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EC number: 215-925-7 | CAS number: 1453-58-3
- 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:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1998-07-21 - 2000-01-07
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP-study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 000
- Report date:
- 2000
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- 3-methylpyrazole
- EC Number:
- 215-925-7
- EC Name:
- 3-methylpyrazole
- Cas Number:
- 1453-58-3
- Molecular formula:
- C4H6N2
- IUPAC Name:
- 3-methyl-1H-pyrazole
- Test material form:
- other: liquid
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- B6C3F1
- Sex:
- male/female
Administration / exposure
- Route of administration:
- oral: drinking water
- Vehicle:
- water
- Details on oral exposure:
- To achieve the target dose levels the test article concentrations in the water were adjusted weekly according to mean water consumption and mean body weight of the animals.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples for the determination of the concentration, homogeneity and stability of the test article mixtures were drawn from the first test article preparations. Intercurrent samples for the determination of the concentration were drawn twice during the study, at monthly intervals. All samples were stored at room temperature prior to analysis by RCC Ltd, Environmental Chemistry and Pharmanalytics Division, CH-4452 Itingen by HPLC.
- Duration of treatment / exposure:
- 13 weeks
Doses / concentrationsopen allclose all
- Dose / conc.:
- 5 mg/kg bw (total dose)
- Remarks:
- Doses / Concentrations:
5 mg/kg
Basis:
nominal in water
- Dose / conc.:
- 10 mg/kg bw (total dose)
- Remarks:
- Doses / Concentrations:
10 mg/kg
Basis:
nominal in water
- Dose / conc.:
- 20 mg/kg bw (total dose)
- Remarks:
- Doses / Concentrations:
20 mg/kg
Basis:
nominal in water
- Dose / conc.:
- 40 mg/kg bw (total dose)
- Remarks:
- Doses / Concentrations:
40 mg/kg
Basis:
nominal in water
- No. of animals per sex per dose:
- 10 animals per sex and dose group
- Control animals:
- yes, concurrent no treatment
- Positive control:
- no
Examinations
- Observations and examinations performed and frequency:
- Observations:
Clinical signs: At least once daily
Viability/mortality: Twice daily
Food consumption: Weekly
Water consumption: Weekly
Body weights: Weekly
Ophthalmoscopic examinations: Pretest: on all mice per sex and group.
At week 13: control and high dose animals.
At week 17: control and high dose animals.
After the application of a mydriatic solution (CIBA Vision AG, 3172 Niederwangen / Switzerland) the cornea, lens, anterior chamber, vitreous body and ocular fundus of both eyes were examined using a Heine Miroflex 2 Ophthalmoscope (Eisenhut Vet AG, Allschwil / Switzerland) and the results were recorded. Unless otherwise indicated in the table, the contralateral eye was without abnormalities. - Sacrifice and pathology:
- All animals were weighed and necropsied. Descriptions of all macroscopic abnormalities were recorded. Necropsies were performed by experienced prosectors supervised by a veterinary pathologist. All animals surviving to the end of the observation period and all moribund animals will be anesthetized by intraperitoneal injection of sodium pentobarbitone and killed by exsanguination.
Samples of the following tissues and organs will be collected from all animals at necropsy and fixed in neutral phosphate buffered 4% formaldehyde solution:
Adrenal glands
Aorta
(Auricles)
Bone marrow (femur)
Brain - including section of medulla/pons,
cerebral and cerebellar cortex
Cecum
Colon
Duodenum
Epididymides
Esophagus
(Exorbital lacrymal glands)
Eyes with optic nerve and Harderian gland
Femur - including articular surface
Heart
Ileum
Jejunum
Kidneys
Liver with gall bladder Lungs, infused with formalin Lymph nodes - mesenteric, mandibular Mammary gland area
Nasal cavity Ovaries Pancreas Pituitary gland Prostate gland Rectum
Salivary glands - mandibular, sublingual
Sciatic nerve
Seminal vesicles
Skeletal muscle
Skin
Spinal cord - cervical, midthoracic, lumbar Spleen
Sternum with bone marrow
Stomach
Testes
Thymus
Thyroid gland / parathyroid gland Trachea
Urinary bladder, infused with formalin
Uterus
Vagina
All gross lesions - Other examinations:
- Blood samples for hematology and clinical biochemistry were collected from all allocation A animals at 13 weeks and from all allocation B animals at 17 weeks under light ether anesthesia. The animals were fasted for approximately 18 hours before blood sampling but allowed access to water ad libitum. Blood samples were collected early in the working day between the hours of 06.00 and 08.35 to reduce biological variation caused by circadian rhythms. Blood samples were drawn from the retro-orbital plexus using a micro-hematocrit glass capillary tube.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Description (incidence and severity):
- Water consumption over treatment was marginally increased in females of groups 4 (20 mg/kg) and 5 (40 mg/kg) and slightly increased in males of groups 2 (5 mg/kg), 3 (10 mg/kg), 4 (20 mg/kg) and 5 (40 mg/kg).
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- The Clara cell alteration noted in mice of groups 10, 20, and 40 mg/kg following the treatment period is considered to represent a mixed degenerative and regenerative process indicating a probable systemic effect of the test article.
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 5 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: toxicological endpoint: effects on Clara cells (lung)
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 10 mg/kg bw (total dose)
- System:
- respiratory system: lower respiratory tract
- Organ:
- lungs
- Treatment related:
- yes
Applicant's summary and conclusion
- Conclusions:
- Based on these results the "no-observed-adverse-effect level (NOAEL)" in this study is considered to be the target dose of 5 mg/kg body weight/day corresponding to a test article intake of 5.20 mg/kg body weight/day in male mice and 5.31 mg/kg body weight/day in female mice.
The dose of 10 mg/kg/day is considered to represent a threshold dose level for the Clara cell alteration, since the incidence and severity of this lesion were substantially lower at this dose level when compared with the higher doses. - Executive summary:
Treatment of SPF-bred Crl:B6C3Fl mice with MP (3-Methylpyrazole) via their drinking water for a period of 13 weeks at doses of 5, 10, 20 or 40 mg/kg had no effect on survival, clinical signs, food consumption, body weight, ophthalmoscopy findings, hematology and clinical biochemistry parameters, organ weights or macroscopical findings. The increased water consumption noted in females of groups 4 (20 mg/kg) and 5 (40 mg/kg) as well in all male groups treated with MP reversed during the 4-week treatment-free recovery period and might reflect impaired palatability of the water by the test article resulting in undetected water spillage. The only other findings observed in this study were confined to histopathology. The Clara cell alteration noted in mice of groups 3 (10 mg/kg), 4 (20 mg/kg), and 5 (40 mg/kg) following the treatment period is considered to represent a mixed degenerative and regenerative process indicating a probable systemic effect of the test article. This Clara cell alteration was dose-dependent in incidence and severity in the groups affected. At the end of the treatment-free recovery period, Clara cell regeneration and repair were noted in association with a persistent Clara cell alteration. The 4-week treatment-free recovery period was insufficient to allow for full reversal of this Clara cell alteration. However the incidence and mean severity of this alteration showed a dose-related decrease in the recovery mice when compared with the mice sacrificed at termination of the treatment period. No Clara cell alterations were noted in mice of group 2 (5 mg/kg). Based on these results the "no-observed-adverse-effect level (NOAEL)" in this study is considered to be the target dose of 5 mg/kg body weight/day corresponding to a test article intake of 5.20 mg/kg body weight/day in male mice and 5.31 mg/kg body weight/day in female mice. The dose of 10 mg/kg/day is considered to represent a threshold dose level for the Clara cell alteration, since the incidence and severity of this lesion were substantially lower at this dose level when compared with the higher doses.
Based on the publications of the German MAK commission for napthalene ( see http://onlinelibrary.wiley.com/doi/10.1002/3527600418.mb9120d0021/full) and of the German Federal Environmental Agency (see http://www.umweltbundesamt.de/gesundheit/publikationen/ad-hoc/Naphthalin.pdf) clara cells of mice are considered to have a specific sensitivity to lung toxicants, because they have a cytochrome P450 dependent oxidation potency, which is 1 to 2 magnitudes higher as of humans (see also Buckpitt A. et al., Relationship of cytochrome P450 activity to Clara cell cytotoxicity. IV. Metabolism of naphthalene and naphthalene oxide in microdissected airways from mice, rats, and hamsters. , http://www.ncbi.nlm.nih.gov/pubmed/7838135). This means, that effects on clara cells of mice are not transferable to man a priori.
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