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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
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EC number: - | CAS number: -
- 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
- Study period:
- 2007
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 2 008
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- GLP compliance:
- yes
Test material
- Reference substance name:
- Milk protein hydrolyzate
- IUPAC Name:
- Milk protein hydrolyzate
- Test material form:
- solid: particulate/powder
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- The animals were about 6 weeks old at the start of the treatment period. The body weights at initiation of treatment ranged from 132 to 169 g (mean 152 g) for males and from 102 to 134 g (mean 118 g) for females. The animals were housed under conventional conditions, in macrolon cages (1 rat/cage) with wood shavings as bedding material and shreds of paper as environmental enrichment. The cages and bedding were changed weekly. During urine collection in week 13, rats were kept individually in stainless-steel metabolism cages. The number of air changes in the animal room was about 10 per h. The temperature in the animal room was between 20 and 24 C; the relative humidity was between 40–70%. Lighting was artificial using fluorescent tubes (12 h light, 12 h dark). Feed (provided as a powder in stainless-steel cans) and drinking water (tap water, provided in polypropylene bottles) were available ad libitum, unless precluded by the collection of blood and urine from fasted rats, and refreshed weekly.
Administration / exposure
- Route of administration:
- oral: feed
- Details on route of administration:
- Tested material was incorporated into purified, AIN-93G based rodent diet, at the expense of casein, at constant levels of 0, 1.2% (low-dose), 2% (mid-dose) and 4% (high-dose). Food consumption was measured per animal by weighing the feeders at the beginning and end of each week. The intake of tested material per kg body weight was calculated from the nominal dietary levels of tested material and the body weight and food intake results.
- Vehicle:
- unchanged (no vehicle)
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The diets were analyzed by liquid chromatography–mass spectrometry (LC–MS/MS) to verify the concentration and homogeneous distribution of tested material in the diets and to confirm stability under the conditions of the study.
- Duration of treatment / exposure:
- 90 days
- No. of animals per sex per dose:
- 20
- Control animals:
- yes
Examinations
- Observations and examinations performed and frequency:
- Each animal was observed daily for clinical signs. The body weight of each animal was recorded once per week, starting at initiation of treatment, and on the day of necropsy. Food consumption was measured per animal by weighing the feeders at the beginning and end of each week.
Neurobehavioural testing was conducted on 10 rats/sex/group (these animals were not the same as those used for blood sampling and urine collection). Detailed clinical observations outside the home cage were performed prior to the first exposure and then once weekly. Functional observational battery (FOB) tests, including assessment of grip strength and sensory reactivity to stimuli of different types, and spontaneous motor activity measurements were performed towards the end of the treatment period.
Routine haematology and clinical chemistry determinations were conducted on 10 rats/sex/group on day 13, day 50 and at termination of the treatment period. The rats were fasted overnight before blood sampling (water was freely available). For the haematological analyses, K2-EDTA was used as anticoagulant. The examination included haemoglobin, packed cell volume, red blood cell count, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, percentage of reticulocytes, total and differential white blood cell counts, thrombocyte count and prothrombin time. The plasma was examined for alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, sorbitol dehydrogenase, 5’-ND nucleotidase, total bilirubin, bile acids, total protein, albumin, albumin/globulin ratio, glucose, total cholesterol, phospholipids, triglycerides, creatinine, urea, inorganic phosphate, calcium, chloride, potassium and sodium.
Urinalysis was conducted on 10 rats/sex/group (the same as those used for haematology and clinical chemistry). The selected animals were deprived of water for 24 h and of food during the last 16 h of this period. During the last 16 h of deprivation, the rats were kept individually in stainless-steel metabolism cages and urine was collected in glass tubes. The volume and density of the urine were measured to assess the renal concentrating ability. The appearance of the urine was recorded and the samples were analysed semi-quantitatively (test strips) for pH, glucose, occult blood, ketones, protein, bilirubin and urobilinogen. Centrifuged sediment was examined microscopically.
Ophthalmoscopic observations were performed in all rats prior to the start of treatment and in all animals of the control group and the high-dose group in the last week of the treatment period.
At the end of the treatment period (males on days 91–92, females on days 93–94; 10 rats/group/day), after overnight fasting (water was freely available), the animals were sacrificed by exsanguination from the abdominal aorta under CO2/O2 anaesthesia and subsequently thoroughly examined for macroscopic changes. A large number of organs were collected and the following organs were weighed: brain, heart, adrenals, kidneys, liver, spleen, thymus, thyroid, testes, epididymides, ovaries and uterus. The relative organ weights (g/kg body weight) were calculated from the absolute organ weights and the terminal body weight of the rats. All samples of organs were preserved in a neutral aqueous phosphate buffered 4% solution of formaldehyde. Samples of the preserved organs from all rats of the control group and the high-dose group were processed, embedded in paraffin, sectioned at 5 lm, stained with haematoxylin and eosin, and examined by light microscopy.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There was no treatment-related mortality and the daily clinical observations revealed no
treatment-related effects. Ophthalmoscopy and neurobehavioural examinations revealed no treatment-related changes either. All groups showed normal growth, food consumption and water
consumption - 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):
- no effects observed
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, non-treatment-related
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Organ weights showed slight increases in the relative weight of the kidneys and the absolute weight of the testes and epididymides in high-dose males. Slight fluctuations in the weights of
the brain, heart and thymus were considered chance findings because there was no dose-related response - Gross pathological findings:
- no effects observed
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 2 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- behaviour (functional findings)
- body weight and weight gain
- clinical biochemistry
- clinical signs
- food consumption and compound intake
- gross pathology
- haematology
- ophthalmological examination
- organ weights and organ / body weight ratios
- serum/plasma biochemistry
- urinalysis
- water consumption and compound intake
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
Applicant's summary and conclusion
- Executive summary:
No adverse effects were observed for the highest dose used and therefore the NOAEL is >2000 mg/kg BW/ day.
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