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EC number: 605-904-4 | CAS number: 180637-89-2
- 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:
- repeated dose toxicity: oral, other
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- November - December 1998
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- Study was conducted at a GLP facility in accourdance with accepted guidance.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 999
- Report date:
- 1999
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- On Day 28 of the study no blood sample was received from animal number 38.
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- 5-[(E)-2-(benzenesulfonyl)ethenyl]-3-{[(2R)-1-methylpyrrolidin-2-yl]methyl}-1H-indole
- EC Number:
- 605-904-4
- Cas Number:
- 180637-89-2
- Molecular formula:
- C22 H24 N2 O2 S
- IUPAC Name:
- 5-[(E)-2-(benzenesulfonyl)ethenyl]-3-{[(2R)-1-methylpyrrolidin-2-yl]methyl}-1H-indole
- Test material form:
- solid: bulk
- Details on test material:
- Buff-colored
1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- Sprague Dawley Crl:CD BR strain rats obtained from Charles River (UK) Limited, Margate, Kent.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- At the start of the study animals were five to eight weeks. The weight variation did not exceed 4- 20% of the mean weight for either sex. Animals were housed in groups of five by sex in polypropylene cages with stainless steel mesh lids and grid bases, suspended over trays containing absorbent paper.
Rat and Mouse SQC Expanded Diet No. 1 (Special Diets Services Limited, Witham, Essex, UK) with batch analysis, and tap water ad libitum.
The diet and drinking water are routinely analysed and are considered not to contain any contaminant that could reasonably be expected to affect the purpose or integrity of the study.
Target temperature: 21 ± 2°C
Target humidity: 55 ± 15%
Lighting: Twelve hours of continuous artificial light in each twenty-four hour period.
Ventilation: At least fifteen air changes per hour.
Administration / exposure
- Route of administration:
- oral: gavage
- Details on route of administration:
- Once daily, by gavage, using a stainless steel dosing cannula attached to a graduated syringe for twenty-eight consecutive days.
- Vehicle:
- propylene glycol
- Details on oral exposure:
- The test material will be dissolved or suspended in a suitable vehicle weekly (subiect to confirmation of stability). Wherever possible, an aqueous formulation will be used, followed by consideration of formulation in vegetable oil (eg Arachis oil), then other specified vehicles. The method of preparation will be documented in the study records.
- Analytical verification of doses or concentrations:
- no
- Details on analytical verification of doses or concentrations:
- The test material formulations were sampled and analysed within three days of preparation. The concentration of UK-114,958 in the test material formulations was determined by high performance liquid chromatography (HPLC) using an external standard technique.
- Duration of treatment / exposure:
- Not specified
- Frequency of treatment:
- Once daily for the duration of the study. Similar time each day wherever possib
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1.5 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 15 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 150 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Remarks:
- vehicle alone
- No. of animals per sex per dose:
- Five animals
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Selection followed the results of a dose sighting study.
- Rationale for animal assignment: animals were selected at random and given a unique number within the study by ear punching. - Positive control:
- None
Examinations
- Observations and examinations performed and frequency:
- Clinical Observations: All animals were examined for overt signs of toxicity, ill health or behavioural changes immediately before dosing and one and five hours after dosing.
Functional Observations: Priot to treatment on days 5, 12, 21 and 27 all animals were observed for signs of functional/behavioural toxicit. Sensory reactivity was tests were also performed on day 27. - Sacrifice and pathology:
- On completionl animals were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded.
Organ Weight: The following organs removed from animals that were killed at the end of the study and observed for organ weight - Adrenals, Brain, Epididymides, Heart, Kidneys, Liver, Ovaries, Spleen, Testes, Thymus
istopathology
Samples of tissues were removed from all animals for microscopic examination.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Animals of either sex treated with 150 mg/kg/day developed clinical signs from Day 2 onwards including fur loss, hunched posture, increased salivation and red/brown staining of the external body surface. By Day 18, all surviving animals appeared hunched whilst additional clinical signs were evident during the treatment period among isolated individuals including ataxia, pilo-erection, noisy respiration, occasional/prolonged body tremors and shuffling or splayed gait. Neither of the females that died during the study showed an appreciable deterioration in condition prior to death. The interim male decedent, however, appeared ataxic and hunched and showed pilo-erection, occasional/prolonged body tremors and splayed gait on the day prior to its death. A probable increase in urine micturation was also noted among animals of either sex at this dose level with cage tray-liners appearing saturated from Day 12 onwards; there was, however, no direct clinical evidence of diuresis.
There were no clinically observable signs of toxicity detected among animals of either sex treated with 15 or 1.5 mg/kg/day. Animals of either sex treated with 15 ring/kg/day showed increased salivation either before or approximately two minutes after dosing from Day 14 onwards.
Increased salivation is often observed around the time of dosing and is considered attributable to an unpleasant tasting or locally irritant test material formulation rather than an indication of systemic toxicity.
One female treated with 1.5 mg/kg/day showed red/brown staining of the fur on Day 28 of the study but such isolated findings are occasionally reported among animals housed in groups and are considered not to be toxicologically significant. - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- One female treated with 150 mg/kg/day was found dead at the start of Day 12 and a male from this treatment group was found dead at the start of Day 22.
A further female treated with 150 mg,/kg/day died on Day 28 but this occurred during blood sampling procedures and was considered to be in no way related to test material toxicity. There were no deaths among animals of either sex treated with 15 or 1.5 mg/kg/day. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Females treated with 150 mg/kg/day showed a statistically significant reduction in group mean bodyweight gain during Weeks 1 and 3 of the study. Males from this treatment group showed a reduced bodyweight gain during the first three weeks of treatment, although statistical significance was not achieved. Animals of either sex treated with 15 or 1.5 mg/kg/day showed similar bodyweight gains to control animals throughout the treatment period. Males treated with 15 or 1.5 mg/kg/day showed a statistically significant increase in bodyweight gain during Week 2 of the study but this is unlikely to represent an adverse effect on health and was disregarded.
- Food efficiency:
- effects observed, treatment-related
- Description (incidence and severity):
- Animals of either sex treated with 150 mg/kg/day showed a reduction in dietary intake during the first three weeks of treatment when compared with controls which extended to the final week of treatment among females at this dose level. Food efficiency (the ratio of bodyweight gain to dietary intake) was reduced among animals of either sex at this dose level during Weeks 1 and 3 of the study.
Animals of either sex treated with 15 or 1.5 mg/kg/day showed a similar dietary intake and food efficiency to control animals throughout the treatment period. - Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Description (incidence and severity):
- Quantitative measurement during the second half of the treatment period revealed an increase in water consumption for females treated with 150 mg/kg/day when compared with controls.
There was no effect on water intake detected for males treated with 150 mg/kg/day or among animals from the 15 or 1.5 mg/kg/day treatment groups. - Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related changes in the blood chemical parameters measured. Statistical analysis of blood chemical data did not reveal any significant intergroup differences.
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- Detailed open-field observations conducted during the study confirmed the clinically observable signs detected among animals at the 150 mg/kg/day dose level. Findings were noted from Week 1 onwards and included hunched posture, pilo-erection, noisy respiration, whole body tremors and spastic or splayed gait although behavioural changes were more evident among females.
There were no treatment-related behavioural differences detected between animals of either sex treated with 15 or 1.5 mg/kg/day and controls.
There were no treatment-related changes in the functional performance parameters measured. Statistical analysis of the data revealed no significant intergroup differences. - Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Females treated with 150 mg/kg/day showed a statistically significant increase in liver weight, both absolute and relative to terminal bodyweight, when compared with controls.
Males treated with 150 mg/kg/day and animals of either sex from the remaining treatment groups showed no treatment-related changes in the organ weights measured. - Gross pathological findings:
- not specified
- Neuropathological findings:
- not specified
- Description (incidence and severity):
- Microscopic examination of bone marrow, lung and spleen sections revealed treatment-related changes among animals of either sex treated with 150 mg/kg/day. An increased severity of fatty infiltration in the bone marrow indicative of myeloid hypoplasia was observed among animals of either sex. A reduction in the thickness of the peripheral gastric musculature was also observed among two animals of either sex whilst females from this treatment group showed an increased incidence and severity of accumulations of alveolar macrophages.
No treatment-related microscopic abnormalities were detected among an of either sex treated with 15 or 1.5 mg/kg/day. - Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Details on results:
- Repeated oral administration of the test material to rats by gavage for a period of up to twenty-eight consecutive days at dose levels of up to 150 mg/kg/day resulted in treatment-related adverse health effects at a dose level of 150 mg/kg/day. There werb no treatment-related changes detected among animals of either sex treated with 15 or 1.5 mg/kg/day
Effect levels
- Dose descriptor:
- NOEL
- Effect level:
- ca. 15 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- mortality
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 150 mg/kg bw/day (nominal)
- System:
- other: respiratory, gastrointestinal track and bone marrow
- Organ:
- bone marrow
- liver
- lungs
- spleen
- other: Gastrointestinal system
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
Applicant's summary and conclusion
- Conclusions:
- The study was designed to investigate the systemic toxicity of the test material.
It complies with the requirements for notification of a new chemical substance in the EC and follows the testing method described in Commission Directive 96/54/EC (Method B7) and OECD Guidelines for Testing of Chemicals No. 407 "Repeated Dose 28 Day Oral Toxicity Study in Rodents" (Adopted 27 July 1995).
The test material was administered by gavage to three groups, each of five male and five female Sprague-Dawley Crl:CD®BR strain rats, for up to twenty-eight consecutive days, at dose levels of 1.5, 15 and 150 mg/kg/day. A 'control group of five males and five females was dosed with vehicle alone (Polyethylene glycol 400).
Clinical signs, functional observations, bodyweight development, food and water consumption were monitored during the study. Haematology and blood chemistry were evaluated for all animals at the end of the study.
All animals were subjected to a gross- necropsy examination and histopathological evaluation of a range of tissues was performed.
Repeated oral administration of the test material to rats by gavage for a period of up to twenty-eight consecutive days at dose levels of up to 150 mg/kg/day resulted in treatment-related adverse health effects at a dose level of 150 mg/kg/day. There werb no treatment-related changes detected among animals of either sex treated with 15 or 1.5 mg/kg/day.
The "No Observed Effect Level" (NOEL) was therefore considered to be 15 mg/kg/day. - Executive summary:
A Repeated Dose 28 Day Oral Toxicity Study in Rodents was performed on the test substance. The test was carried out in a GLP faclilty in accordance with OECD guideline No. 407. Data gathered during the study were used to determine the "No Observed Effect Level" (NOEL) for the substance. The NOEL for the test substance is 15 mg/kg/day.
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