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Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Objective of study:
absorption
Qualifier:
no guideline available
Principles of method if other than guideline:
- Principle of test: The absorption of sucrose monostearate was determined by administering a single dose intravenously to male rats.
- Short description of test conditions: A dose of 1 mg/kg bw was administered.
- Parameters analysed / observed: Samples were taken over the 24 hrs after dosing to determine the blood plasma concentration.
GLP compliance:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Mitsubishi-Kagaku Foods Corporation

FORM AS APPLIED IN THE TEST (if different from that of starting material): dissolved in water
Radiolabelling:
no
Species:
rat
Strain:
Fischer 344/DuCrj
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Japan Inc.
- Age at study initiation: 8 weeks
- Weight at study initiation: 161-206 g males, 113-133 g females
- Diet: fasting 15 hrs before dosing until 6 hrs after dosing
- Water: ad libitum
- Acclimation period: 5 days

Route of administration:
intravenous
Vehicle:
other: 0.9% saline solution
Duration and frequency of treatment / exposure:
Single intravenous dose
Dose / conc.:
1 mg/kg bw/day (nominal)
No. of animals per sex per dose:
4
Control animals:
no
Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: plasma
- Time and frequency of sampling: 0.0833, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hrs after dosing
- Method type(s) for identification: GC-MS
Type:
metabolism
Results:
Plasma levels of sucrose monostearate were below the limit of detection within 24 hrs after dosage.
Key result
Toxicokinetic parameters:
half-life 1st: 0.41 hrs
Key result
Toxicokinetic parameters:
half-life 2nd: 6.9 hrs
Key result
Toxicokinetic parameters:
AUC: 2.39 µg*hr/mL
Bioaccessibility testing results:
The bioavailability was 0.3%.
Conclusions:
Sucrose monostearate was rapidly eliminated from the blood plasma in a biphasic manner with a half-life of only 0.41 hrs. Within 24 hrs, the amount in the blood plasma was below the limit of detection.
Executive summary:

The absorption of sucrose monostearate was determined by administering a single dose intravenously to male rats. A dose of 1 mg/kg was administered, and the blood plasma levels were determined over the next 24 hrs. Sucrose monostearate was rapidly eliminated from the blood plasma in a biphasic manner with a half-life of only 0.41 hrs.  Within 24 hrs, the amount in the blood plasma was below the limit of detection.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Objective of study:
absorption
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Principle of test: Groups of three rats were given a single oral dose of sucrose monostearate in order to determine the absorption and elimination rate of the test substance.
- Short description of test conditions: Single oral administration of 50, 100, or 200 mg sucrose esters/10 mL water to groups of three rats. The blood plasma concentrations were then measured over the next 24 hrs.
- Parameters analysed / observed: The blood plasma concentrations were then measured over the next 24 hrs post dosing.
GLP compliance:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Mitsubishi-Kagaku Foods Corporation

FORM AS APPLIED IN THE TEST (if different from that of starting material): dissolved in water
Radiolabelling:
no
Species:
rat
Strain:
Fischer 344/DuCrj
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Japan Inc.
- Age at study initiation: 8 weeks
- Weight at study initiation: 161-206 g males, 113-133 g females
- Diet: fasting 15 hrs before dosing until 6 hrs after dosing
- Water: ad libitum
- Acclimation period: 5 days

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Dosing solutions were prepared by ultrasonication.

Duration and frequency of treatment / exposure:
Single dose
Dose / conc.:
50 mg/kg bw/day (nominal)
Remarks:
male only
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
Remarks:
male only
No. of animals per sex per dose:
4
Control animals:
no
Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: plasma
- Time and frequency of sampling: 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24 hrs after dosing
- Method type(s) for identification: GC-MS
Key result
Toxicokinetic parameters:
Cmax: 0.28 µg/kg
Key result
Toxicokinetic parameters:
Tmax: 1 hr
Key result
Toxicokinetic parameters:
half-life 1st: 2.4-4.1 hrs
Key result
Toxicokinetic parameters:
AUC: 1.68 µg*kg/mL
Bioaccessibility testing results:
The bioavailibility value for sucrose monostearate was 0.33%.

 Parameter  50 mg/kg Male  100 mg/kg Male  100 mg/kg Female  200 mg/kg Male
 Cmax (ug/mL) 0.06   0.13  0.28  0.19
 Tmax (hr)  1  2  2  2
 T1/2 (hr)  4.1  2.4  2.9  3.1
 AUC0 -t (µg*hr/mL)  0.34  0.68  1.33  1.14
 AUC(0 -infinity) (µg*hr/mL)  0.40  0.71  1.23  1.68
 Bioavailability (%)  0.33  0.30  --  0.26
Conclusions:
Blood plasma levels peaked 1-2 hrs after administration of a single dose, and declined rapidly thereafter, with a half-life of 2.4-4.1 hrs. The bioavailability was about 0.3% regardless of the dose.
Executive summary:

The absorption of sucrose monostearate into the body was studied by oral administration of 50, 100, or 200 mg/10 mL to groups of three rats. The blood plasma concentrations were then measured over the next 24 hrs. Blood plasma levels peaked 1-2 hrs after administration of a single dose, and declined rapidly thereafter, with a half-life of 2.4-4.1 hrs.  The bioavailability was about 0.3% regardless of the dose.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Objective of study:
absorption
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Principle of test: The absorption and distribution of sucrose monoesters were determined in an oral dosage study in rats.
- Short description of test conditions: Groups of rats were exposed to either 1% or 5% of sucrose esters in the diet for 1, 2, or 4 weeks, with a recovery time of up to 2 weeks.
- Parameters analysed / observed: The amount of sucrose monopalmitate and monostearate in the blood plasma and organ tissues were then determined.
GLP compliance:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Mitsubishi-Kagaku Foods Corporation
Radiolabelling:
no
Species:
rat
Strain:
Fischer 344/DuCrj
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Japan
- Age at study initiation: 8 weeks
- Weight at study initiation: 161-206 g males, 113-133 g females
- Diet (e.g. ad libitum): ad libitum
- Acclimation period: 5 days
Route of administration:
oral: feed
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Appropriate amount of test substance was added to powdered feed.

Duration and frequency of treatment / exposure:
1, 2, or 4 weeks
Dose / conc.:
1 other: % diet
Dose / conc.:
5 other: % diet
No. of animals per sex per dose:
4
Control animals:
no
Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood, liver, kidneys, heart, lung, spleen, white fat
- Time and frequency of sampling: 9-12 hrs after completion of treatment for animals in the administration phase animals.
- Method type(s) for identification: GC-MS
- Limits of detection and quantification: plasma 0.01 µg/mL, white fat 0.05 µg/g, liver and kidneys 0.01 µg/mL, heart and spleen 0.02 µg/mL, lung 0.04 µg/mL
Type:
absorption
Results:
Blood plasma levels of sucrose monostearate reached a maximum of 0.07 µg/mL. Levels of sucrose monostearate were not detectable by 3 days after the end of treatment. Sucrose monopalmitate levels in blood plasma remained below detection limits.
Type:
distribution
Results:
The sucrose esters mainly distributed to the liver, with the least amount partitioning to the blood plasma.
Details on absorption:
In the 1% dose group, sucrose monopalmitate levels in blood plasma remained below detection limits regardless of the exposure time. Within 3 days of completing treatment, sucrose monopalmitate was not detectable in the plasma. For sucrose monostearate, blood plasma levels reached a peak of 0.03 µg/mL at 14 days, and were 0.02 µg/mL at 28 days. By 3 days after completion of treatment, the plasma had no detectable levels of sucrose monostearate.

In the high dose group (5% of diet), blood plasma levels of sucrose monopalmitate was 0.01 µg/mL after 14 days of treatment. Blood plasma levels of sucrose monostearate reached a maximum of 0.07 µg/mL by 14 days after treatment. Levels of sucrose monostearate were not detectable by 3 days after the end of treatment.

Details on distribution in tissues:
In the 1% dose group, sucrose monopalmitate levels in white fat tissue remained below detection limits regardless of the exposure time. The level in liver, kidney, heart, and spleen remained fairly constant regardless of the exposure time at 0.02-0.06 µg/g. Detectable levels of sucrose monopalmitate were only found in the lungs after 28 days of treatment (0.05 µg/g). Within 3 days of completing treatment, sucrose monopalmitate was not detectable in any of the tissues. For sucrose monostearate levels in the liver, kidneys, heart, spleen, and lungs were remained fairly constant throughout the administration period. The highest amounts were found in the kidneys (0.72-0.75 µg/g), and the lowest amount in the spleen (0.06-0.10 µg/g). White fat tissue only showed detectable levels of sucrose monostearate at 14 days of treatment (0.08 µg/g). By 3 days after completion of treatment, no tissues had detectable levels of sucrose monostearate.

In the high dose group (5% of diet), levels of sucrose monopalmitate in the liver, kidneys, heart, spleen, and lungs were remained fairly constant throughout the administration period. The highest amounts were found in the liver (0.32-0.35 µg/g), and the lowest amount in the heart (0.04-0.06 µg/g). Sucrose monopalmitate was not detected in the white fat tissues. No organs had detectable amounts by 7 days after the end of treatment. Levels of sucrose monostearate in the kidney, heart and white fat tissues remained fairly constant throughout the study with the highest levels in the kidneys (1.27 µg/g) and the lowest levels in the white fat tissues (0.06 µg/g). Levels in the liver, spleen, and lungs increased throughout the study reaching a maximum of 5.65 µg/g in the liver. By 7 days after the end of treatment, no detectable levels were seen in any tissues.

Percent Tissue Distribution of Sucrose Esters (1% of Diet Dose)

   Day 7  Day 14  Day 28
 Plasma 0.00023% 0.00088% 0.00061%
 Liver 0.01859% 0.01969% 0.02286%
 Kidney 0.00116% 0.00117%  0.00112%
 Heart 0.00021% 0.00023% 0.00032%
 Spleen 0.0004% 0.00041% 0.00036%
 Lung 0.00038% 0.00060% 0.00075%
 Fat 0.00108% 0.00518% 0.00044%
Conclusions:
Sucrose monopalmitate and sucrose monostearate were rapidly eliminated from blood plasma even after 4 weeks of treatment. Blood plasma levels were not elevated after 4 weeks of treatment. Sucrose esters are distributed in the organs, with the highest amounts in the liver, but are rapidly eliminated. The amount of sucrose esters distributed to the organs was small compared to the dose.
Executive summary:

The absorption and distribution of sucrose monoesters were determined in an oral dosage study in rats. Groups of rats were exposed to either 1% or 5% of sucrose esters for 1, 2, or 4 weeks, with a recovery time of up to 2 weeks. The amount of sucrose monopalmitate and monostearate in the blood plasma and organ tissues were then determined. Sucrose monopalmitate and sucrose monostearate were rapidly eliminated from blood plasma even after 4 weeks of treatment.  Blood plasma levels were not elevated after 4 weeks of treatment.  Sucrose esters are distributed in the organs, with the highest amounts in the liver, but are rapidly eliminated.  The amount of sucrose esters distributed to the organs was small compared to the dose.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Qualifier:
no guideline available
Principles of method if other than guideline:
- Principle of test: The absorption and distribution of sucrose esters was studied in a 2-year oral diet exposure test.
- Short description of test conditions: Groups of 5 male and female rats were exposed to either 1, 3, or 5% of sucrose esters in the diet for 2 years
- Parameters analysed / observed: The amount of sucrose esters in the blood plasma and liver was then determined.
GLP compliance:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Mitsubishi-Kagaku Foods Corporation

FORM AS APPLIED IN THE TEST (if different from that of starting material): in diet
Radiolabelling:
no
Species:
rat
Strain:
Fischer 344/DuCrj
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Japan
- Age at study initiation: 5 weeks
- Weight at study initiation: 104-120 g males, 85-99 g females
- Diet: ad libitum
- Acclimation period: 5 days
Route of administration:
oral: feed
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Mixed with diet to give 1%, 3%, or 5% of test substance in diet.
Duration and frequency of treatment / exposure:
2 years
Dose / conc.:
1 other: % in diet
Remarks:
338.4 mg/kg bw/day males
410.6 mg/kg bw/day females
Dose / conc.:
3 other: % in diet
Remarks:
939.2 mg/kg bw/day males
1124 mg/kg bw/day females
Dose / conc.:
5 other: % in diet
Remarks:
1684.0 mg/kg bw/day males
2182.0 mg/kg bw/day females
No. of animals per sex per dose:
5
Control animals:
no
Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: liver
- Method type(s) for identification: GC-MS
- Limits of detection and quantification: 0.01 ug/g wet tissue, plasma 0.01 ug/mL
Type:
absorption
Results:
In males, detectable levels of sucrose monopalmitate were only seen in the 5% dose group, and in females in the 3%, and 5% dose groups. Detectable levels of sucrose monostearate were seen in both females and males in all dose groups (0.15 µg/mL max.).
Type:
distribution
Results:
Detectable amounts of sucrose monopalmitate were found in both males and females of all dose groups (0.09 µg/g max.). Detectable amounts of sucrose monostearate were also found in both males and females of all dose groups (0.63 µg/g max.).
Details on absorption:
In the males, levels of sucrose monopalmitate in plasma were below limits of detection for the 1% and 3% dose groups. For the 5% dose group, the level was 0.03 µg/mL. For females, sucrose monopalmitate was below the limit of detection in the 1% dose group, 0.02 µg/mL in the 3% group, and 0.01 µg/mL in the 5% group.

In males, levels of sucrose monostearate in the blood plasma were 0.03 µg/mL (1% dose group), 0.05 µg/mL (3% dose group), and 0.15 µg/mL (5% dose group). In females, levels of sucrose monostearate in the blood plasma were 0.02 µg/mL (1% dose group), 0.08 µg/mL (3% dose group), and 0.06 µg/mL (5% dose group).

The maximum percent retention of sucrose esters in the plasma was 0.00186% (3% dose males).
Details on distribution in tissues:
Detectable amounts of sucrose monopalmitate in the liver were found in both males and females of all dose groups. The highest detected amount was 0.09 µg/g in the high dose females. Detectable amounts of sucrose monostearate were also found in both males and females of all dose groups. The highest detected amount was 0.63 µg/g in both high dose males and females.

The maximum retention of sucrose esters in the liver was 0.00798% in 1% dose males.

Percent of Sucrose Esters in Tissues after 2 Year Exposure

   1% in Diet  3% in Diet  5% in Diet
% in Blood Plasma (Males)  0.00170% 0.00186%   0.00224%
% in Blood Plasma (Females)  0.00179% 0.00167%   0.00064%
% in Livers (Males)  0.00798% 0.00514%   0.00613%
% in Livers (Females)  0.00422% 0.00522%   0.00389%
Conclusions:
The maximum amount of sucrose monopalmitate in blood plasma was 0.03 µg/mL (5% diet in males). The maximum amount of sucrose monostearate in blood plasma was 0.15 µmg/mL (5% diet in males). The maximum amount of sucrose monopalmitate in the liver was 0.09 µg/g (5% diet in females). The maximum amount of sucrose monostearate in the liver was 0.63 µg/g (5% diet in females/males).
Executive summary:

The absorption and distribution of sucrose esters was studied in a 2-year oral diet exposure test. Groups of 5 male and female rats were exposed to either 1, 3, or 5% of sucrose esters in the diet for 2 years. The amount of sucrose esters in the blood plasma and livers was then determined. The maximum amount of sucrose monopalmitate in blood plasma was 0.03 µg/mL (5% diet in males).  The maximum amount of sucrose monostearate in blood plasma was 0.15 µg/mL (5% diet in males).  The maximum amount of sucrose monopalmitate in the liver was 0.09 µg/g (5% diet in females).  The maximum amount of sucrose monostearate in the liver was 0.63 µg/g (5% diet in females/males).

Description of key information

Available toxicokinetic data on sucrose esters in rats suggest that the substance is extensively hydrolysed in the gastrointestinal tract to the respective fatty acid and sucrose prior to absorption. Only small amounts of intact monoesters are absorbed. It is unlikely that di- and tri esters are absorbed intact. Based on physico-chemical parameters the dermal absorption potential is considered to range between very low and high for the main constituents and inhalative absorption potential is considered to be low.

There is no evidence of tissue accumulation of the absorbed intact monoesters. Hydrolysation products fatty acids mainly distribute into fat tissue, lymph nodes and liver, while sucrose is metabolised in the intestinal mucosa to glucose and fructose, which can then be incorporated in the standard metabolic pathways of glycolysis and gluconeogenesis. Fatty acids are degraded by mitochondrial β-oxidation and used for energy generation. Sucrose esters, including Fatty acids C16-18 (even numbered), mono, di and triesters with sucrose (no CAS), are mainly excreted via the faeces and as CO2 in the expired air as a result of metabolism. Incompletely hydrolysed sucrose esters appear to be excreted in the faeces.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

In accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) 1907/2006 and with ‘Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance’ (ECHA, 2017), an assessment of the toxicokinetic behaviour of the test substance is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physico-chemical and toxicological properties according to the Chapter R.7c Guidance document (ECHA, 2017) and taking into account further available information from source substances. Additionally, there are studies in rats available evaluating the toxicokinetic properties of the substance.

Fatty acids C16-18 (even numbered), mono, di and triesters with sucrose (no CAS) is a UVCB substance covering mainly mono-, di- and triesters of steacric and palmitic acid with sucrose at varying proportions and small proportions (<25%) of tetra- and pentraesters. The molecular weight ranges from approx. 600 to 2500 g/mol. The substance is a solid (flakes) at room temperature, has an estimated water solubility < 1.51 mg/L at 20 °C and an estimated vapour pressure of 946.4 Pa at 25 °C. The log Pow was estimated to be > 4.2 at 20 °C.

Absorption

The major routes by which the test substance can enter the body are via the lung, the gastrointestinal tract, and the skin. To be absorbed, the test substances must transverse across biological membranes either by active transport mechanisms or - as being the case for most compounds - by passive diffusion. The latter is dependent on compound properties such as molecular weight, lipophilicity, or water solubility (ECHA, 2017).

 Oral

Generally the smaller the molecule the more easily it may be taken up. Molecular weights below 500 are favourable for absorption; molecular weights above 1000 do not favour absorption. The molecular weight of the test substance is between 600 to 2500 g/mol, thus a moderate oral absorption is presumed. However, the absorption of highly lipophilic substances (log Pow >4) may be limited by the inability to dissolve into gastrointestinal fluids and hence make contact with the mucosal surface. Lipophilic compounds may be taken up by micellar solubilisation by bile salts; this mechanism is important for highly lipophilic compounds (log Pow > 4), in particular for those that are poorly soluble in water (≤ 1 mg/L) as these would otherwise be poorly absorbed (Aungst and Chen, 1986; ECHA, 2017).

The available data on acute and repeated dose oral toxicity support a conclusion of no/low toxicity.

In an acute oral toxicity study conducted with the test substance in rats no signs of adverse effects were observed and no mortality occurred. Therefore, the LD50 is > 2000 mg/kg bw (Lowe, 2016).

In a 13-week feeding study in rats no mortality or clinical signs related to the test substance occurred. A significant increase in glutamic-pyruvic transaminase (GPT) in the medium and high dose male groups and high dose female groups was observed. The observed values were within the control range. Therefore, it is not clear if this effect is treatment related. As there were no definitive treatment related effects, the NOAEL for both males and females was the highest dose, 5% of feed (equivalent to 3240 and 3430 mg/kg bw/day for males and females, respectively) (Takeda, 1991).

Four studies on the absorption and distribution of Fatty acids C16-18 (even numbered), mono, di and triesters with sucrose (no CAS) were conducted in male and female F344 rats. Fatty acids C16-18 (even numbered), mono, di and triesters with sucrose (no CAS) was administered as a single oral dose of 50, 100 or 200 mg/kg bw (males) or 100 mg/kg bw (females), or as a single i.v. injection of 1 mg/kg bw (males only). Blood samples were collected from the vena cava of 4 animals/group at varying intervals for 24 h after dosing and sucrose monostearate (SMS) concentrations in the plasma were determined using GC-MS. Following oral administration, peak plasma concentrations of SMS (Cmax ) in the males were reached at 1, 2 and 2 h (Tmax) at doses of 50, 100 and 200 mg/kg bw, respectively. The half-lives for elimination of SMS from the plasma were 4.1, 2.4 and 3.1 h for these same groups, suggesting that SMS was eliminated from the plasma within 24 h of ingestion. In females receiving 100 mg/kg bw, values for Tmax and T´ were consistent with those observed in their male counterparts, while the values for Cmax and AUC0-infinity were twice those in the males. The bioavailability of SMS was very low, 0.26 - 0.33%.

 

Plasma and organ tissue levels of sucrose monostearate (SMS) and sucrose monopalmitate (SMP) were determined after 4-weeks of daily oral administration of Fatty acids C16-18 (even numbered), mono, di and triesters with sucrose (no CAS) in rats. Diets containing 1% and 5% of the test substance were fed ad libitum to groups of four male rats for 1, 2 or 4 weeks. The 4 weeks feeding group included additional groups for studies of 3 days, 1 week and 2 weeks recovery. The mean intakes of the test substance after 1, 2, 3 and 4 weeks of treatment in the 1% group were 720, 690, 640 and 590 mg/kg bw and day, respectively, and in the 5% group 3670, 3520, 3370 and 3030 mg/kg and day, respectively. After the various treatment periods SMP and SMS were measured in the plasma and revealed plasma levels proportional to the dose. Further, sucrose monopalmitate and sucrose monostearate were rapidly eliminated from blood plasma even after 4 weeks of treatment and distributed to the organs (Mitsubishi, 1994a; summarised in WHO, 1995 and EFSA, 2004).

 

The absorption and distribution of Fatty acids C16-18 (even numbered), mono, di and triesters with sucrose (no CAS) were further studied in a 2-year oral diet exposure test. Groups of 5 male and female rats were exposed to either 1, 3, or 5% of sucrose esters in the diet for 2 years. The amount of sucrose esters in the blood plasma and livers was then determined. Plasma SMP concentrations were below or close to the detection limit at all dose levels whereas the plasma levels of SMS in the 1%, 3% and 5% dose groups were 0.03, 0.05 and 0.15 μg/mL and 0.02, 0.08 and 0.06 μg/mL in males and females, respectively (Mitsubishi, 1994a; summarised in WHO, 1995 and EFSA, 2004).

 

The potential of a substance to be absorbed from the gastrointestinal tract may be influenced by several parameters, like chemical changes taking place in gastrointestinal fluids, as a result of metabolism by gastrointestinal flora, by enzymes released into the gastrointestinal tract or by hydrolysis. These changes will alter the physico-chemical characteristics of the substance and hence predictions based upon the physico-chemical characteristics of the parent substance may in some cases no longer apply (ECHA, 2017).

In the reviews/opinions prepared by the WHO (1995, 1998) and EFSA (2004) and the references therein, several in vitro and in vivo experiments in rats, dogs and human on the hydrolysis of sucrose esters (SE) were conducted. These studies confirm that extensive hydrolysation of SE occurs in gastrointestinal tract prior to absorption and that only small amounts of intact monoesters are absorbed. Further it is shown from studies on oligoesters, that the degree of absorption is inversely related to the degree of esterification of the sucrose moiety (Noker, 1997; Shigeoka, 1984).

Overall, available studies indicate that the test substance is predicted to undergo hydrolysis in the gastrointestinal tract and absorption of the hydrolysis products sucrose and fatty acids rather than the parent substance is likely.

 

Dermal

The dermal uptake of solids is generally expected to be lower than that of liquid substances. Dry particulates will have to dissolve into the surface moisture of the skin before uptake can begin. Additionally, the substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore if the water solubility of the substance is below 1 mg/L, dermal uptake is likely to be low. For substances with log Pow above 4 the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high (ECHA, 2017)

The dermal permeability constant Kp of the substance was estimated to be between 1.57E-4 and 8.65E4 cm/h using DermwinTM (v.2.02) and taking into account a determined log Pow of 3.4 and 21.29 and molecular weights of 580.72 and 1141.7 g/mol for the main constituents with the lowest and highest molecular weight. Thus, based on the main constituents the dermal absorption of the test substance is anticipated to range between very low and high.

If a substance shows skin irritating or corrosive properties, damage to the skin surface may enhance penetration. If the substance has been identified as a skin sensitiser then some uptake must have occurred although it may only have been a small fraction of the applied dose (ECHA, 2017).

The available data provide no indications for skin irritating effects of Fatty acids C16-18 (even numbered), mono, di and triesters with sucrose in rabbits. No skin effects were noted in the acute dermal toxicity study at the limit dose of 2000 mg/kg bw and no sensitisation was observed in skin sensitisation tests in guinea pigs (GMPT). Therefore, no enhanced penetration of the substance due to skin damage is expected.

Taking all available information into account, dermal absorption potential is assumed.

 

Inhalation

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. Granulometry revealed that over 90% of the substance has a particle diameter of 5.6 mm, with 100% having a particle diameter of greater than 1.0 mm. Negligible amount of the material had a size less than 20 µm. Therefore, inhalation of particles is unlikely.

 

Distribution and Accumulation

Distribution of a compound within the body depends on the physico-chemical properties of the substance; especially the molecular weight, the lipophilic character and the water solubility. 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, 2017).

As discussed for oral absorption, Fatty acids C16-18 (even numbered), mono, di and triesters with sucrose are hydrolysed in the gastrointestinal tract prior to absorption. Therefore, distribution and accumulation of the hydrolysis products is considered the most relevant.

After being absorbed, fatty acids are (re-)esterified along with other fatty acids into triglycerides and released in chylomicrons into the lymphatic system. Chylomicrons are transported in the lymph to the thoracic duct and subsequently to the venous system. On contact with the capillaries, enzymatic hydrolysis of chylomicron triacylglycerol fatty acids by lipoprotein lipase takes place. Most of the resulting fatty acids are taken up by adipose tissue and re-esterified into triglycerides for storage (Bloom et al., 1951; IOM, 2005; Johnson, 1990; Lehninger, 1998; NTP, 1994; Stryer, 1996). In contrast, sucrose is metabolised in the intestinal mucosa to glucose and fructose; these are transported by the portal vein to the liver where they are rapidly metabolized (Stryer, 1996; Noker, 1997).

There is a continuous turnover of stored fatty acids, as these are constantly metabolised to generate energy and then excreted as CO. Accumulation of fatty acids takes place only if their intake exceeds the caloric requirements of the organism. In contrast, sucrose is metabolised in the intestinal mucosa to glucose and fructose; these are transported by the portal vein to the liver where they are rapidly metabolised and incorporated into physiological pathways (Lehninger, 1998; Noker et al. 1995).

The absorption and distribution of sucrose esters were determined in studies in male and female F344 rats (Mitsubishi, 1994a: summarised in WHO, 1995 and EFSA, 2004).

Plasma and organ tissue levels of sucrose monostearate (SMS) and sucrose monopalmitate (SMP) were determined after 4-weeks of daily oral administration of Fatty acids C16-18 (even numbered), mono, di and triesters with sucrose (no CAS) in rats (previously described under ‘oral absorption’). Diets containing 1% and 5% of the test substance were fed ad libitum to groups of four male rats for 1, 2 or 4 weeks. The 4 weeks feeding group included additional groups for studies of 3 days, 1 week and 2 weeks recovery. The mean intakes of the test substance after 1, 2, 3 and 4 weeks of treatment in the 1% group were 720, 690, 640 and 590 mg/kg bw and day, respectively, and in the 5% group 3670, 3520, 3370 and 3030 mg/kg and day, respectively. After the various treatment periods SMP and SMS were measured in the plasma, liver, kidney, heart, spleen, lung and white (perirenal) fat. In the groups fed 1% of the test substance the SMP concentrations remained almost constant in plasma and tissues during the 4 weeks and were close to or below the limits of detection (0.01-0.06 μg/g). At the 5% level slightly increased levels of SMP were seen with similar amounts detected at the various sampling points, with the highest concentrations in the liver (0.3-0.4 μg/g) followed by the kidney, lung, spleen, heart and plasma. SMS could be detected in plasma and tissues at both dose levels proportional to the dose administered. At the 1% dose level SMS levels remained almost constant in all tissues after 7, 14 or 28 days of dosing, whereas at the 5% dose level, the tissue concentrations in the liver, spleen and lung increased with duration of treatment. The highest concentration found (after 4 weeks at the 5% dose level) was in the liver (5.65 μg/g), followed by the white fat (1.27 μg/g), lung (1.05 μg/g), kidney (0.96 μg/g), spleen (0.64 μg/g) and heart (0.26 μg/g). At the 5% dose level, the retention ratios (tissue content in relation to the final daily dose) determined after 7, 14 and 28 days of treatment (SMS intake 742-899 mg/kg bw and day; SMP intake 318-385 mg/kg bw and day) were 4-5 fold higher for SMS than for SMP in the liver and kidney, and 2-3 folds for the heart, spleen and lung. The retention in the liver of SMS and SMP (combined) after 4 weeks at the 5% dose level was 0.018-0.031%. SMP and SMS levels of all tissues were below the limit of detection 3 days after completion of the 28- day treatment (Mitsubishi, 1994a; summarised in WHO, 1995 and EFSA, 2004).

 

In a second study, which was performed as a part of a chronic toxicity and carcinogenicity study, plasma and liver concentrations of SMP and SMS were measured in 5 rats per sex and group after 2-years of daily oral administration of Fatty acids C16-18 (even numbered), mono, di and triesters with sucrose (no CAS). The rats had been fed the test substance at 1% (males 338 mg/kg bw/day, females 411 mg/kg bw/day), 3% (males 939 mg/kg bw/day, females 1124 mg/kg bw/day) and 5% (males 1684 mg/kg bw/day, females 2182 mg/kg bw/day) for 2 years. The actual intakes of the test substance were measured during the final week of the study. Plasma SMP concentrations were below or close to the detection limit at all dose levels whereas the plasma levels of SMS in the 1%, 3% and 5% dose groups were 0.03, 0.05 and 0.15 μg/mL and 0.02, 0.08 and 0.06 μg/mL in males and females, respectively. The concentrations of SMP (0.01-0.09 μg/g) and SMS (0.11-0.63 μg/g) in the liver were dose dependent in both males and females. The retention in the liver of SMS and SMP (combined) at the 5% dose level were 0.039-0.063%, which is comparable to the results obtained in the previously described 4 week study. Thus, there was no time dependent accumulation of sucrose monoesters in the liver (Mitsubishi, 1994a; summarised in WHO, 1995 and EFSA, 2004).

Overall, available studies indicate that after being absorbed sucrose esters are distributed in the organs, with highest tissue concentrations in the liver, followed by white fat, lung, kidney, spleen and heart. The amount of sucrose esters distributed to the organs was small compared to the dose. There is no evidence of tissue accumulation of the intact absorbed monoesters.

 

Metabolism

As discussed previously, Fatty acids C16-18 (even numbered), mono, di and triesters with sucrose are hydrolysed in the gastrointestinal tract prior to absorption, whereas the extent of absorption and metabolism is inversely related to the degree of esterification of the glucose molecule (Noker, et al. 1997; Shigeoka, 1984). Only small amounts of intact monoesters which escape hydrolysis are absorbed. Some hydrolysis occurs in the presence of blood esterase: however, the rate is extremely slow compared to the other enzyme systems like in the gastrointestinal tract (Shigeoka, 1979). Absorbed monoesters are completely metabolised to carbon dioxide or integrated into other endogenous constituents (Mitsubishi, 1994a, Mitsubishi, 1994b, Shigeoka, 1984, Noker, 1997: summarised in WHO, 1980, WHO, 1995, WHO, 1998 and EFSA, 2004).

Sucrose is metabolised in the intestinal mucosa to glucose and fructose, which can then be incorporated in the standard metabolic pathways of glycolysis and gluconeogenesis. Fatty acids are degraded by mitochondrial β-oxidation which takes place in most animal tissues and uses an enzyme complex for a series of oxidation- and hydration reactions, resulting in the cleavage of acetate groups in the form of acetyl-CoA. The alkyl chain length is reduced by 2 carbon atoms during each β-oxidation cycle. Alternative pathways for oxidation can be found in the liver (ω-oxidation) and the brain (α-oxidation). Each two-carbon unit resulting from β-oxidation enters the citric acid cycle as acetyl-CoA, through which they are completely oxidised to CO(CIR, 1987; IOM, 2005; Lehninger, 1998; Stryer, 1996).

The potential metabolites following enzymatic metabolism of the test substance were predicted using the QSAR OECD toolbox (OECD, 2014). This QSAR tool predicts which primary and secondary metabolites of the test substance may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. Up to 18 hepatic metabolites and up to 32 dermal metabolites were predicted for the 6 main constituents of the test substance. Primarily, the ester bond is broken both in the liver and in the skin, after which the hydrolysis products may be metabolised further. The resulting liver and skin metabolites are the products of alpha-, beta- or omega-oxidation (= addition of hydroxyl group). The ester bond may also remain intact, in which case a hydroxyl group is added to, or substituted with, a methyl group. In general, the hydroxyl groups make the substances more water-soluble and susceptible to metabolism by phase II-enzymes. The metabolites formed in the skin are expected to enter the blood circulation and have the same fate as the hepatic metabolites. Up to 349 metabolites were predicted to result from all kinds of microbiological metabolism. The high number includes many minor variations in the c-chain length and number of carbonyl- and hydroxyl groups; reflecting the diversity of microbial enzymes identified. Not all of these reactions are expected to take place in the human GI-tract. The results of the OECD toolbox simulation support the information on metabolism routes retrieved in the literature.

There is no indication that Fatty acids C16-18 (even numbered), mono, di and triesters with sucrose is activated to reactive intermediates under the relevant test conditions. The experimental studies performed on genotoxicity (Ames test, gene mutation in mammalian cells in vitro, micronucleus test in vivo) using the test substance were consistently negative, with and without metabolic activation. The result of the skin sensitisation studies performed in guinea pigs were likewise negative.

 

Excretion

In general, the hydrolysis products sucrose and fatty acids are catabolised entirely by oxidative physiologic pathways, ultimately leading to the formation of carbon dioxide and water. Small amounts of ketone bodies resulting from the oxidation of fatty acids may be excreted via the urine; however, the major part of the fatty acids will enter an oxidative pathway as described above under ‘Metabolism’ (Lehninger, 1998; IOM, 2005; Stryer, 1996).

In the reviews/opinions prepared by the WHO (1995, 1998) and EFSA (2004) and the references therein, several in vitro and in vivo experiments on the excretion of sucrose esters (SE) in rats, dogs and human were evaluated, demonstrating that the non-absorbed fraction of sucrose esters that is not hydrolysed in the gastrointestinal tract will be mainly excreted via the faeces, whereas hydrolysis products are excreted via the faeces or expired as COas a result of metabolism.

In conclusion, incompletely hydrolysed sucrose esters of Fatty acids C16-18 (even numbered), mono, di and tristers with sucrose are expected to be mainly excreted via the faeces or as COafter being metabolised.

A detailed reference list is provided in the technical dossier (see IUCLID 6, section 13) and within the CSR.

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