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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
Genetic toxicity: in vivo
Administrative data
- Endpoint:
- in vivo mammalian germ cell study: cytogenicity / chromosome aberration
- Remarks:
- Type of genotoxicity: chromosome aberration
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- 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:
- 1 990
- Report date:
- 1990
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: Merck Sharp & Dohme Research Laboratories, Genetic Toxicity, SOP, Assay for Chromosal Aberrations in Mouse Bone Marrow
- Deviations:
- yes
- Remarks:
- see below:
- Principles of method if other than guideline:
- Fewer than fifty mitotic cells were availalbe for scoring for one animal in the 150 mg/kg L-158,086 dose group (animal #1307) at the 48 hour sacrifice; one animal in the 500 mg/kg group at the 48 hr sacrifice; two animals in the 1.0 mg/kg Mitomycin C group at the 24 hr sacrifice. Fewer than fifty mitotic cells were scored for one animal in the 3.5 mg/kg Mitomycin dose group which had no mitotic cells available for scoring.
- GLP compliance:
- yes
- Type of assay:
- chromosome aberration assay
Test material
- Reference substance name:
- L-158,086
- IUPAC Name:
- L-158,086
- Reference substance name:
- losartan
- IUPAC Name:
- losartan
- Details on test material:
- - Name of test material (as cited in study report):L-158,086
- Analytical purity:99.8%
- Lot/batch No.:158,086-005H010
- Stability under test conditions: stable
Constituent 1
Constituent 2
Test animals
- Species:
- mouse
- Strain:
- other: Crl:CD-1R(ICR) BR
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source:Charles River Breeding Farms, Raleigh, N.C.
- Age at study initiation:Thirty days
- Weight at study initiation: 20.0-28.6 g
- Assigned to test groups randomly: [no/yes, under following basis: ]
- Fasting period before study: not specified
- Housing: 4 to 12 mice per cage
- Diet (e.g. ad libitum): purina certified rodent chow- ad libitum
- Water (e.g. ad libitum): tap water - ad libitum
- Acclimation period: 7 days
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- dH20
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Test substance (oral gavage)
1500,500 and 150 mg/kg levels were prepared as solutions in dH20. The top levle was a clear yellow solution.
High dose: 150 mg/mL in dH20
Middle: 50 mg/mL by dilution from high dose
Low: 15 mg/mL by dilution from high dose
Positive control (intraperitoneal injection)
substance: mitomycin c
vehicle: saline
concentration: 350 microg/ml and 100 microg/ml
negative control (oral gavage):
dH20 - Duration of treatment / exposure:
- animals sacrificed at 6, 24 and 48 hours (positive control at 24 hrs)
- Frequency of treatment:
- single dose at time 0 for all treatment groups
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
1500 mg/kg
Basis:
nominal conc.
- Remarks:
- Doses / Concentrations:
500 mg/kg
Basis:
nominal conc.
- Remarks:
- Doses / Concentrations:
150 mg/kg
Basis:
nominal conc.
- No. of animals per sex per dose:
- Negative control: 36 mice
1500 mg/kg: 30
500 mg/kg:24
150 mg/kg:24
positive control 12 - Control animals:
- yes, concurrent vehicle
- Positive control(s):
- mitomycin C;
- Route of administration:intraperitoneal injection
- Doses / concentrations: 1 mg/kg
Examinations
- Details of tissue and slide preparation:
- Slide preparation:
a) fixed celss were dropped on to clean , wet slides and allowed to dry
b) as soon as fixed cells were spread on each slide, that slide was coded with a random number which had been correlated with the animal number. Random numbers were generated by coputer by the cytogen system
c) all slides were stained wth Giemsa and coverslips were applied to them.
d) all slides were checked for quality and chromosome spreading.
Slide analysis:
Slide analysis was done according to criteria in the SOP. - Evaluation criteria:
- P<0.001
- Statistics:
- Statistical analysis was carried out by the Biometrics Department, MSDRL, West Point, PA and is described in SOP. The proportion of aberrant cells for each mouse was used as a data point. Individual dose level results were compared by a least significatn difference procedure with concurrent negative controls.
Also, a trend test was used to investigate evidence for a dose relation. The proportion of animals with aberrant cells in each group was also analyzed.
Results and discussion
Test results
- Sex:
- male
- Genotoxicity:
- negative
- Toxicity:
- no effects
- Vehicle controls validity:
- valid
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- RESULTS OF RANGE-FINDING STUDY
- Dose range:808-3000 mg/kg
- Solubility:
- Clinical signs of toxicity in test animals:ataxia, decreased activity, bradypnea and ptosis. The signs were seen at the 3000 mg/kg dose level at 15 min and at 2308 mg/kg within 90 minutes. No signs were seen at lower doses on the first day. There were three deaths at 2308 mg/kg and five deaths at 3000 mg/kg. Deaths occured in about 3 to 4.25 hours and were precede by a loss of righting reflex. Surviving mice appeared normal at 3 to 4 hours. On the second day ataxia and bradypnea were seen at the 1775 mg/kg dose. By the end of hte second day all survivors appeared normal. The LD50 was calculated to be 2248 mg/kg.
- Evidence of cytotoxicity in tissue analyzed:
- Rationale for exposure:
- Harvest times:
- High dose with and without activation:
- Other:
RESULTS OF DEFINITIVE STUDY
- Types of structural aberrations for significant dose levels (for Cytogenetic or SCE assay):
- Induction of micronuclei (for Micronucleus assay):
- Ratio of PCE/NCE (for Micronucleus assay):
- Appropriateness of dose levels and route:
- Statistical evaluation:
Any other information on results incl. tables
Mean Proportions (%) of Aberrant Cells | ||||
Sacrifice Time | Control | 150mg/kg | 500mg/kg | 1500 mg/kg |
6 hr | 0.5 | 0 | 0 | 0.5 |
24 hr | 0.83 | 0.5 | 1 | 1 |
48 hr | 0.67 | 1.32 | 0.52 | 0.25 |
Combined | 0.67 | 0.59 | 0.51 | 0.58 |
Results of Statistical Tests (P-values) on the Rankit-Transformed Proportions: Doses compared to the negative control (a) | ||||
Sacrifice Time | Trend | 150 mg/kg | 500mg/kg | 1500mg/kg |
6 hr | 0.35 | 0.060N | 0.060N | 0.5 |
24 hr | 0.248 | 0.316N | 0.458 | 0.315 |
48 hr | 0.132N | 0.134 | 0.424N | 0.246N |
Combined | 0.399N | 0.394 | 0.275N | 0.458N |
(a): a one-tailed LSD procedure was computed for the individual L-158,086 dose group vs. negative control comparison. The P-values are adjusted for multiple comparisons against a common control. This adjustment is applied to only those P-values <=0.05
N: Indicates a reverse effect, i.e., the mean proportion of aberrant celss is lower for the L-158 ,086 treatment group than for the negative control group
In vivo assay for chromosomal aberrations in bone marrow cells from mice treated with L-158,086
Proportions (Pa) of Animals with at Least One Aberrant Cell
Proportions (Pa) of Animals with at Least One Aberrant Cell | ||||
Sacrifice Time | Control | 150 mg/kg | 500 mg/kg | 1500 mg/kg |
6 hr | 3/12 | 0/8 | 0/8 | 2/8 |
24 hr | 4/12 | 2/8 | 2/8 | 4/8 |
48 hr | 3/12 | 3/8 | 2/8 | 1/8 |
Combined | 10/36 | 5/24 | 4/24 | 7/24 |
Resutls of Statistical Tests (p-values)
Proportions (Pa) of Animals with at Least One Aberrant Cell | ||||
Sacrifice Time | Trend | 150 mg/kg | 500 mg/kg | 1500 mg/kg |
6 hr | 0.307 | 0.193N | 0.193N | 0.693 |
24 hr | 0.172 | 0.545N | 0.545N | 0.388 |
48 hr | 0.187N | 0.455 | 0.693 | 0.465N |
Combined | 0.374 | 0.385N | 0.249N | 0.566 |
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): negative
There was no evidence for induction of chromosom aberrations in animals treated with L-158,086 under the conditions of this test. This result also applies to the read-across substance losartan free acid.
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