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EC number: 222-793-4 | CAS number: 3615-41-6
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
Cross-reference
- Reason / purpose for cross-reference:
- read-across: supporting information
Reference
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Justification for type of information:
- Additional documentation, provided within the IUCLID Assessment Reports (Section 13), supports the read-across approach.
- Reason / purpose for cross-reference:
- read-across source
- Reason / purpose for cross-reference:
- reference to same study
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 other: % in diet
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects observed at highest dose tested
- Key result
- Critical effects observed:
- no
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 2 015
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guideline M3(R2) (ICH, 2009). 2.2.1.
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: US FDA Redbook Guideline for Subchronic Toxicity Studies with Rodents (US FDA, 2003)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 6-deoxy-L-β-galactose
- EC Number:
- 219-452-7
- EC Name:
- 6-deoxy-L-β-galactose
- Cas Number:
- 2438-80-4
- Molecular formula:
- C6H12O5
- IUPAC Name:
- 6-deoxyhexopyranose
- Test material form:
- solid: particulate/powder
- Details on test material:
- - Purity: 98.8%
Constituent 1
- Specific details on test material used for the study:
- - Purity: 98.8%
-Impurities: Not reported
Test animals
- Species:
- rat
- Strain:
- other: Crl:CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: PND 21
- Weight at study initiation: not reported
- Housing: F1 pups post-weaning, were individually housed in suspended, stainless steel, wire-mesh type cages,
- Diet: Meal Lab Diet Certified Rodent Diet #5002 (ad libitum)
- Water: tap water (ad libitum)
ENVIRONMENTAL CONDITIONS
- Temperature: 20–26 °C
- Humidity: 30–70%
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- TEST SUBSTANCE PREPARATION
- Preparation frequency: weekly
- Preparation details: administered in the diet
- Adjusted for purity: no - Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- Not reported
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- Daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0.25 other: %
- Remarks:
- nominal in diet
- Dose / conc.:
- 0.5 other: %
- Remarks:
- nominal in diet
- Dose / conc.:
- 1 other: %
- Remarks:
- nominal in diet
- No. of animals per sex per dose:
- Control and high dose groups (F1) consisted of 30 animals/sex, for which 10 animals/sex were used in a one-month recovery group. Low and middle dose groups consisted of 20 animals/sex.
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: : The concentration levels were selected based on a previous preliminary study in which no compound-related effects were observed in P females or their offspring following maternal dosing at the same concentrations for 14 days starting from PND 7. The highest dietary concentration of 1% was selected as the top dose to allow for a sufficient margin of safety when compared to potential human infant exposures. The test item was administered in the diet at dose levels of 0.25%, 0.5%, and 1.0% to groups of 26 male (during mating) and female (28 days prior to mating through weaning of the F1 generation) rats.
- Rationale for animal assignment (if not random): : At weaning on PND 21, selected F1 pups were weighed and observed individually, and one male or one female from each litter in each group was randomly selected to continue onto the 13-week phase.
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily for mortality and moribundity
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical cage side examinations were performed daily and detailed clinical examiniations were performed weekly.
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly
FOOD CONSUMPTION: Yes
- Time schedule for examinations: Weekly
FOOD EFFICIENCY: Yes
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Prior to administration of test substance and at the end of the study
HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of the 13-week administration period
- Anaesthetic used for blood collection: carbon dioxide
- Animals fasted: Yes
- How many animals: 5 animals/sex/group
- Blood samples were analysed for routine haematology, coagulation, and clinical chemistry parameters. Standard haematology parameters were measured using an automated instrument or were calculated from measured values. Blood cells also were examined for morphology. Coagulation parameters were analysed with a Stago Compact.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of the 13-week administration period
- Anaesthetic used for blood collection: carbon dioxide
- Animals fasted: Yes
- How many animals: 5 animals/sex/group
- Standard clinical chemistry parameters were analysed with an Olympus Au2700/Au640.
URINALYSIS: Yes
- Time schedule for collection of urine: end of the 13-week administration period
- Metabolism cages used for collection of urine: yes
- Animals fasted: not reported
- Urinalysis was performed to examineappearance, colour, volume, specific gravity, and pH, and the presence of protein, glucose, bilirubin, ketone bodies, occult blood. Urine sediments also were microscopically examined.
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Study week 12
OTHER: Yes
- 1 Generation Reproduction Study - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
- All necropsied animals (sacrificed on Day 92 of the 13-week study) were examined carefully for external abnormalities including palpable masses, and were subjected to a full and detailed macroscopic examination of organs and tissues and the results recorded. Body weights and organ weights were recorded for F1 animals of the 13-week study and recovery groups. Paired organs were weighed together. Organ weight ratios were calculated relative to body and brain weights. Organs and tissues from all animals were fixed in 10% neutral buffered formalin. Formalin was infused into the lungs via the trachea and into the urinary bladder. The eye (with optic nerve), testes, and epididymides were fixed in a modified Davidson’s fixative. Target organs, gross lesions, and tissue masses with regional lymph nodes also were collected and fixed in formalin. Fixed tissue samples were paraffin-embedded, sectioned, and stained with haematoxylin–eosin.
HISTOPATHOLOGY: Yes
- Routine histopathological examination of all organs/tissues was performed for F1 animals in the control and high-dose groups (10 animals/sex/group). Histopathological examination of target organs, gross lesions, and tissue masses (with regional lymph nodes) also was performed for all animals. - Statistics:
- Statistical analyses were conducted comparing each treated group to the control group for each sex and each endpoint. The results of all pair-wise comparisons were reported at the 0.05 and 0.01 significance levels.
Group pair-wise comparisons were performed to analyse the following endpoints: body weight, body weight changes, food consumption, haematology (except leukocyte counts), blood coagulation, clinical chemistry, absolute and relative organ weights, continuous functional observational battery parameters (body weight, body temperature, urination, defecation, rearing, thermal response, forelimb and hindlimb grip strength, and hindlimb splay), and locomotor activity. For total and differential leukocyte counts, a log transformation was first performed, and the transformed data then analysed by group pair-wise comparison. Levene’s test was applied to analyse the homogeneity of group variances for these endpoints. If the results of Levene’s test was not significant (p > 0.01) (i.e., homogeneity of variance), a pooled estimate of the variance (mean square error) was computed from a one-way analysis of variance and utilized by a Dunnett’s comparison of each test group with the control group. If the results of Levene’s test was significant (p < 0.01), comparisons with the control group were performed using Welch’s t-test with a Bonferroni correction.
All endpoints were analysed using two-tailed tests. The data for food efficiency, urine volume, urine specific gravity, and urinary pH was first subjected to a rank transformation, and the transformed data then analysed by Dunnett’s test (two-tailed).
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- After 13-weeks of administration, the only statistically significant finding in the haematology and coagulation data was a slightly increased absolute reticulocyte count in high-dose females compared to control females (163.59 vs. 128.40E10e3/mm3). Given the small magnitude of change and the fact that all values were within historical control ranges for this parameter, this lone finding was not ascribed any toxicological significance. At the end of the 4-week recovery period, a very slight, yet statistically significant, decrease in the mean corpuscular haemoglobin (MCH) was observed in high-dose males relative to control males (16.98 vs. 17.50 pg). In high-dose females, slight, yet statistically significant, differences at the end of the recovery period consisted of increased haematocrit (49.26% vs. 46.16%), mean corpuscular volume (MCV) (57.18 vs. 55.16 fL), and MCH (18.36 vs. 17.80 pg) and decreased neutrophil count (0.744 vs. 1.224 10e3/µL) relative to control females. While a few statistically significant differences were noted in the haematology results in the treated groups, no dose-dependent responses were identified, and the changes were considered to be incidental variations.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- A single statistically significant change was noted in the analysis of the clinical chemistry data, and consisted of a very slight increase in chloride in females of the high-dose group compared to control females (101.7 vs. 99.9 mEq/L); values, however, were within historical control ranges. At the end of the 4-week recovery period, in the high-dose males, statistically significant differences consisted of decreased potassium (7.52 vs. 9.70 mg/dL) and phosphorus (7.52 vs. 9.70 mg/dL) and slightly increased globulin (3.54 vs. 3.26 g/dL) relative to the controls. In high-dose females, following the 4-week of recovery period, creatinine was slightly increased relative to the controls (0.46 vs. 0.40 mg/dL). While a few statistically significant differences were noted in the clinical chemistry results in the treated groups, no dose-dependent responses were identified, and the changes were considered to be incidental variations.
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- The only statistically significant finding was decreased relative-to-body pituitary gland weight in the mid-dose (0.5%) females compared to control females (0.0064% vs. 0.0073%). The magnitude of decrease was very minimal and showed no dose-dependency. No statistically significant changes were observed in males. At the end of the recovery period, a few statistically significant differences were observed in high-dose animals compared to controls. The relative to brain weight, but not absolute or relative to body weight, of the pituitary gland was slightly decreased in high-dose males compared to the controls (0.0081% vs. 0.0091%). Also, a slight decrease in absolute (1.805 vs. 2.250 g) and relative to brain weights (0.8064% vs. 1.0117%) of the seminal vesicles was observed in recovery group males. The absolute weight (3.912 vs. 4.122 g) of the testes was slightly reduced; however, no statistically significant differences in the relative weights of the testes were noted. In high-dose recovery group females, the absolute (0.079 vs. 0.064 g), relative-to-body (0.0271% vs. 0.0214%), and relative-to-brain (0.0389% vs. 0.0312%) weights of the adrenal glands were slightly increased relative to control females.
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Description (incidence and severity):
- One high-dose female was found to present with a mass in the subcutis of the left inguinal area. Upon histopathological examination, this mass correlated with a mammary adenocarcinoma; however, similar findings were not observed in other animals and no evidence of preneoplastic and/or proliferative changes were observed in the mammary glands of other high-dose females.
- Other effects:
- no effects observed
- Description (incidence and severity):
- 1 Generation Reproduction Study. A statistically significant reduction in pup body weight in females on PND 21 in the low-dose group was considered of no toxicological significance given the absence of any dose–response relationship, occurrence in a single sex, and small magnitude of effect. At the high-dose level, pup weights were nearly identical to the controls. The NOAEL for the reproduction study is equal to 1% in diet, the highest dose tested.
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 other: % in diet
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects at highest dose tested
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- Male NOAEL = 1% in diet (516 mg/kg/day)
Female NOAEL = 1% in diet (665 mg/kg/day) - Executive summary:
The test item was administered in the diet at dose levels of 0.25%, 0.5%, and 1.0% to groups of 26 male (during mating) and female (28 days prior to mating through weaning of the F1 generation) rats. At weaning on PND 21, selected F1 pups were weighed and observed individually, and one male or one female from each litter in each group was randomly selected to continue onto the 13-week phase. In the 13-week feeding study, control and high dose groups (F1) consisted of 30 animals/sex, for which 10 animals/sex were used in a one-month recovery group. Low and middle dose groups consisted of 20 animals/sex. Dose levels were 0.25%, 0.5%, and 1.0% in the diet of the F1 animals. Reproductive parameters were evaluated. Feed consumption, body-weight gain, selected organ-weights, gross pathology and appropriate histopathology were also evaluated.
In the 13-week study performed in the F1 generation, body weight, body weight gain, feed consumption, clinical pathology, urinalysis, and FOB measurements/analyses showed no effects of the test item administration up to the highest concentration tested of 1.0% in the diet. While a few statistically significant differences were noted in the haematology and clinical chemistry results in the test item administered groups, no dose-dependent responses were identified, and the changes were considered to be incidental variations. Coagulation parameters were unaffected. Likewise, there were no effects on organ weights or on the results of the macroscopic or histopathological examinations.
Based on the results of the 13-week study, the test item was considered to be without compound-related adverse effects at dietary levels of up to 1.0%, the highest level administered. As a result, the corresponding no-observed-adverse-effect level (NOAEL) for oral toxicity was determined to be 516 mg/ kg bw/day in male rats and 665 mg/kg bw/day in female rats.
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