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EC number: 601-329-8 | CAS number: 114798-26-4
- 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:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- May 31, 1989 through September 1, 1989
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- Although the study was conducted according to GLP and well documented methods, " Practical guide 10: How to avoid unnecessary testing on animals", Section 3.3.2 states it is important that the reliability indicator (Klimisch score) reflects the assumptions of similarity. Thus, a score of 1 (reliable without restrictions) should normally not be used for results derived from read-across.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 989
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: Guideline not specified but method well documented
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- DuP 753
- IUPAC Name:
- DuP 753
- Reference substance name:
- losartan potassium
- IUPAC Name:
- losartan potassium
- Details on test material:
- - Name of test material (as cited in study report): DuP 753
- Substance type: bulk powder
- Physical state: solid
- Analytical purity: 97.9 %
- Lot/batch No.: INE 3340-19M
- Stability under test conditions: confirmed through analysis of one gram sample of bulk powder, collected at pre-test and termination.
- Storage condition of test material: tightly sealed container at ambient room temperature, protected from excessive light exposure.
Constituent 1
Constituent 2
Test animals
- Species:
- dog
- Strain:
- Beagle
- Sex:
- male/female
Administration / exposure
- Route of administration:
- oral: capsule
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 5, 25, 125
Basis:
actual ingested
- No. of animals per sex per dose:
- 5 female, 5 male
- Control animals:
- yes, concurrent vehicle
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- 125 mg/kg/day= no mortality. gastrointestinal effects. Fecal occult blood.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 125 mg/kg/day= no mortality. gastrointestinal effects. Fecal occult blood.
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- 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
- Description (incidence and severity):
- a trend toward decreased mean absolute heart weight in the 125 mg/kg day dogs, but was not statistically significant
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- 125 mg/kg/day= 1 female, moderate lymphocyctic infiltration in gastric mucosa. The relationship of this finding in the gastric mucosa to treatment with DuP 753 was considered to be equivocal based upon the low incidence rate.
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- 1- dose-related increase in the incidence of clinical signs suggesting treatment-related gastrointestinal disturbance. These signs included a dose-related increase in the incidence of salivation, vomition and fecal abnormalities. The emetic response following dosing occurred with greatest frequency in the 125 mg/kg/day female group, with animals from this group vomiting on 24-32 days of this study.
Fecal abnormalities were generally limited to the 125 mg/kg-day groups and included abnormal consistency and/or colour of the stool and positive fecal occult blood. All 125 mg/kg day dogs tested positive for fecal occult blood (at least 3 consecutive days) during the study period. Several high dose dogs tested positive for fecal occult blood over several periods of at least three consecutive days.
2- a trend toward decreased mean absolute heart weight in the 125 mg/kg day dogs
3- moderate lymphocytic infiltration in the gastric mucosa of one high dose female dog, which was compatible with gastric irritation.
There were clinical signs suggestive of gastrointestinal irritation, increased salivation and emesis in the 25 mg/kg group at slightly higher frequency than the control group. There were no other effects in this group.
Effect levels
open allclose all
- Dose descriptor:
- NOEL
- Effect level:
- 5 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Dose descriptor:
- NOAEL
- Effect level:
- 25 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- Based upon the results of this study, the maxium-tolerated-dosage (MTD) for losartan potassium, and losartan free acid by read-across, was >=125 mg/kg/day, the NOAEL 25 mg/kg/day and the NOEL was 5 mg/kg/day.
- Executive summary:
The objective of the study was to characterise the potential toxicity of DuP 753, resulting from daily oral administration.
DuP 753 was administered via liquid-filled gelatin capsules to groups of 5 male and 5 female beagle dogs at daily dosages of 0, 5, 25, or 125 mg/kg for approximately 3 months. Evaluations were made of clinical signs, body weight, food consumption, fecal occult blood, ophthalmoscopic examinations, hematology, serum chemistry, urinalysis, electrocardiography, physical examinations, organ weights, and gross and microscopic post-mortem examinations. Additionally, blood samples were obtained at designated times during the study to determine the plasma levels of DuP 753.DuP 753 administered in this study was well tolerated in the dog. There were no toxicologically significant effects of treatment on body weight, food consumption, clinical pathology, electrocardiography, physical examinations, ophthalmoscopic examinations, or gross microscopic post-mortem findings. A treatment-related increase in the incidence of vomiting and fecal abnormalities was apparent in the 125 mg/kg/day dogs. These antemortem findings and microscopic evidence of lymphocytic infiltration in the gastric mucosa suggested a dose-related gastrointestinal irritation. There were clinical signs suggestive of gastrointestinal irritation, increased salivation and emesis in the 25 mg/kg group at slightly higher frequency than the control group. There were no other effects in this group. Based upon the results of this study, the maxium-tolerated-dosage (MTD) for losartan potassium, and losartan free acid by read-across was >=125 mg/kg/day, the NOAEL 25 mg/kg/day and the NOEL was 5 mg/kg/day.
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