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EC number: 469-110-8 | 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:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 09 March - 06 April 2006
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Study was performed according to OECD and EC guidelines and according to GLP principles.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 006
- Report date:
- 2006
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: Directive 96/54/EEC, B.7 OECD 407 (1995) OPPTS 870.3050, Office of Prevention, Pesticides and Toxic Substances (7101), EPA 712-C-00-366, 2000.
- GLP compliance:
- yes
- Limit test:
- yes
Test material
- Details on test material:
- - Name of test material (as cited in study report): AD-1000
- Substance type: white powder
- Physical state: powder
- Storage condition of test material: at room temperature in the dark
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation:
- Weight at study initiation:
- Fasting period before study:
- Housing: Group housing of 5 animals per sex in Macrolon plastic cages (MIV type, height 18 cm; during overnight activity monitoring individual housing in MIII type; height 15 cm.) with sterilised sawdust as bedding material and paper as cage-enrichment. No cage-enrichment was provided during overnight activity monitoring.
- Diet (e.g. ad libitum): Free access to pelleted rodent diet
- Water (e.g. ad libitum): Free access to tap water.
- Acclimation period: at least 5 days before start of treatment under laboratory conditions.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.2 – 23.4
- Humidity (%): 43 - 92
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- propylene glycol
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
Formulations (w/w) were prepared daily within 4 hours prior to dosing and were homogenised to a visually acceptable level. Adjustment was made for specific gravity of the vehicle.
DIET PREPARATION
- Rate of preparation of diet (frequency): daily within 4 hours prior to dosing
- Storage temperature of food: At ambient temperature
VEHICLE: Propylene glycol
- Justification for use and choice of vehicle (if other than water): Based on trial formulations performed at NOTOX and on information from the sponsor.
- Concentration in vehicle: 0, 50, 100, 1000 mg/kg/day
- Amount of vehicle (if gavage): 5 ml/kg body weight - Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 50, 100, 1000 mg/kg/day
Basis:
nominal in diet
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were selected on the basis of a 5-day dose range finding study
- Rationale for animal assignment (if not random): Prior to commencement of treatment, by computer-generated random algorithm according to body weight, with all animals within ± 20% of the sex mean. - Positive control:
- not required
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Mortality / Viability: At least twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: At least once daily.
BODY WEIGHT: Yes
- Time schedule for examinations: On days 1, 8, 15, 22 and 28.
FOOD CONSUMPTION:
- Weekly
WATER CONSUMPTION: Yes
- Time schedule for examinations: Subjective appraisal was maintained during the study, but no quantitative investigation introduced as no effect was suspected.
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: During week 4 of treatment
- Dose groups that were examined: all
HAEMATOLOGY: Yes
- Time schedule for collection of blood: immediately prior to scheduled post mortem examination
- Anaesthetic used for blood collection: Yes; iso-flurane anaesthesia
- Animals fasted: Yes
- How many animals: all
- Parameters examined: White blood cells, Differential leucocyte count, Red blood cells, Reticulocytes, Red blood cell distribution width, Haemoglobin
Haematocrit, Mean corpuscular volume, Mean corpuscular haemoglobin, Mean corpuscular haemoglobin concentration, Platelets
Clotting Potential: Prothrombin time, Activated Partial thromboplastin time
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: immediately prior to scheduled post mortem examination
- Animals fasted: Yes
- How many animals: all
- Parameters c were examined.
Clinical Biochemistry: Alanine aminotransferase, Aspartate aminotransferase, Alkaline phosphatase, Total Protein, Albumin, Total Bilirubin, Urea
Creatinine, Glucose, Cholesterol, Sodium, Potassium, Chloride, Calcium, Inorganic Phosphate
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: During week 4 of treatment, the following tests were performed on all animals
- Dose groups that were examined: all
- Battery of functions tested:
- hearing ability (HEARING), pupillary reflex (PUPIL L/R), static righting reflex (STATIC R) and grip strength (GRIP) (Score 0 = normal/present, score 1 = abnormal/absent).
- motor activity test (recording period: 12 hours during overnight for individual animals, using a computerised monitoring system, Pearson Technical Services, Debenham, Stowmarket, England). - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes Tissues mentioned within brackets were not examined microscopically as there were no signs of toxicity or target organ involvement.
Adrenal glands
Aorta
Brain [cerebellum, mid-brain, cortex]
Caecum
Cervix
(Clitoral gland)
Colon
Duodenum
Epididymides
(Eyes with optic nerve [if detectable] and
Harderian gland)
(Female mammary gland area)
(Femur including joint)
Heart
Ileum
Jejunum
Kidneys
(Larynx)
(Lacrimal gland, exorbital)
Liver
Lung, infused with formalin
Lymph nodes - mandibular, mesenteric
(Nasopharynx)
Oesophagus
Ovaries
Pancreas
Peyer's patches [jejunum, ileum] if detectable
Pituitary gland
(Preputial gland)
Prostate gland
Rectum
(Salivary glands - mandibular, sublingual)
Sciatic nerve
(Seminal vesicles)
(Skeletal muscle)
(Skin)
Spinal cord -cervical, midthoracic, lumbar
Spleen
Sternum with bone marrow
Stomach
Testes
Thymus
Thyroid including parathyroid [if detectable]
(Tongue)
Trachea
Urinary bladder
Uterus
Vagina
All gross lesions
Organ Weights
Adrenal glands
Brain
Epididymides
Heart
Kidneys
Liver
Spleen
Testes
Thymus
HISTOPATHOLOGY: Yes
All organs and tissue samples, as mentioned in the histopathology report were processed, embedded and cut at a thickness of 2-4 micrometers and stained with haematoxylin and eosin.
The following slides were examined by a pathologist:
- all tissues collected at the scheduled sacrifice from all animals of the control and the highest
dose group
- all gross lesions - Other examinations:
- none
- Statistics:
- The following statistical methods were used to analyse the data:
- If the variables could be assumed to follow a normal distribution, the Dunnett-test1 (many-to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
- The Steel-test2 (many-to-one rank test) was applied when the data could not be assumed to follow a normal distribution.
- The exact Fisher-test3 was applied to frequency data.
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:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY
No mortality occurred during the study period.
There were no clinical signs of toxicity noted over the 28-day observation period.
Incidental findings that were noted included alopecia and scabs in group 3 and 4 females. These findings are commonly noted in rats of this age and strain that are housed and treated under the conditions in this study. At the incidence observed, these were considered signs of no toxicological significance. No clinical signs were noted in all male groups, and in control females and females at 50 mg/kg/day.
BODY WEIGHT AND WEIGHT GAIN
Body weights and body weight gain were considered to have been unaffected by treatment.
FOOD CONSUMPTION
Food consumption before or after allowance for body weight was similar between treated and control animals.
OPHTHALMOSCOPIC EXAMINATION
Hearing ability was normal
HAEMATOLOGY
No toxicologically relevant changes occurred in haematological parameters of treated rats.
Minor statistically significant differences were considered to have occurred by chance as no dose-response was apparent and/or means remained well within the historical control range. These changes comprised higher relative neutrophil counts in males at 50 and 1000 mg/kg/day, lower relative lymphocyte counts in males at 50 and 1000 mg/kg/day and lower platelet counts in females at 50 mg/kg/day.
CLINICAL CHEMISTRY
There were no differences noted between control and treated rats that were considered to be related to treatment with AD-1000.
The statistically significant lower glucose and total bilirubin values in males at 150 and 50 mg/kg/day respectively were considered to have arisen by chance as a treatment-related distribution was absent.
NEUROBEHAVIOUR
Hearing ability, pupillary reflex, static righting reflex and grip strength were normal in all animals.
The variation in motor activity did not indicate a relation with treatment.
ORGAN WEIGHTS
No toxicologically significant changes were noted regarding absolute and/or relative organ weights.
The statistically significant lower spleen and liver weight at 50 mg/kg/day in males and females respectively were considered to have occurred by chance as means remained well within the historical control range and no dose-response relationship was present.
GROSS PATHOLOGY
Necropsy did not reveal any toxicologically relevant macroscopic alterations.
Incidental findings among control and/or treated animals included red foci on the thymus and red discolouration of the thymus, enlargement of the mandibular lymph nodes and fluid in the uterus. These findings are occasionally seen among rats used in these types of studies. In the absence of a treatment-related distribution they were considered changes of no toxicological significance. No macroscopic abnormalities were noted in males at 50 mg/kg/day and higher.
HISTOPATHOLOGY:
There were no microscopic findings recorded which could be attributed to treatment with the test substance.
All microscopic findings were within the range of background pathology encountered in Wistar rats of this age and strain and occurred at similar incidences and severity in both control and treated rats.
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Basis for effect level:
- other: original NCD unit is mg/kg/day.
- Dose descriptor:
- NOEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Basis for effect level:
- other: original NCD unit is mg/kg/day.
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- Wistar rats were treated with AD-1000 for 28 consecutive days by oral gavage at dose levels up to 1000 mg/kg/day.
There were no changes at determination of clinical appearance, performance of functional observations, body weight and food consumption measurements, or alterations during clinical laboratory investigations, macroscopic examination, organ weight determination and microscopic examination that were considered to be an effect of treatment.
From the results presented in this report a definitive No Observed Adverse Effect Level (NOAEL) for AD-1000 of 1000 mg/kg/day was established.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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