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EC number: 208-436-5 | CAS number: 528-50-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Direct observations: clinical cases, poisoning incidents and other
Administrative data
- Endpoint:
- direct observations: clinical cases, poisoning incidents and other
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- fall 2017 to spring 2018
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Data source
Reference
- Reference Type:
- publication (copyright not owned for reproduction)
- Title:
- Unnamed
- Year:
- 2 019
- Report date:
- 2019
Materials and methods
- Study type:
- study with volunteers
- Endpoint addressed:
- other: maximum tolerated dose (oral route), acute and subacute
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- The goal of this single-arm, dose-escalation study was to evaluate the safety and tolerability of cellobiose and to determine the maximum tolerated dose of cellobiose in healthy subjects. Following a baseline period, consecutive cohorts of six subjects each consumed either single doses of 10, 15, 20 and 25 g, while 12 subjects each received multiple doses of 15 g or 20 g cellobiose (twice daily, 14 days). The main recorded parameters were stool consistency, gastrointestinal well-being (Gastrointestinal Symptom Rating Scale) and adverse events.
- GLP compliance:
- not specified
- Remarks:
- The study was in conformity with the ethical principles for medical research involving human subjects of the World Medical Association Declaration of Helsinki as well as the EU recommendations for Good Clinical Practice (CPMP/ICH/135/95), ICH E6 (R2)
Test material
- Reference substance name:
- D-cellobiose
- EC Number:
- 208-436-5
- EC Name:
- D-cellobiose
- Cas Number:
- 528-50-7
- Molecular formula:
- C12H22O11
- IUPAC Name:
- (2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-[(2R,3S,4R,5R,6R)- 4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol
Constituent 1
Method
- Type of population:
- general
- Subjects:
- - Number of subjects exposed: 52 (total
- Sex: females and males
- Age: adults
- Race: no information ,but likely kaukasian
- Demographic information: none
- Known diseases: none
- Other: mean BMI approx. 24 - Ethical approval:
- confirmed, but no further information available
- Route of exposure:
- oral
- Reason of exposure:
- intentional
- Exposure assessment:
- not specified
- Details on exposure:
- see 'Any other information on materials and methods incl. tables'
- Examinations:
- - gastrointestinal symptoms
- stool consistency acc. to the Bristol Stool Form Scale (BSFS)
- full blood count parameters (haemoglobin, haematocrit, erythrocytes, thrombocytes, and leucocytes) and liver and renal function parameters (alanine transaminase, aspartate aminotransferase, gamma-GT, alkaline phosphatase, bilirubin; creatinine, urea, uric acid)
- lipid metabolism parameters (total cholesterol, HDL- and LDL-cholesterol), the carbohydrate metabolism parameter glycated haemoglobin HbA1c, glucose and thyroidal parameter TSH
- Dipstick urinalyses for the assessment of glucose, proteins and infection parameters
- Sitting blood pressure and pulse rate
Results and discussion
- Clinical signs:
When administered as a single dose, adverse events like flatulence plus borborygmus (n = 2) and diarrhoea (n = 1) occurred in 50% of the subjects (3 of 6) after consuming 25 g cellobiose, whereas 20 g cellobiose resulted in only one case of flatulence plus borborygmus among six subjects (17%). No adverse GI events were caused by 10 g or 15 g cellobiose. There were no significant stool consistency changes (three days after V2 compared to baseline) when comparing the cohorts of the SAD phase. In one case, diarrhoea occurred after consuming 25 g cellobiose, this normalised again one day later. In all single-dose groups, the mean GSRS scores remained in the same range (15.0 ± 0 and 19.5 ± 4.7). Based on the observed low level of adverse events, BSFS types and the GSRS results, as well as on the 100% global tolerability rating, the tolerable cellobiose intake level was set to 20 g cellobiose daily for single use. Higher acute doses may result in a substantial level of adverse GI events, as observed in this study with 25 g cellobiose. This dose approximately corresponds to the literature data with a single dose no-observed-effect level of 0.36 g/kg bw/day [15] (25.2 g for a 70 kg person) [15].
There were clear differences between the two multiple-dose groups (20 g bid versus 15 g cellobiose bid): Whereas 20 g cellobiose bid caused a GI adverse event rate of 58%, the GI AE rate was 8% in the 15 g bid group. The mean stool consistency was significantly thinner in the 20 g cellobiose bid group compared to the 15 g bid group three days after V2; also, in the 20 g bid group (but not in the 15 g bid group), the GSRS values were elevated during intake (Figure 5). These results, as well as the 92.6% global tolerability rating for the 15 g bid group, support a tolerable dose of repeated cellobiose consumption of 15 g twice daily (30 g total). This daily dose is 6 × higher than what was previously reported as the multiple-dose in literature [14].
Some parameters did not result in any group differences, e.g., time of bowel movement, bowel movement frequency, occurrence of headache/thirst or safety laboratory parameters and vital signs. Considering that the upper SAD and MAD dosage groups only had slightly more loose stools, this is plausible. Increased bowel movement frequencies would only be expected for more severe diarrhoea. To confirm safety, it is reassuring that laboratory safety parameters did not change in a clinically relevant manner. The occurrence of headache or thirst did not correlate with the dosages and may therefore not be related to cellobiose intake.
As to be expected, some individuals were more sensitive to cellobiose than others, regarding gastrointestinal disturbances. For example, the two subjects that suffered from the adverse event recurrent diarrhoea after the intake of 20 g cellobiose bid also suffered from flatulence. At the same time, five of 12 individuals did not experience any GI events at this high dose.
Additionally, some of the recorded GI events may have been unspecific and not related to the cellobiose intake. In this regard, one subject that ingested 15 g cellobiose bid experienced diarrhoea three days after cellobiose discontinuation (Figure 4A). However, the same subject also experienced diarrhoea on day five of the baseline period; accordingly, the observed diarrhoea on day 17 may have been a result of a general tendency towards GI disturbance, rather than a (late) cellobiose effect.
Applicant's summary and conclusion
- Conclusions:
- In a study evaluating cellobiose in healthy subjects for 14 days evidence of gastrointestinal tolerance at lower dosages (up to 15 g twice daily or 20 g once daily) and a fairly good safety profile at the highest dosage tested (25 g daily or 20 g twice daily). Mild signs of intolerance expressed as gastrointestinal complaints were observed in sensitive subjects. Based on the study results, the tolerable dose of cellobiose consumption is proposed to be 20 g cellobiose daily for single-use and 15 g twice daily (30 g total) for repeated consumption.
- Executive summary:
In a study evaluating cellobiose in healthy subjects for 14 days evidence of gastrointestinal tolerance at lower dosages (up to 15 g twice daily or 20 g once daily) and a fairly good safety profile at the highest dosage tested (25 g daily or 20 g twice daily). Mild signs of intolerance expressed as gastrointestinal complaints were observed in sensitive subjects. Based on the study results, the tolerable dose of cellobiose consumption is proposed to be 20 g cellobiose daily for single-use and 15 g twice daily (30 g total) for repeated consumption.
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