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EC number: 942-597-9 | 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
Endpoint summary
Administrative data
Description of key information
In line with OECD Guideline No.407, Repeated Dose 28-day Oral Toxicity Study in Rodents, 2008, Wistar rats were treated with GR-50-1408 for 28 consecutive days by dietary administration at dose levels of 0, 1000, 3000 and 10000 ppm, followed by a 14-day treatment-free recovery period. The dietary administration up to 10000 ppm was well tolerated by the animals. No mortality occurred in this study and no toxicologically relevant changes were noted in clinical appearance and functional observations.
There were no toxicologically relevant changes in males and females treated at 1000 and 3000 ppm. Based on the morphological changes in the kidneys, a No Observed Adverse Effect Level (NOAEL) for GR-50-1408 of 3000 ppm (corresponding to an actual test article intake of 296 and 300 mg/kg for males and females, respectively) was established.
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2015
- Reliability:
- 1 (reliable without restriction)
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- yes
- Specific details on test material used for the study:
- GR-50-1408 is the Givaudan identification code which was employed for ROSYFOLIA during the early, developmental and testing period.
- Species:
- rat
- Strain:
- other: Crl:WI(Han) (outbred, SPF-Quality).
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Test system Rat: Crl:WI(Han) (outbred, SPF-Quality).
Rationale: Recognized by international guidelines as the recommended test system (e.g. EPA, FDA, OECD and EC).
Source: Charles River Deutschland, Sulzfeld, Germany.
Total number of animals: 30 males, 30 females (females were nulliparous and non-pregnant).
Age at start of treatment: Approximately 6 weeks.
Identification: Earmark and tattoo.
Randomization: By computer-generated random algorithm according to body weight, with all animals within ± 20% of the sex mean.
Acclimatization period: At least 5 days before the start of treatment under laboratory conditions.
Health inspection Upon receipt of the animals.
Environmental controls for the animal room were set to maintain 18 to 24°C, a relative humidity of 40 to 70%, at least 10 air changes/hour, and a 12-hour light/12-hour dark cycle. Any variations to these conditions were maintained in the raw data and had no effect on the outcome of the study.
Group housing of 5 animals per sex in in polycarbonate cages type 2000P (height 21.5 cm) with sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) and paper as cage-enrichment (Enviro-dri, Wm. Lilico & Son (Wonham Mill Ltd), Surrey, United Kingdom). During locomotor activity monitoring, animals were housed individually in a Hi-temp polycarbonate cage (Ancare corp., USA; dimensions: 48.3 x 26.7 x 20.3 cm) without cage-enrichment, bedding material, food and water.
Free access to standard powder rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
During motor activity measurements, animals had no access to food. The diet was provided in stainless steel containers, covered by a stainless steel grid to prevent spillage. The same diets remained in the food hopper for a maximum of 4 days, and on the day of weighing the remaining food in the food hopper was replaced with new room temperature-acclimated diet retained from the freezer. Food hoppers were shaken on a daily basis to divide any sawdust equally over the diet in order to facilitate food consumption.
Free access to tap water except during motor activity measurements.
Diet, water, bedding and cage enrichment evaluation for contaminants and/or nutrients was performed according to facility standard procedures. There were no findings that could interfere with the study - Route of administration:
- oral: feed
- Details on route of administration:
- The oral route was selected as it is a possible route of human exposure during manufacture, handling or use of the registration substance.
- Vehicle:
- unchanged (no vehicle)
- Remarks:
- the tested substance is directly mixed with diet
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- daily
- Dose / conc.:
- 0 ppm
- Remarks:
- diet
- Dose / conc.:
- 1 000 ppm
- Remarks:
- Diet
- Dose / conc.:
- 3 000 ppm
- Remarks:
- Diet
- Dose / conc.:
- 10 000 ppm
- Remarks:
- Diet
- No. of animals per sex per dose:
- 30 males, 30 females (females were nulliparous and non-pregnant).
- Control animals:
- yes
- Observations and examinations performed and frequency:
- At least once daily from start of treatment onwards, detailed clinical observations were made in all animals. Once prior to start of treatment and at weekly intervals, this was also performed outside the home cage in a standard arena. The time of onset, grade and duration of any observed signs were recorded.
- Sacrifice and pathology:
- On the scheduled day of necropsy, animals were deeply anaesthetized using isoflurane (Abbott B.V., Hoofddorp, The Netherlands) and subsequently exsanguinated and subjected to a full post mortem examination. Animals were deprived of food overnight (with a maximum of 24 hours) prior to scheduled necropsy. All animals assigned to the study were necropsied and descriptions of all macroscopic abnormalities recorded.
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No clinical signs were noted during the observation period that were considered to be toxicologically relevant. No abnormalities were noted during weekly arena observations.
Clinical signs noted during the observation period occurred within the range of background findings to be expected for rats of this age and strain which are housed and treated under the conditions in this study and/or did not show any apparent dose-related trend. At the incidence observed, these were considered to be unrelated to treatment. - Mortality:
- no mortality observed
- Description (incidence):
- No mortality occurred during the study period.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Body weights and body weight gain of males and females at 10000 ppm were slightly lower compared to controls (statistically significant on Days 4, 7 and/or 10 only). During the recovery period, the males showed high body weights and body weight gain (statistically significant on Day 15 of Recovery).
Males at 3000 ppm showed slightly higher body weight and body weight gain compared to controls from Day 13 onwards (statistically significant for body weight on Days 16 and 19 only). No body weight changes were noted in animals at 1000 ppm and females at 3000 ppm.
Since all the changes in body weights and food consumption were slight and/or reversible these findings were considered not toxicologically relevant. - Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- A slightly lower food consumption was noted for males and females at 10000 ppm during the first 4 days of treatment, which recovered to levels similar to those seen in controls thereafter.
Higher food consumption was observed for males at 10000 ppm during Days 8-15 of the Recovery period.
No apparent treatment-related changes in food consumption before or after correction for body weight were recorded for animals treated at 1000 and 3000 ppmx.
Since all the changes in body weights and food consumption were slight and/or reversible these findings were considered not toxicologically relevant. - Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The following statistically significant changes in haematology parameters distinguished treated from control animals:
− Lower red blood cell count in males and females at 10000 ppm.
− Lower haemoglobin level in males at 10000 ppm (also appeared lower for females but not statistically significant).
− Lower haematocrit level in males at 10000 ppm (also appeared lower for females but not statistically significant).
At the end of recovery all treatment related findings recovered. In addition slightly higher red blood cell distribution width (RDW) and mean corpuscular volume (MCV) were observed in females (also appeared higher for males but not statistically significant).
Any other statistically significant changes in haematology parameters were considered to be unrelated to treatment as these occurred in the absence of a dose-related trend or occurred only at the end of recovery period.
These changes in haematologic and clinical biochemical parameters were slight and/or recovered after a 14-day recovery period and were not supported by any related morphological changes and therefore not considered to be adverse. - Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The following statistically significant changes in clinical biochemistry parameters distinguished treated from control animals at the end of treatment period:
− Lower total protein and albumin level in males at 10000 ppm.
− Lower total bilirubin in males and females at 3000 and 10000 ppm.
− Lower glucose in males at 10000 ppm.
− Lower bile acid level in males at 10000 ppm.
− Higher cholesterol level in females at 10000 ppm.
At the end of recovery all treatment related findings recovered, except for total bilirubin level, which remained lower in females at 10000 ppm compared to controls.
A lower calcium level was observed in males and females at 1000 and 10000 ppm. These changes occurred in absence of a clear dose related trend and without any corresponding morphological changes. Therefore this change was considered not toxicologically relevant.
Any other statistically significant changes in clinical biochemistry parameters were considered to be unrelated to treatment as these occurred in the absence of a dose-related trend, occurred at the end of recovery phase only and/or were within the range expected for rats of this strain and age. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 296 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: morphological changes in the kidneys
- Key result
- Critical effects observed:
- not specified
- Conclusions:
- Based on the morphological changes in the kidneys, a No Observed Adverse Effect Level (NOAEL) for GR-50-1408 of 3000 ppm (corresponding to an actual test article intake of 296 and 300 mg/kg for males and females, respectively) was established.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 296 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- GLP compliance
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
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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