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EC number: 608-681-1 | CAS number: 319-24-4
- 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:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP- and Guideline-Study with no or minor deficiencies.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 004
- Report date:
- 2004
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Qualifier:
- according to guideline
- Guideline:
- other: U.S. EPA: OPPTS 870.3050, Health Effects Test Guidelines: Repeated dose 28-day oral toxicity study in rodents, July 2000
- Qualifier:
- according to guideline
- Guideline:
- other: Commission Directive 96/54/EC Annex IV D Method B.7."Subacute Oral Toxicity"
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- methyl 2-amino-5-fluorobenzoate
- EC Number:
- 608-681-1
- Cas Number:
- 319-24-4
- Molecular formula:
- C8 H8 F N O2
- IUPAC Name:
- methyl 2-amino-5-fluorobenzoate
- Test material form:
- other: brown liquid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Room temperature: 22±3°C
Relative humidity: 50±20 %
Lightning hours: 12 hours light/dark cycle
Diet: Ssniff (ad libitum)
Water: tap water in plastic bottles (ad libitum)
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- sesame oil
- Details on oral exposure:
- Application volume: 0,5 ml/kg bw
- Duration of treatment / exposure:
- 28 d
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
0 mg/kg bw per day (control)
Basis:
- Remarks:
- Doses / Concentrations:
62.5 mg/kg bw per day
Basis:
- Remarks:
- Doses / Concentrations:
250 mg/kg bw per day
Basis:
- Remarks:
- Doses / Concentrations:
1000 mg/kg bw per day
Basis:
- No. of animals per sex per dose:
- 5
- Control animals:
- yes
Examinations
- Observations and examinations performed and frequency:
- General health conditions: twice daily (weekend, public holiday once daily)
clinical symptoms of toxicity: once daily
functional observation battery: neurotoxicological examinations: weekly
motor activity, sensory reactivity, grip strength: week 4
body weight development: twice weekly
food consumption: twice weekly
hematology: once, end of treatment
clinical chemistry: once, end of treatment
urinalysis: once (week 4) - Sacrifice and pathology:
- Organs examined (macroscopic and microscopic): Heart, kidneys, liver, lungs and trachea, spleen, thymus, iliac and mandibular lymph node, stomach, small (ileum) and large intestine (colon), brain with medulla oblongata, spinal cord (cervical), sciatic nerve, adrenals, thyroid gland with epithelial body, urinary bladder, testes, epididymides, prostate, seminal vesicle, ovaries, uterus, and bone marrow.
- Statistics:
- two-sided ordinal step-down test
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- in high dose group
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- in high dose group
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- cholesterin and triglycerid levels increased in the high dose group
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- decreased pH in the high dose (both sexes) as well as an increased urine volume
- Behaviour (functional findings):
- effects observed, treatment-related
- Description (incidence and severity):
- Female animals of the intermediate dose showed a significant reduction in the number of movements
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- absolut liver weight was increased
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- the female animal found dead had an enlarged spleen
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 250 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
No deaths occurred throughout the study. Only one female animal of the 1000 mg/kg body weight group was found dead on day 27 of the study showing immunodeficiency. In the high dose group (1000 mg/kg) several animals showed clinical symptoms such as stupor, prone position, hypoactivity, stilted gait, squatting posture, irregular respiration, bristled coat, drawn in flanks as well as straddled hind limbs. Clinical signs started between day 14 and 26.
Behavior, body weight development, food consumption and neurotoxicological parameters remained unaffected by the administration of the test compound in all dose groups.
Evaluation of hematological data indicated reduction in red blood cell counts in females of the high dose group correlated with an increase in reticulocytes.
Clinical chemistry revealed findings in the high dose groups such as increases in total cholesterin and triglycerid levels exceeding the normal range. A slight but statistically significant increase in total cholesterin was also observed in male animals of the low and intermediate dose group. This slight increase represents no adverse effect, because values did not exceed the normal range and showed no histopathological correlation (e. g. in liver). As the range in low dose and control animals showed distinct overlapping, the slight increase in mean values is not considered as substantial substance related effect in this dose group. Moreover, total bilirubin levels were increased in male animals of the high dose group and calcium levels were slightly increased in the intermediate and high dose group in both sexes, but not in a toxicologically relevant manner.
Urine in females of the high dose group showed red discoloration, as well as urine of two male animals of the intermediate dose group and of four males in the high dose group. No blood was detected in urine. Bilirubine was detected in urine of all animals of the high dose group. Moreover, urinalysis revealed decreased pH values (below the historical control data range) in the high dose group with both sexes as well as increased urine volume. Alterations in urine volume and/or pH in animals dosed with 62.5 or 250 mg/kg test item were slight compared with controls in indi-vidual sexes, and are therefore not considered as toxicologically relevant effects.
Organ weight analysis revealed increased absolute liver and spleen weights in female animals of the high dose group. Both, relative and absolute values in this group, were above the historical control data range. Male animals showed also significantly increased relative liver weights, which exceeded the normal range only slightly. No histopathological correlates were observed in liver.
Histological assessment revealed erythroid hyperplasia in the spleens of nearly all female animals in the high dose group with an average grading of 2.3, compared to an average grading of 1.0 to 1.3 in the other groups including the control. Additionally, atrophy/hypoplasia/hypocellularity in the spleen (in combination with an haemorrhage), the thymus, iliac and mandibular lymph nodes (partly with haemorrhage) and the bone marrow were observed in one female (animal 36, which died on day 27) and one male animal (animal 19, showing clinical signs) of the high dose group reflecting immunodeficiency.
Applicant's summary and conclusion
- Conclusions:
- In conclusion, repeated administration of 2-Amino-5-fluorbenzoesaeuremethylester at a dose level of 62.5 mg/kg body weight and day did not cause any substantial substance related alterations. Slight alterations were observed after administration of 250 mg/kg, which did not represent ad-verse findings. Repeated administration of 1000 mg/kg caused alterations such as clinical signs of toxicity in several animals, deviations in cholesterine and triglycerides, alterations in hematology in females correlated with erythoid hyperplasia in spleen, as well as death of one female animal showing immunodeficiency.
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