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Administrative data

Description of key information

Oral, rat: estimated LD50: 29 700 mg/kg bw (females) (Boyd et al., 1965)

Oral, rat: estimated LD50: 35 400 mg/kg bw (males) (Boyd et al., 1965)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
acute toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented publication report which meets basic scientific principles.
no guideline followed
Principles of method if other than guideline:
Wistar rats were exposed to high dosages of sucrose ranging from 5000 - 80 000 mg/kg bw in a single application via gavage to calculate the LD50 value. Clinical signs and pathological findings were correlated to the time point of death of nonsurviving animals after gavage. The reversibility of treatment-related effects was established in surviving animals 2 and 4 weeks after substance administration.
GLP compliance:
Test type:
standard acute method
Limit test:
Details on test animals or test system and environmental conditions:
- Source: Department of Pharmacology, Queen´s University, Kingston, Ontario, Canada
- Age at study initiation: adult
- Weight at study initiation: 300-500 g (males), 250 - 300 g (females)
- Fasting period before study: Animals were fasted 16 h prior to administration (only food starvation, water was provided ad libitum).
- Housing: individual in metabolism cages
- Diet: Purina Fox Chow Checkers, Ralston Purina Company, St. Louis, Missouri, ad libitum
- Water: ad libitum

Route of administration:
oral: gavage
other: distilled water
Details on oral exposure:
- Amount of vehicle (if gavage): 60 mL/kg bw


5000 - 80 000 mg/kg bw (divided in 19 dosages), not further specified
No. of animals per sex per dose:
males: 48 (controls), 16 - 20 (mid-dose groups), 4 - 8 (the lowest 4 and highest 3 dose groups)
females: 30 (not further specified)
Control animals:
Details on study design:
- Duration of observation period following administration: 14 days and 1 month
- Frequency of observations and weighing: animals were observed 6 days a week for 2 weeks followed by casual observations up to 1 month
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights, gross and histopathology, other: food and water intake, colonic temperature, determination of water levels in the organs, urinalyses.
To determine the above mentioned parameter, the following organs were examined: adrenal glands, brain, gastrontestinal tract including cardiac and pyloric stomach, small bowel, caecum and the colon, heart, kidneys, liver, lungs, muscle of the abdominal wall, skin, spleen, testes and the thymus gland in addition to the residual caracsses.
Statistical methods used were those described by Croxton (1953, Elementary Statistics with Applications in Medicine. Prentice-Hall, New York).
Dose descriptor:
Effect level:
29 700 mg/kg bw
Based on:
test mat.
Dose descriptor:
Effect level:
35 400 mg/kg bw
Based on:
test mat.
In the lower dose groups ranging from 5 000 - 24 000 mg/kg bw, no deaths occured whereas all animals died from the high-dose groups (60 000, 70 000 and 80 000 mg/kg bw). The frequency distribution of deaths versus time of animals exposed to up to 50 000 mg/kg bw showed a peak at 4 h, a valley at 9 h and a broad plateau at 12 - 48 h. In detail, 76 deaths occured at 9 h or less, all except 1 animal given 35 000 mg/kg bw and more. 43 deaths occured beyond 9 h with 23 of them in animals given less than 35 000 mg/kg bw. 38 deaths occured within 10 - 48 h and 5 deaths within 2 - 11 days. In addition, 2 control animals died on the 5th day possibly due to the toxic effects of distilled water.
Clinical signs:
In general, dehydration of test animals was observed following administration. Further, initial clinical signs including hypokinesia, prostration, abdominal bloating and diarrhea were observed in test and control animals with controls showing the symptoms to a lesser extent and period of time. In detail, test animals showed stronger effects during the first 6 h which persisted to 24 - 48 h. At that time, controls were already free of clinical signs. In addition, cyanosis was observed only in test animals. Further, gastroenteritis appeared after 1 - 3 h and disappeared at 1 - 4 days.
Premortal signs were tonic-clonic convulsions followed by stupor and respiratory failure observed in animals that died within 9 h after gavage.
Body weight:
Animals exposed to more than 20 000 mg sucrose/kg bw revealed a significantly decreased body weight ( p < 0.001) which was due to anorexia and diarrhoe. Moreover, food intake was depressed during the first 24 h following administration in all surviving rats given dosages above 20 000 mg/kg bw whereas the water intake rose in rats given dosages up to 20 000 mg/kg bw and varied thereafter erratically with a second peak in animals exposed to approx. 45 000 mg/kg bw.
Gross pathology:
In parallel to the generalized dehydration and loss of body weight, the following findings were detected in nonsurviving animals: severe but temporary gastroenteritis, a temporary mild hepatitis, marked nephritis and encephalities, focal necrosis of the heart, moderate stressor reactions in the adrenal and thymus gland, inhibition of spermatogenesis and arteriolitis. In contrast, the parenchyma of the lungs, pancreas, salivary glands, spleen and the skin appeared normal.
Organs of surviving animals appeared grossly normal.
Other findings:
Organ weights: the autopsy of 16 nonsurviving test animals (dose groups are not further specified) showed a significant loss of wet weight in the carcasses (- 13.9%), the liver (- 42.6%) and testes (- 7.2%). Moreover, water levels decreased significantly in the carcass (- 28.9%) and the following organs: pyloric stomach (- 39.6%), small bawel (- 25.7%), caecum (- 43.5%), colon (- 27.2%), lungs (- 22.5%), muscle of the abdominal wall (- 19.6%), skin (- 24.2%) and testes (- 15.8%). In contrast, a significant increase in wet weight was observed for the small bowel of the gastrointestinal tract (+ 16.4%). No significant increases in the water levels were observed.
In surviving test animals, significantly increased organ weights were determined 2 weeks after substance administration for the adrenal gland (+ 35.5 %), stomach (cardiac stomach: + 29.4%, pyloric stomach: + 25.9%), small bowel (+ 52.7%), caecum (+ 66.3%) and striated muscle (+ 27.8%) while the weights of the heart (- 14.6%), kidney (- 12.8%), liver (- 14.4%) and spleen (-20.5%) were significantly decreased. 1 months after substance administration, a significant decrease in liver wet weight was determined (- 26.1%). Significant low water levels were found in the brain (- 3.7%), the polyoric stomach (- 7.2%) and the spleen (- 10.8%).

Histopathology of nonsurviving animals revealed the following findings (the given time reflects the time frame between substance administration and death):
gastrointestinal tract: Gastroenteritis appeared at 1 - 3 h and disappeared at 1 - 4 days and was confined mostly to the stomach, the small bowel and the cardiac stomach with capillary, arteriolar and venous congestion of the lamina propria and submucosa. Areas of lysis of the surface layers of stratified squamous epithelium was observed in the cardiac stomach. Along with a similar vascular reaction in the pyloric stomach, a marked lysis of the surface of columnar epithelium and moucous neck cells, somewhat less lysis of the parietal cells was observed. Further, shrinkage of the zymogens with swelling of the lamina propria at the base of the gastric glands was detected. The villi of the small bowel were congested, the lamin propria edematous and the columnar epithelium completely denuded in many areas with very little heamorrhage in the lumen. An inflammatory reaction in the caecum was confined to capillary congestion and edema of the lamina propria and in the colon to a mild capillary congestion. Animals that died at 24 h did not show alterations in the latter 2 structures while the upper part of the alimentary canal was largely normal. Animals that died 4 days after administration showed occasional mild congestion in the submucosa and some edema of the arteriolar walls.

liver: The marked loss of weight was correlated to a shrinkage of hepatic cells: the sinusoids were distended and filled with red blood cells. The Kupffer cells were shrunken and often lysed away from the lining of the sinusoids. This effect was mostly evident at 3 h. By 24 h, the liver appeared microscopically normal.

kidney:Already 1 h after administration of a lethal dose of sucrose, alterations in the kidney were observed including shrunken glomeruli, increased subcapsular space, shrunken and distorted proximal tubular cells, prominent granules at the base of the brush border. At 3 h, the lumen of the proximal convoluted tubular cells were swollen and obliterated. Further, the loop cells were edematous and the distal tubular cells were shrunken with casts in the lumen. Vacuolar degeneration of the proximal tubular cells appeared at 24 h and bits of tubular debris was detected refluxed into the glomerular space beneath Bowman´s capsule. In addition, at this time, the squamous epithelium lining in the descending limb of the loop of Henle was swollen and some necrosis of the cuboidal epithelium lining the ascending limb was evident. An inflammatory reaction was less marked in the distal convoluted and collecting tubular cells were shrunken with casts in the lumen. A vacuolar degeneration was observed in animals that died at 4 days.

coronary arteries: The coronary arteries were dilated and the arterial wall was swollen and pale stained 3 h after administration in nonsurviving animals. In parallel, a marked capillary vasodilatation of the myocardium with minute areas of capillary heamorrhage was present. 1 - 4 days after substance administration, minute areas of focal necrosis with leucocyte infiltration were found scattered throughout the heart muscle.

adrenal glands: 1 - 3 h after gavage, cortical sinusoids of the adrenal glands were either congested or collapsed. Subsequently, they appeared normal but enlarged.

thymus gland: The microscopic appearance of the thymus gland varied. However, common findings were mild capillary and venous congestion in parallel to some loss of thymocytes.

testes: 1 h after gavage, a shrinkage of the seminiferous tubules was evident. When death was delayed to 4 days, spermatogenic cells were found separated from the tubular wall. The sperm was shriveled and wrinkled. Further, leucocyte infiltration in the interstitial tissue was observed.

arterioles: In the lung, a periarteriolar edema was observed 1 h after the lethal dose was applied. At 3 h, the intima and media of the splenic arterioles were edematous and pale stained. In the heart and the mesentery, the edema extended to the tunica externa. In the blood stream, large numbers of leucocytes were recorded.

minor changes in nonsurvivors: Phagocytosis was active in macrophages in the thymus and the spleen. The M disks of striated muscle were prominent in animals dying at 1 h. Later the muscle fibers were swollen in some animals and shrunken in the others. Further, the subcutaneous tissues were shrunken. Microscopical analyses of animals that died 4 days after gavage indicated a reactive hypertrophy of the gastrointestinal mucosa which appearently counted for the increase in weight of the alimentary organs at day 14.

-Microscopical analyses of surviving animals: 1 months after substance administration, livers of surviving test animals were significantly smaller (wet weight: - 26.1% of controls). Further, the water content of the thymus gland showed a significant decrease around 28% compared to controls.

- Other observations:
Colonic temperature over the first 24 h after substance administration: An increased colonic temperature was determined in test animals exposed to up to 30 000 mg/kg bw sucrose. Test animals of higher dose groups showed erratically decreased colonic temperatures with the mean over all dosages above 30 000 mg/kg bw beeing significantly reduced (p = 0.005).

Urinalyses: A dose-dependent increase in the excretion of glucose and the volume of urine was observed in animals with a peak near the LD50 value (urine volume at approx. 30 000 mg/kg bw; glucose content at approx. 25 000 - 35 000 mg/kg bw). In test animals exposed to higher dosages, no dose-dependent trend was obvious in these parameters. Moreover, the daily urinary output of protein revealed no treatment-related effect. In contrast, the urinary pH was decreased in test animals in a dose-dependent manner.


The analyses indicated that the above mentioned clinical signs observed in nonsurviving animals were reversible in animals which survived the study. Clinical signs like hypokinesia, prostration, cyanosis, abdominal bloating, diarrhea, anorexia, glycosuria and weight loss disappeared by the 3rd day while polydispia and polyuria, the elevated body temperature and alkalinuria disappeared by the 6th day.

Potential target organs: brain and meninges, gastrointestinal tract, liver (seems to be capable to recover rapidly within 24 h in regard to histopathological findings)

Interpretation of results:
not classified
Migrated information Criteria used for interpretation of results: EU
CLP: not classified
DSD: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 2) of one major component with structural similarities and intrinsic properties to the remaining ingredients. Read-across is justified based on common functional group(s), common breakdown products, similarities in PC/ECO/TOX properties (refer to endpoint discussion for further details).

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Acute toxicity

Justification for read-across

There are no data available on the acute toxicity 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 VII, 8.5.

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, sucrose (CAS 57-50-1) and isomaltulose (CAS 13718-94-0) are selected as source substances for assessment of acute toxicity.

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).


Acute oral toxicity

Animal data

The acute toxic potential of sucrose was determined by Boyd et al. (1965). Wistar rats were exposed to dose levels ranging from 5000 - 80 000 mg sucrose/kg bw via gavage. Reversibility of treatment-related effects was established in surviving animals 2 and 4 weeks after substance administration.In the lower dose groups ranging from 5 000 - 24 000 mg sucrose/kg bw, no deaths occurred whereas all animals exposed to dose levels above 60 000 mg/kg bw died. In general, dehydration of test animals and hypokinesia, prostration, abdominal bloating, diarrhoea and cyanosis were observed following sucrose administration. Premortal signs were tonic-clonic convulsions followed by stupor and respiratory failure. Animals exposed to more than 20 000 mg sucrose/kg bw revealed a significantly decreased body weight due to anorexia and diarrhoea. Food intake was depressed in all surviving rats exposed to ≥ 20 000 mg/kg bw. Nonsurviving animals revealed temporary gastroenteritis, mild hepatitis, marked nephritis and encephalities, focal necrosis of the heart, moderate stressor reactions in the adrenal and thymus gland, inhibition of spermatogenesis and arteriolitis. Histopathology of nonsurviving animals revealed adverse effects on the gastrointestinal tract, e.g. gastroenteritis, arteriolar and venous congestion of the lamina propria and submucosa, lysis of the surface layers of stratified squamous epithelium in the cardiac stomach and of the surface of columnar epithelium and moucous neck cells and inflammatory reaction in the caecum. In surviving animals, all clinical signs were reversible. As potential target organs, the brain and meninges, the gastrointestinal tract and the liver were identified.Based on the mortality rates, oral LD50 values of 29 700 and 35 400 mg sucrose/kg bw were estimated for females and males, respectively.

Human data

Several clinical studies have been conducted which demonstrate the tolerability of isomaltulose in humans. Isomaltulose administered either as a powder or provided in food did not vary flatulence, diarrhoea, and stool frequency in concentrations ranging from 12 to 50 g isomaltulose/day (Spengler and Sommerauer 1989; Kawai et al., 1985, 1989) or up to 1 g/kg body weight (Mac Donald and Daniel 1983). Consumption of 12 or 24 g isomaltulose/day for a period of 10 days by 6 healthy volunteers was reported by Kashimura et al. (1990) not to induce any changes on faecal microflora populations, pH, or water content. A slight increase in total cholesterol was reported to occur with the isomaltulose intake. No significant effects were reported on low-density lipoprotein (LDL), very low-density lipid cholesterol (VLDLC), high-density lipoprotein cholesterol (HDLC), or total cholesterol (TC) (Kashimura et al., 1989, 1990, 1993).

Overall based on the results of the studies described above, there exists clear evidence of tolerability to isomaltulose at doses of up to 1 g/kg body weight (~70 g isomaltulose), administered under bolus dosing conditions. Additionally, unpublished Shin Mitsui Sugar Co.’s test reports indicate that 80 g of isomaltulose administered as an aqueous solution to healthy fasting volunteers did not induce any laxative effects, as evidenced by no reports of diarrhoea following consumption of the isomaltulose solution (Shin Mitsui Sugar Co., 2003, unpublished). Thus, higher total daily intakes of isomaltulose are expected to be well-tolerated, especially when isomaltulose is administered in smaller amounts throughout the day. Considering the similarity of the metabolism pathways of trehalulose and isomaltulose, an equal tolerability can be assumed for trehalulose.

Fructose and glucose 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). 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 substances sucrose and 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 induce adverse health effects after acute oral exposure.


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 condens ates 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.

Kashimura, J.; Hara, T. and Nakajinma, Y. 1993. Effects of isomaltulose-based oligomers on the human intestinal environment. Nihon Eiyo Shokuryo Gakkaishi 46(2):117-122.

Kashimura, J.; Nakajima, Y.; Benno, Y.; Endo, K.; Mitsuoka, T. 1989. Effects of palatinose and its condensate intake on human faecal microflora. Bifidobact Microflora 8(1):45-50.

Kashimura, J.; Nakajima, Y.; Benno, Y.; Misuoka, T. 1990. Comparison of faecal microflora among subjects given palatinose and its condensates. Nihon Eiyo Shokuryo Gakkaishi 43(3):175-180

Kawai, K.; Okuda, Y.; Yamashita, K. 1985. Changes in blood glucose and insulin after an oral palatinose administration in normal s ubjects. Endocrino l Jpn 32(6):933-936.

Kawai, K.; Yoshikawa, H.; Murayama, Y.; Okuda, Y.; Yamashita, K. 1989. Usefulness of palatinose as a caloric sweetener for diabetic patients.Horm Metab Res 21:338-340.

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.

Shin Mitsui Sugar Co., 2003. Cerestar. 2003. [Private Communication RE: Isomaltulose: Comparison of the Specifications and Production Methods of Cerestar, Südzucker and Shin Mitsui Sugar Co.]. Cerestar, a Cargill Company; Belgium.

Spengler, M.; Sommerauer, B. 1989. Toleranz und Akzeptans von Isomaltulose (Palatinose®) im Vergleich zu Saccharose bei 12-Wüchiger Oraler Gabe von Aufsteigenden Dosen (12 - 48 g) am Gesunden Probanden. Isomaltulose-Studie Nr. 101, Bayer Bericht Nr. 17792 (P) vom 7.3.1989. Cited In: Lina et al., 2002.

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 acute toxicity – oral 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.

Justification for selection of acute toxicity – inhalation endpoint

No study required since exposure of humans via inhalation is unlikely taking into account the physicochemical properties of the substances and the lack of exposure to aerosols, particles or droplets of inhalable size under normal conditions of use.

Justification for selection of acute toxicity – dermal endpoint

No study required since sufficient weight of evidence is available to exclude that 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 toxic after acute dermal exposure considering the available data on read-across to the main components, which have been shown not to be irritating, sensitising or toxic after acute or repeated oral exposure. Moreover, sufficient information is known for the ingredients glucose, fructose and sucrose to consider them as non-hazardous and to include them in Annex IV of Regulation (EC) No. 987/2008.  Therefore, in accordance with Annex XI, Section 1.2 of Regulation (EC) 1907/2006 further testing on vertebrate animals for that property shall be omitted and further testing not involving vertebrate animals may be omitted.  

Justification for classification or non-classification

Based on read-across, the available data on acute toxicity 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.