Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Skin irritation (OECD 439): not irritating

Eye irritation (OECD 437): not corrosive/severe irritant

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vitro / ex vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
26 Sep - 01 Oct 2012
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP-Guideline study, tested with the source substance Isomaltulose (Cas# 13718-94-0). According to the ECHA guidance document "Practical guide 6: How to report read-across and categories (March 2010)", the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.
Qualifier:
according to guideline
Guideline:
OECD Guideline 439 (In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.46 (In Vitro Skin Irritation: Reconstructed Human Epidermis Model Test)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: L´Oréal Standard Operating Procedure: “EpiSkinTM SKIN IRRITATION TEST METHOD 15 min – 42 hours” – ECVAM Skin Irritation Validation Study – VALIDATION OF THE EpiSkinTM TEST METHOD 15 min – 42 hours FOR THE PREDICTION OF ACUTE SKIN IRRITATION OF CHEMICALS.
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
(BAYERISCHES LANDESAMT FÜR GESUNDHEIT UND LEBENSMITTELSICHERHEIT, LANDESINSTITUT FÜR ARBEITSSCHUTZ UND PRODUKTSICHERHEIT, München, Germany)
Species:
human
Strain:
other: EPISKIN-SM (TM): reconstructed three-dimensional human epidermis model
Details on test animals or test system and environmental conditions:
TEST SKIN MODEL
- Source: SkinEthic laboratories, Lyon, France
- Test system:
The model represents a reconstructed three-dimensional skin model based on normal human-derived epidermal keratinocytes which have been cultured on a collagen matrix for 13 days in cell culture inserts to form a multilayered epidermis including basal, spinous and granular layers, and a multi-layered stratum corneum. Irritant materials are identified by their ability to penetrate the stratum corneum and to damage the underlaying cell layers which is determined through a decrease in cell viability as determined by MTT reduction assay.
- Adaptation to cell culture conditions: Upon receipt, tissues were transferred into 12-well plates containing 2 mL prewarmed maintenance medium per well and preincubated in a humidified incubator for at least 24 h (37 ± 1 °C, 5% CO2) before use.

ENVIRONMENTAL CONDITIONS (Incubator)
- Temperature (°C): 37 ± 1
- CO2 gas concentration (%): 5
- Humidity: maximum
Type of coverage:
open
Preparation of test site:
other: intact reconstructed human epidermis
Vehicle:
unchanged (no vehicle)
Controls:
other: concurrent control tissues treated with phosphate buffered saline served as negative controls, positive controls were exposed to 5% SDS.
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 10 mg (26.3 mg/cm²)

POSITIVE CONTROL SUBSTANCE
- SDS, 5% (v/v) in aqua dest.
Duration of treatment / exposure:
15 ± 0.5 min
Observation period:
Not applicable. Post-treatment incubation period: 42 ± 1 h
Number of animals:
Not applicable.The test was performed in triplicates for each treatment and control group.
Details on study design:
TEST SITE
- Area of exposure: 0.38 cm²

REMOVAL OF TEST SUBSTANCE
- Washing: The test item was washed from the epidermal surface with phosphate buffered saline (PBS). Excess PBS was removed by blotting bottom with blotting paper.
- Time after start of exposure: 15 ± 0.5 min
- Post-treatment incubation period: 42 ± 1 h


CELL VIABILITY MEASUREMENTS
For determining alterations in cell viability, MTT reduction assays were performed 42 ± 1 h after the incubation period. Therefore, tissues were incubated in 2 mL prewarmed MTT solution for 3 h ± 5 min at 37 ± 1 °C and 5% CO2. Afterwards, tissues were dried on blotting paper and a total biopsy of the epidermis was performed. After separation of the epidermis and the collagen matrix, extraction of the formazan product from both parts was carried out in 500 µL acidic isopropanol. At the end of the extraction, extracts from the epidermis and collagen part were mixed and the optical density of 2 x 200 µL aliquots per sample was measured at 550 nm wave length in a plate spectrophotometer (Tecan Infinite 200, Tecan Austria).
Irritation / corrosion parameter:
other: other: cell viability (%)
Value:
100
Remarks on result:
other:
Remarks:
Basis: other: mean value of negative controls (PBS). Time point: 15 min. Reversibility: other: not applicable. (migrated information)
Irritation / corrosion parameter:
other: other: cell viability (% of negative control)
Value:
7
Remarks on result:
other:
Remarks:
Basis: other: mean value of positive controls (5% SDS). Time point: 15 min. Reversibility: other: not applicable. (migrated information)
Irritation / corrosion parameter:
other: other: cell viability (% of negative control)
Value:
95
Remarks on result:
other:
Remarks:
Basis: other: mean value of the test item. Time point: 15 min. Reversibility: other: not applicable. (migrated information)
Irritant / corrosive response data:
Topical application of Isomaltulose did not result in a decreased cell viability in the EPISKIN-SM model compared to the negative control tissues treated with PBS. In contrast, exposure to 5% SDS decreased the cell viability to 7% of the negative control tissues.



Table 1: MTT assay after 15 min exposure

 

Negative Control

Positive Control

Test Item

Blank

Tissue

1

2

3

1

2

3

1

2

3

OD550

0.901

0.827

0.707

0.113

0.092

0.092

0.742

0.816

0.757

0.043

0.899

0.817

0.697

0.107

0.088

0.087

0.741

0.813

0.762

OD550(mean, blank corrected)

0.857

0.779

0.659

0.067

0.047

0.047

0.698

0.771

0.717

SDOD550

0.089

0.011

0.034

OD550(mean values of triplicates)

0.765

0.053

0.729

SD tissue viability (%)

13.1

1.5

4.9

Viability (%)

100

7

95

According to the Test Acceptance Criteria, the validity criteria are fulfilled:

1.   mean OD550 nm of the 3 negative control tissues is ≥ 0.6 and ≤ 1.5

2.   OD550of the blank is < 0.1

3.   mean relative tissue viability of the 3 positive control tissues is 40%

4.   the standard deviation (SD) obtained from the three concurrently tested tissues is

< 18%.

 

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
CLP: not classified
DSD: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vitro / ex vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
30 Oct 2012
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP-Guideline study, tested with the source substance isomaltulose (Cas# 13718-94-0). According to the ECHA guidance document "Practical guide 6: How to report read-across and categories (March 2010)", the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.
Qualifier:
according to guideline
Guideline:
EU method B.47 (Bovine corneal opacity and permeability test method for identifying ocular corrosives and severe irritants)
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 437 (Bovine Corneal Opacity and Permeability Test Method for Identifying Ocular Corrosives and Severe Irritants)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
BAYERISCHES LANDESAMT FÜR GESUNDHEIT UND LEBENSMITTELSICHERHEIT, LANDESINSTITUT FÜR ARBEITSSCHUTZ UND PRODUKTSICHERHEIT, München, Germany
Species:
other: cattle
Strain:
not specified
Details on test animals or tissues and environmental conditions:
IDENTIFICATION OF THE SOURCE OF THE EYES, STORAGE AND TRANSPORT CONDITIONS
- Source: Attenberger Fleisch GmbH & Co. KG, Munich, Germany
- Date of eye collection: 30 Oct 2012
- Transport medium and temperature conditions: Hanks´ Balanced Salt Solution (HBSS) containing 5% penicillin/streptomycin on ice

PREPARATION OF THE EYES (BEFORE EXPOSURE)
- Eyes free of defects (scratches, neovascularisation): yes
- Dissection of the eyes and treatment: corneas were dissected with a 2 to 3 mm rim of sclera. Isolated corneas were mounted in cornea holders.
- Type of cornea holder used: MC2, Clermont, France
- Description of the cornea holder: the cornea holders consist of an anterior and a posterior compartment, which interface with the epithelial and endothelial side of the cornea.
- Test medium and temperature conditions used in the cornea holder: RPMI 1640 without phenol red supplemented with 1% [v/v] fetal bovine serum and 2 mM L-glutamine
- Equilibration time: 1 h at 32 ± 1 °C in a water bath
- Quality check of the equilibrated corneas: initial opacity measurement; corneas with an initial opacity above 7 in the opacitometer were discarded.

DETERMINATION OF THE INITIAL OPACITY
- Method: Corneal opacity was determined by the amount of light transmission through the cornea via an opacitometer.
- Specification of the device: MC2, Clermont, France
Vehicle:
physiological saline
Controls:
other: 3 corneas each for the negative (physiological saline, 0.9% NaCl) and the positive control (20% imidazole)
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied in the test: 750 µL
- Concentration (if solution): 20%

VEHICLE
- Amount(s) applied in the test: 750 µL
- Lot/batch no. (if required): 111214

POSITIVE SUBSTANCE
- Substance: imidazole
- Concentration: 20%
- Solvent: physiol. saline
- Amount(s) applied in the test: 750 µL
- Lot/batch no.: 109K5306V

Duration of treatment / exposure:
4 h ± 5 min at 32 ± 1 °C
Observation period (in vivo):
not applicable
Number of animals or in vitro replicates:
3 corneas for the test item
Details on study design:
TEST CONDITIONS
- Short description of the method used: closed-chamber method.
The test substance or control substances were introduced into the anterior chamber.

POST-EXPOSURE TREATMENT
- Removal of the test substance: The test substance was removed after 4 h incubation and the epithelium washed at least three times with MEM.
- Medium for washing the corneas: MEM containing phenol red
- Medium for final rinsing: RPMI 1640 without phenol red

DETERMINATION OF THE FINAL OPACITY
- Method: Corneal opacity was determined by the amount of light transmission through the cornea via an opacitometer.
- Time of determination: After refilling the anterior chamber with fresh RPMI 1640, the final opacity was measured.
- Specification of the device: MC2, Clermont, France

DETERMINATION OF THE CORNEAL PERMEABILITY:
- Method: Sodium fluorescein solution was added to the anterior chamber of the cornea holder while the posterior chamber was filled with fresh medium. The amount of sodium fluorescein that crosses into the posterior chamber was quantitatively measured via UV/VIS spectrophotometry at 490 nm recorded as optical density (OD490).
- Amount and concentration of the dye: 1 mL sodium fluorescein solution (5 mg/mL)
- Incubation time: 90 min at 32 ± 1 °C
Irritation parameter:
in vitro irritation score
Value:
0.75
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
no indication of irritation
Irritation parameter:
other: opacity
Basis:
other: mean (out of all 3 eyes)
Time point:
other: 4 h
Score:
1
Reversibility:
other: not applicable
Remarks on result:
other: negative control (0.9% NaCl)
Irritation parameter:
other: opacity
Basis:
other: mean (out of all 3 eyes)
Time point:
other: 4 h
Score:
166.67
Reversibility:
other: not applicable
Remarks on result:
other: positive control (20% imidazole)
Irritation parameter:
other: opacity
Basis:
other: mean (out of all 3 eyes)
Time point:
other: 4 h
Score:
1.33
Reversibility:
other: not applicable
Remarks on result:
other: test item (20% isomaltulose)
Irritation parameter:
other: permeability
Basis:
other: mean (out of all 3 eyes)
Time point:
other: 5 h 30 min
Score:
0.017
Reversibility:
other: not applicable
Remarks on result:
other: negative control (0.9% NaCl)
Irritation parameter:
other: permeability
Basis:
other: mean (out of all 3 eyes)
Time point:
other: 5 h 30 min
Score:
1.846
Reversibility:
other: not applicable
Remarks on result:
other: positive control (20% imidazole)
Irritation parameter:
other: permeability
Basis:
other: mean (out of all 3 eyes)
Time point:
other: 5 h 30 min
Score:
0.028
Reversibility:
other: not applicable
Remarks on result:
other: test item (20% isomaltulose)
Irritation parameter:
other: IVIS
Basis:
other: mean (out of all 3 eyes)
Score:
1.26
Reversibility:
other: not applicable
Remarks on result:
other: negative control (0.9% NaCl)
Irritation parameter:
other: IVIS
Basis:
other: mean (out of all 3 eyes)
Score:
193.35
Reversibility:
other: not applicable
Remarks on result:
other: positive control (20% imidazole)
Irritation parameter:
other: IVIS
Basis:
other: mean (out of all 3 eyes)
Score:
0.75
Reversibility:
other: not applicable
Remarks on result:
other: test item (20% isomaltulose)
Irritant / corrosive response data:
Isomaltulose at a concenration of 20% (v/v) reached an in vitro irritation score of 0.75. According to the evaluation criteria, the test substance is not considerd as severe eye irritant.
The in vitro irritation score obtained with the positve control fell within the two standard deviations of the current historical mean and therefore the assay is considered to be valid.

Table 1: Opacity values

Parameter

Initial opacity

Final opacity

Opacity change

Mean opacity change of NC

Corrected opacity change

Mean opacity value

Negative control

(0.9% NaCl)

2

4

2

1

-

-

3

3

0

3

4

1

Positive control

4

155

151

-

150

165.67

4

183

179

178

4

174

170

169

Test substance

4

5

1

-

0

0.33

2

3

1

0

1

3

2

1

 

 

Table 2: Permeability values (optical density (OD) at 490 nm)

Parameter

OD490 change

Mean OD490 change of NC

Corrected OD490 change

Mean OD490 value

Negative control

(0.9% NaCl)

0.015

0.017

 

 

0.012

0.024

Positive control

1.812

 

1.795

1.846

1.906

1.889

1.870

1.853

Test substance

0.014

 

-0.003

0.028

0.035

0.018

0.086

0.069

 

 Table 3: Historical Data

 

IVIS (positive control)

 

Mean value (MV)

 

203.04

Standard Deviation (SD)

 

27.63

MV – 2x SD

 

147.79

MV + 2x SD

 

258.29

Interpretation of results:
other: not corrosive/severe irritant
Conclusions:
There is regulatory acceptance in the EU that a substance can be considered a severe eye irritant (Serious eye damage Category 1/R41) based on a positive result in the Bovine Corneal Opacity and Permeability (BCOP) test. Negative in vitro corrosivity responses are not conclusive with respect to non-classification or classification as irritant (Category 2/R36) and shall therefore be subject to further evaluation.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin Irritation

Justification for read-across

There are no data available on the skin and eye irritation of Reaction mass of 1-O-α-D-glucopyranosyl-D-fructose and 6-O-α-D-glucopyranosyl-D-fructose and fructose and glucose and sucrose. In accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5, read-across from structurally related substances is conducted to fulfill the standard information requirements set out in Regulation (EC) No 1907/2006, Annex VIII, 8.1 and 8.2.

According to 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) “to avoid the need to test every substance for every endpoint”.

All substances contained in Reaction mass of 1-O-α-D-glucopyranosyl-D-fructose and 6-O-α-D-glucopyranosyl-D-fructose and fructose and glucose and sucrose represent mono- or disaccharides which all consist of glucose and/or fructose. Reaction mass of 1-O-α-D-glucopyranosyl-D-fructose and 6-O-α-D-glucopyranosyl-D-fructose and fructose and glucose and sucrose is the aqueous solution (syrup) of the reaction mass of isomaltulose (CAS 13718-94-0), trehalulose (CAS 51411-23-5), fructose (CAS 57-48-7), glucose (CAS 50-99-7), sucrose (CAS 57-50-1), isomaltose (CAS 499-40-1) and oligosaccharides.

All ingredients are substances naturally occurring in fruits, vegetables and other crops or honey.

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, whereby physicochemical, toxicological and ecotoxicological properties may be predicted from data for reference substance(s) by interpolation to other substances on the basis of structural similarity, isomaltulose (CAS 13718-94-0) is selected as source substances for assessment of skin and eye irritation.

The read-across is based on the presence of common functional groups and common breakdown products via biological processes, which result in structurally similar chemicals. In general, disaccharides like isomaltulose, trehalulose and sucrose are enzymatically hydrolysed at the glycosidic bond between the monosaccharide units to equal parts in glucose and fructose (Cheetham, 1982; Goda and Hosoya, 1983; MacDonald and Daniel, 1983; Yamada et al., 1985; Ziesenitz, 1986; Goda et al., 1991; Würsch, 1991; Günther and Heymann, 1998), which subsequently enter well-characterized carbohydrate metabolic pathways (Lina et al ., 2002) as essential energy substrate or they are converted to storable glycogen (see Toxicokinetics). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Skin irritation in vitro

The skin irritation potential of isomaltulose (CAS 13718-94-0) was determined in a GLP-compliant in vitro skin irritation test according to OECD 439 on EpiSkinTM human skin equivalents (SkinEthic laboratories, Lyon, France) after moistening (Lehmeier, 2012). After exposure to 10 mg isomaltulose and a post-incubation period of 42 h, cytotoxicity measurements revealed a relative mean tissue viability of 95% compared to the respective controls. In contrast, application of the positive control substance SDS (5%) reduced the relative tissue cell viability to 7% of the control tissues thereby validating the study. In accordance with the classification criteria given in OECD guideline 439 and Regulation (EC) No 1272/2008, isomalutlose is considered as non-irritant.

According to Regulation (EC) 1907/2006, Annex XI, section 1.4, an in vivo study is not considered necessary to confirm the negative test result as the results are derived from a scientific valid in vitro method (ECVAM, http://ihcp.jrc.ec.europa.eu/our_labs/eurl-ecvam/validation-regulatory-acceptance), which is adequate for the purpose of classification and labelling, and adequate and reliable documentation is provided in the technical dossier. Therefore, all conditions for waiving an in vivo skin irritation/corrosion study are met according to Annex XI, Section 1.4, of Regulation (EC) 1907/2006.Furthermore, no signs of skin irritation were noted in a Local Lymph Node Assay conducted with isomaltulose. Thus, together with the available data on in vitro skin irritation, there is sufficient weight of evidence available leading to the conclusion that isomaltulose and hence Reaction mass of 1-O-α-D-glucopyranosyl-D-fructose and 6-O-α-D-glucopyranosyl-D-fructose and fructose and glucose and sucrose is not irritating to skin.

Fructose, glucose and sucrose are not further described in the present dossier as sufficient information is known about the intrinsic properties to consider them as non-hazardous which resulted in inclusion on Annex IV of Regulation (EC) 1907/2006. This has been recently verified by the Comission as reviewed by Blainey et al. (2010). The remainder isomaltose occurs naturally at branch sites within amylopectin in starches and is thus present in commercially available starch hydrolysates and maltodextrines, which are both included in Annex IV.

Based on the available data on the surrogate substance isomaltulose, Reaction mass of 1-O-α-D-glucopyranosyl-D-fructose and 6-O-α-D-glucopyranosyl-D-fructose and fructose and glucose and sucrose is not considered to exhibit irritating properties to the skin.

 

Eye Irritation

Eye irritation in vitro

The eye irritation/corrosion potential of isomaltulose was tested in a GLP-compliant in vitro bovine corneal opacity and permeability test according to OECD 437 (Lütkenhaus, 2011a).750 µL of the test item solution, 20% dissolved in 0.9% NaCl, were introduced into the anterior chamber of the corneal holders for 4 h. Subsequent measurements after rinsing revealed a mean opacity value of 1.33 and a mean permeability value of 0.028 resulting in an in vitro irritancy score (IVIS) of 0.75. According to the evaluation criteria given in OECD 437, the conducted in vitro test did not identify isomaltulose as an ocular corrosive.

An in vivo study to confirm the non-irritating properties is considered as not necessary as the result is derived from a scientific valid in vitro method (ECVAM,http://ihcp.jrc.ec.europa.eu/our_labs/eurl-ecvam/validation-regulatory-acceptance/topical-toxicity/eye-irritation), reliable documentation is provided in the technical dossier and the everyday use of sugars - in crystalline and liquid form - in virtually every household with historical safe use proves the low intrinsic toxicological profile of sugars including irritation properties. Furthermore, the ingredients glucose, fructose and sucrose are included in Annex IV thereby certifying non-hazardous potential to human health. Thus, together with the available data on in vitro eye irritation, sufficient weight of evidence is available leading to the conclusion that isomaltulose and hence Reaction mass of 1-O-α-D-glucopyranosyl-D-fructose and 6-O-α-D-glucopyranosyl-D-fructose and fructose and glucose and sucrose is not irritating to eyes.

Fructose, glucose and sucrose are not further described in the present dossier as sufficient information is known about the intrinsic properties to consider them as non-hazardous which resulted in inclusion on Annex IV of Regulation (EC) 1907/2006. This has been recently verified by the Comission as reviewed by Blainey et al. (2010). The remainder isomaltose occurs naturally at branch sites within amylopectin in starches and is thus present in commercially available starch hydrolysates and maltodextrines, which are both included in Annex IV.

Based on the available data on the surrogate substance isomaltulose, Reaction mass of 1-O-α-D-glucopyranosyl-D-fructose and 6-O-α-D-glucopyranosyl-D-fructose and fructose and glucose and sucrose is anticipated not to exhibit irritating properties to the eyes.

 

References not included in IUCLID:

Blainey M, Avila Cd, van der Zandt P. Review of REACH Annex IV--establishing the minimum risk of a substance based on its intrinsic properties. Regul Toxicol Pharmacol. 2010 Feb; 56(1):111-20.

Cheetham, P.S.J. 1982. The human sucrase-isomaltase complex: Physiological, biochemical, nutritional and medical aspects. In: Lee, C.K.; Lindley, M.G. (Eds.). Developments in Food Carbohydrate - 3. Disaccharidases. Applied Science Publishers; London, Engl./Englewood, New Jersey, pp. 107-140.

Goda, T.; Hoyosa, N. 1983. Hydrolysis of palatinose by rat intestinal sucrase-isomaltase complex. Nihon Eiyo Shokuryo Gakkaishi 36:169-173. Cited In: Würsch, 1991.

Goda, T.; Takase, S.; Hosoya, N. 1991. Hydrolysis of palatinose condensates by rat intestinal disaccharidases. Nihon Eiyo Shokuryo Gakkaishi 44(5):395-398.

Günther, S.; Heymann, H. 1998. Di- and oligosaccharide substrate specificities and subsite binding engergies of pig intestinal glycoamylase-maltase.Arch Biochem Biophys 354(1):111-116.

Lina, B.A.R.; Jonker, D.; Kozianowski, G. 2002.Isomaltulose (Palatinose®): A review of biological and toxicological studies. Food Chem Toxicol 40(10):1375-1381

MacDonald, I.; Daniel, J.W. 1983. The bioavailability of isomaltulose in man and rat. Nutr Rep Int 28(5):1083-1090.

Würsch, P. 1991. Metabolism and tolerance of sugarless sweeteners. In: Rugg-Gunn, A.J.(Ed.). Sugarless: The Way Forward. Else vier Applied Science; New York, pp. 32-51.

Yamada, K.; Shinohara, H.; Hosoya, N. 1985. Hydrolysis of 1-O-α-D-glucopyranosyl-D-fructofuranose (Trehalulose) by rat intestinal surcrase-isomaltase complex.Nutrition Reports International 32 (5): 1211 - 1220

Ziesenitz, S.C. 1986. Carbohydrasen aus jejunalmucosa des Menschen = [Carbohydrases from the human jejunal mucosa]. Z Ernährungswiss 25(4):253-258. Cited In: Würsch, 1991.

Justification for selection of skin irritation / corrosion endpoint:

Hazard assessment is conducted by means of a read-across from a structural surrogate. The selected study is an adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall quality assessment (refer to the endpoint discussion for further details).

Justification for selection of eye irritation endpoint:

Hazard assessment is conducted by means of a read-across from a structural surrogate. The selected study is an adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall quality assessment (refer to the endpoint discussion for further details).

Justification for classification or non-classification

Based on read-across, the available data on skin or eye irritation do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.