% was determined after feeding the stearate label.16-44% of the radioactive labeled D-glucitol was found in the urine whereas only 1% of the labeled stearate was determined. Feeding of stearate labeled substance dissolved in water resulted in an urinary excretion rate of 69-76% of the fed 14C as CHCl3 soluble. When the stearate labeled compound was fed in oil, lower excretion values of 33-37% were obtained in the urine. Hence, administration of esters in oil decreased renal elimination thereby increasing intestinal absorption as indicated by the diminished C14 content in the faeces.

Overall, the available information indicates that components of Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol will be expired as CO2 after metabolic degradation. Moreover, depending on the cleavage products, biliary excretion with the faeces (fatty acids) and via urine is likely for the alcohol moiety.

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within CSR.

References not used in IUCLID

Allison, R. G. 1979. Dietary sugars in health and disease III. Sorbitol. Contract No. 223-75-2090, Bureau of foods, Food and Drug Administration, Dept. of Health and Human Services, Washington, DC 20204, USA

 

CIR (1987). Final report on the safety assessment of oleic acid, lauric acid, palmitic acid, myristic acid, stearic acid. J. of the Am. Coll. of Toxicol.6 (3): 321-401

 

ECHA (2012), Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance, European Chemicals Agency, Helsinki

 

Fukami and Yokoi (2012). The Emerging Role of Human Esterases. Drug Metabolism and Pharmacokinetics, Advance publication July 17th, 2012

 

International Chemical Safety Cards.International Chemical Safety Cards, http://www.cdc.gov/niosh/ipcsneng/neng0892.html

 

Masoro (1977). Lipids and lipid metabolism. Ann. Rev. Physiol.39: 301-321.

 

Mattson, F. H. and Nolen, G. A., 1972: Absorbability by rats of compounds containing from one to eight ester groups. J Nutrition, 102: 1171-1176

 

Peters, R., Lock R.H. (1958): Laxative effect of sorbitol. Br Med J 2: 677 -678

 

Ramirez et al. (2001). Absorption and distribution of dietary fatty acids from different sources.Early Human Development 65 Suppl.: S95–S101

 

Senti, F. R. 1986. Health aspects of sugar alcohols and lactose. Contract No. 223-83-2020, Center for food safety and applied nutrition, Food and Drug Administration, Dept. of Health and Human Services, Washington, DC 20204, USA

 

Touster, O. 1975: Metabolism and physiological effects of polyols (alditols). In: Physiological effects of food carbohydrates. Washington, DC: American Chemical Society. p 229-239

 

Treon J. F. et al., 1967: Physiologic and metabolic patterns of non-ionic surfactants: Chem. Phys. Appl. Surface Active Subst., Proc. Int. Congr., 4th, 1964, 3, 381-395. Edited by Paquot, C., Gordon Breach Sci. Publ., London, England