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EC number: 456-880-5 | CAS number: 439685-79-7
- 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
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- 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
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- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
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- Nanomaterial crystalline phase
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- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
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- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
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- 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
Endpoint summary
Administrative data
Description of key information
In a 28-day repeated dose oral toxicity study conducted according to the OECD Guideline 407 in rats, the NOEL was 1000 mg/kg bw/day.
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 12 October 2004 - 21 January 2005
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP study conducted according to OECD Guideline 408 with minor deviation: some fluctuations of temperature and humidity outside the range were observed on a day
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- some fluctuations of temperature and humidity outside the range were observed on a day
- Principles of method if other than guideline:
- Not applicable
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories France, L’Arbresle, France
- Age at study initiation: Approximately 6 weeks
- Weight at study initiation: Males: 198-228 g (mean: 213 g); females: 133-174 g (mean: 155 g)
- Housing: Housed in groups of 2/sex in suspended wire-mesh cages
- Diet: SSNIFF R/M-H pelleted maintenance diet (SSNIFF Spezialdiäten GmbH, Soest, Germany), ad libitum
- Water: Tap water (filtered with a 0.22 μm filter), ad libitum
- Acclimation period: 8 days
ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 2 °C
- Humidity: 50 ± 20 %
- Air changes: Approximately 12 cycles/h of filtered, non-recycled air
- Photoperiod: 12 h dark / 12 h light - Route of administration:
- oral: gavage
- Vehicle:
- other: 60/40 (w/w) purified water/propylene glycol
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
- Test item was diluted with the required quantity of vehicle in order to achieve the desired concentrations and then homogenized using a magnetic stirrer.
- Test item dosage forms were prepared for up to 9 days and stored at +4 °C. They were used each day within a maximum of 6 h storage at room temperature.
VEHICLE
- Concentration in vehicle: 20, 60 and 200 mg/mL
- Dose volume administered (for vehicle and treatment groups): 5 mL/kg bw/day
- Lot/batch no. of propylene glycol: S21645-174, S21645-284, S21645-334 and U10221
- Source of propylene glycol: Aldrich (Saint-Quentin-Fallavier, France)
- Source of purified water: Obtained by reverse osmosis using a Milli-Ro 8 plus apparatus (Millipore SA, Saint-Quentin en Yvelines, France)
STABILITY:
- Two dosage forms were prepared at 10 and 200 mg/mL of test item to cover all the concentrations intended for use in this study.
- To evaluate the stability, each dosage form was sampled (in duplicate) after 0 (just after preparation), 6 h storage at room temperature, then after 4 and 9 days storage at +4 °C. The aliquots sampled on Day 4 were analysed immediately after sampling.
- Results of the analyses demonstrated the satisfactory stability of the two dosage forms investigated (10 and 200 mg/mL) over a 6 h period at room temperature and a 9-day period at +4 °C (protected from light). - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- - Concentration of test item in samples taken from each dosage form (including the control) prepared for use in Weeks 1, 4, 8 and 13 was determined.
- Results of analysis: Satisfactory agreement was observed between the nominal and actual concentrations of the test item in the administered dosage forms analysed as the deviations from nominal concentration were in an acceptable range of ± 10 %. - Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- Once daily
- Remarks:
- Doses / Concentrations:
100, 300 and 1000 mg/kg bw/day
Basis:
actual ingested - No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Dose levels were selected on the basis of the results of a previous study (Study No. 28461 TSR) in which the test item was given orally to Sprague-Dawley rats for 2 weeks at dose-levels of 100, 300 or 1000 mg/kg bw/day. In absence of signs of toxicity at the high dose-level, 1000 mg/kg bw/day was selected as the highest dose-level.
- Rationale for animal assignment: Animals were selected according to body weight and clinical condition and grouped (by sex) according to a computerised stratification procedure, so that the average body weight of each group was similar. - Positive control:
- Not applicable
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
Time schedule:
- Mortality and morbidity: Twice a day
- Clinical signs: Once daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before the beginning of the treatment period and then once a week until the end of the study
BODY WEIGHT: Yes
- Time schedule for examinations: Once before group allocation, on the first day of treatment, then twice a week until the end of the study and before sacrifice.
FOOD CONSUMPTION:
- Food consumption for each animal was recorded once a week and mean daily diet consumption was calculated as g food/animal/day
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Ophthalmological examinations were performed on all animals, before the beginning of the treatment period and on animals of the control and high-dose groups on one occasion at the end of the treatment period.
HAEMATOLOGY AND CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood samples were taken from the orbital sinus of all the animals at the end of the treatment period.
- Anaesthetic used for blood collection: Yes, isoflurane
- Animals fasted: Yes
- Parameters checked (haematology): Hemoglobin, erythrocyte, mean cell volume, packed cell volume, mean cell hemoglobin concentration (MCHC), mean cell hemoglobin (MCH), thrombocytes, leucocytes, differential white cell count (neutrophils, lymphocytes, monocytes, eosinophils, basophils), reticulocytes, prothrombin time, activated partial thromboplastin time and fibrinogen
- Parameters checked (clinical chemistry): Sodium (Na+), potassium (K+), chloride (Cl-), calcium (Ca++), inorganic phosphorus, urea, creatinine, glucose, total bilirubin, direct bilirubin, total protein, albumin, albumin/globulin ratio, total cholesterol, triglycerides, alkaline phosphatase (ALP), aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT)
URINALYSIS: Yes,
- Time schedule: Urinalysis was performed in all animals at the end of the treatment period.
- Metabolism cages used for collection of urine: Yes, animals were individually placed in metabolism cages for an overnight period of at least 14 h.
- Animals fasted: Yes
- Parameters checked: Appearance, color, volume, specific gravity, pH, protein, glucose, ketones, bilirubin, nitrites, blood, urobilinogen, cytology of sediment (leucocytes, erythrocytes, cylinders, magnesium ammonium phosphate crystals, calcium phosphate crystals, calcium oxalate crystals and cells)
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Each animal was observed once in Week 12, in the cage, in the hand and in the standard arena.
Battery of functions tested:
- In the cage: ‘Touch escape’ or ease of removal from the cage.
- In the hand: Fur appearance, salivation, lachrymation, piloerection, exophthalmia, reactivity to handling, pupil size (presence of myosis or mydriasis),
- In the standard arena (two-minute recording): Grooming, palpebral closure, defecation and urination counts, tremors, twitches, convulsions, gait, arousal (hypo- and hyper-activity), posture, stereotypy and breathing, ataxia, hypotonia.
In addition, the following parameters, reflexes and responses were recorded:
- touch response, forelimb grip strength, pupil reflex, visual stimulus, auditory startle reflex, tail pinch response, righting reflex, landing foot splay, rectal temperature at the end of observation.
- Motor activity of each animal was also measured by automated infra-red sensor equipment over a 1 h period. - Sacrifice and pathology:
- - GROSS PATHOLOGY: On completion of the treatment period, after at least 14 h fasting, all surviving animals were anesthetized with carbon dioxide and then sacrificed by exsanguinations. A complete macroscopic post-mortem examination was performed on all study animals. This included examination of the external surfaces, all orifices, the cranial cavity, the external surfaces of the brain and spinal cord, the thoracic, abdominal and pelvic cavities with their associated organs and tissues and the neck with its associated organs and tissues.
- ORGAN WEIGHTS: Body weight of each animal was recorded before sacrifice and the organs specified in the table 7.5.1/1 were weighed wet as soon as possible after dissection. The ratio of organ weight to body weight (recorded immediately before sacrifice) was calculated.
- HISTOPATHOLOGY: For all animals, the tissues specified in the table 7.5.1/1 were preserved in 10 % buffered formalin (except for the eyes and Harderian glands which were fixed in Davidson's fixative, and the testes and epididymides which were preserved in Bouin's fluid). All tissues required for microscopic examination were embedded in paraffin wax, sectioned at a thickness of approximately 4 µm and stained with hematoxylin-eosin (except testes and epididymides which were stained with hematoxylin/PAS).
Microscopic examination was performed on:
- all tissues listed in the table 7.5.1/1 for animals in control and 1000 mg/kg bw/day treatment groups sacrificed at the end of the treatment period and for all animals that died
- all macroscopic lesions from all the animals in 100 and 300 mg/kg bw/day treatment groups sacrificed on completion of the treatment period - Other examinations:
- None
- Statistics:
- Refer figure 7.5.1/1 for the details of statistical analysis
- 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):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- 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:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY:
- No unscheduled deaths occurred during the study.
- No clinical signs related to the test item treatment were observed.
- Alopecia of forelimbs, thinning of hair, scabs on head and hyperactivity were considered not to be of toxicological importance as they were noted at a low incidence, without clear dose-relationships, and/or these signs are commonly recorded among rats of this strain and age.
BODY WEIGHT AND WEIGHT GAIN:
- Body weight gain of test item-treated animals was comparable to that of the controls.
FOOD CONSUMPTION:
- Food consumption of treated animals was comparable to that of the controls throughout the study.
OPHTHALMOSCOPIC EXAMINATION:
- There were no ocular findings which could be related to the test item treatment.
- An increase in the corneal thickness was observed in one male and one female given 1000 mg/kg bw/day. As this finding was recorded at a low incidence, a relationship to treatment with the test item was doubtful and it was considered to have occurred by chance.
HAEMATOLOGY:
- No differences of toxicological importance on hematological parameters noted between test item-treated and control animals.
- Few minor statistically significant differences were considered not to be biologically significant, as the observed changes were not dose-related, all individual values were within historical data range [for white blood cell in males (7.41-17.09 G/L); for platelet in females (479-1326 G/L) and/or were probably due to high control values].
CLINICAL CHEMISTRY:
- No differences of toxicological importance were noted between test item-treated and control animals among the blood biochemical parameters.
- Increase in inorganic phosphorus recorded in the female group treated at 1000 mg/kg bw/day (1.79 vs. 1.53 mmol/L, +17 %) reached statistical significance (p<0.05). All individual values were within historical data range (1.33-2.45 mmol/L). In the absence of a clear dose-relationship, this very slight change was considered to bear no toxicological importance.
URINALYSIS:
- There were no changes in the urinary parameters evaluated qualitatively or quantitatively that could be attributed to treatment with the test item.
NEUROBEHAVIOUR:
- There were no perturbations of the autonomic or physiological functions in any test item-treated animals.
- Motor activity of both males and females measured over a 60-minute period was unaffected by treatment.
ORGAN WEIGHTS:
- No treatment-related effects were noted for organ weights at the end of treatment period.
- Few differences noted between test item-treated and control groups were slight, not dose-related, of opposing trend in the different groups and sexes and were without relevant histopathological findings in the organs examined microscopically, and therefore they were considered to be of no toxicological importance.
GROSS PATHOLOGY AND HISTOPATHOLOGY:
- No treatment-related necropsy or microscopic findings were noted.
- All necropsy or microscopic findings reported at the end of treatment period were those which are commonly occurring in this strain of rat kept under laboratory conditions and were considered to be of no toxicological importance. - Dose descriptor:
- NOEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no treatment-related effects on clinical signs; mortality; body weight; food consumption; ophthalmoscopic examination; haematology; clinical chemistry; urinalysis; gross pathology; organ weights and histopathology
- Critical effects observed:
- not specified
- Conclusions:
- Under the test conditions, the No Observed Effect Level (NOEL) of test item was considered to be 1000 mg/kg bw/day in Sprague-Dawley rats.
- Executive summary:
In a 90-days repeated dose oral toxicity study conducted according to the OECD Guideline 408 and in compliance with GLP, test item was administered daily by oral gavage to groups of Sprague-Dawley, Crl CD® (SD) IGS BR rats (10/sex/dose) at the dose-levels of 0 (vehicle), 100, 300 or 1000 mg/kg bw/day in 60/40 (w/w) purified water/propylene glycol. Examinations during the study included: mortality, clinical signs, functional observation battery (including motor activity), body weight change, food consumption, ophthalmology, hematology, blood chemistry, urinalysis, organ weights, macroscopic examination and histopathology.
No deaths occurred and no major clinical signs were observed during the study. Body weight gains and food consumption were not affected by treatment with the test item. No treatment-related changes were noted in the hematological parameters, blood biochemistry, urinalysis, ophthalmology and neurotoxicological parameters at any dose-level. No treatment-related effects were noted on organ weights or necropsy and microscopic findings.
Under the test conditions, the No Observed Effect Level (NOEL) of test item was considered to be 1000 mg/kg bw/day in Sprague-Dawley rats.
Reference
None
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- The available information as a whole meets the tonnage driven data requirement of REACH. Moreover, reliability and consistency are observed across the different studies.
Additional information
In a 28-day repeated dose oral toxicity study conducted according to the OECD Guideline 407 and in compliance with GLP, MEXORYL SBF was administered daily by oral gavage to groups of Sprague-Dawley rats (5/sex/dose) at the dose-levels of 0 (vehicle), 150, 450 or 1000 mg/kg bw/day in purified water. No treatment-related changes were noted in all the parameters studied therefore the NOEL was 1000 mg/ kg bw/day.
Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Key study performed on Mexoryl SBF in compliance with OECD Guideline 407 and GLP.
Justification for classification or non-classification
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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