Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 214-353-5 | CAS number: 1122-58-3
- 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:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Review of GLP guideline study data by an authoritative body, the European Medicines Agency
Data source
Reference
- Reference Type:
- review article or handbook
- Title:
- Unnamed
- Year:
- 2 011
- Report date:
- 2011
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
- GLP compliance:
- yes
- Remarks:
- The studies formally adhered to GLP standards; the required toxicokinetics component of the studies were undertaken at different times and were evaluated by EMEA as valid.
- Limit test:
- no
Test material
- Reference substance name:
- 4-pyridylamine
- EC Number:
- 207-987-9
- EC Name:
- 4-pyridylamine
- Cas Number:
- 504-24-5
- IUPAC Name:
- pyridin-4-amine
- Test material form:
- not specified
- Details on test material:
- Pyridine-4-amine (fampridine) was described by the manufacturer as a white-to off-white non hygroscopic powder, practically soluble in water. Its pKa is 9.17 (protonated free base), its logP is 0.76 and the pH of its solution (50 mg/ml in water) is 11.
Constituent 1
Test animals
- Species:
- rat
- Strain:
- not specified
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- according to g
Administration / exposure
- Route of administration:
- oral: feed
- Details on oral exposure:
- The pivotal study was a 26-week study in rats (dietary administration.
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 26 weeks
- Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
2, 6 and 18 mg/kg bw/d
Basis:
nominal in diet
- No. of animals per sex per dose:
- 50
Results and discussion
Results of examinations
- Details on results:
- Exposure to 4-aminopyridine at or up to 26 weeks revealed CNS associated events that included tremor, trembling, convulsions, ataxia, decreased activity, prostration, ptyalism, dilated pupils, increased respiratory rate and laboured breathing. A clear cause of death could not be identified for most animals that died during the studies; however, CNS toxicity and multiple organ failure were regarded as most likely reasons. A decrease in body weight was seen in the mid and high dose groups; in rat also a decrease in food consumption and effects on the locomotor system were observed, such as impaired righting reflex or uncoordinated aerial righting, splay of (hind) limbs and hind limb grip strength. In addition, some effects on the behaviour were noted in rats, such as increased activity, arousal and aggressive behaviour especially in the long studies. The observed effects, especially on food consumption and body weights, were more pronounced in males than females. In rats, the urogenital tract was identified as a target for fampridine toxicity. No effects were noted in ophthalmology and urinalysis.
4-Aminopyridine plasma concentrations (mean) at week 26 were: Dose 2 mg/kg/d: 40.2 ng/ml in males and 26.4 ng/ml in females, Dose 6 mg/kg/d: 131 ng/ml in males and 92.7 ng/ml in females, and Dose 18 mg/kg/d: 319 ng/ml in males and 268 ng/ml in females.
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- < 2 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: noted by EMEA as < 2 mg/kg bw/d
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
The CNS effects were attributed to the pharmacology of fampridine; they were rapid in onset and seemed to alleviate during continued dosing and also to reverse in surviving animals after discontinuation of treatment. The urogenital tract was identified as a target for fampridine toxicity studies in rats leading to cause of death in certain instances. The clinical relevance of the findings of urinary tract obstruction or bladder distention remains unclear. However, taking into account the almost exclusive renal elimination of fampridine, the general susceptibility of MS (Multiple Sclerosis) patients toward bladder disorders and the potential pharmacological activities of 4-aminopyridine on urinary tract smooth muscles and/or bladder innervation, the Committee noted that this issue is not addressed sufficiently.
The EMEA Committee did not raise any objections precluding granting of marketing authorisation based on the provided non-clinical data
Applicant's summary and conclusion
- Conclusions:
- 4 -Aminopyridine was administered in the diet to male and female rats for 26 weeks, at doses of 0, 2, 6, and 18 mg/kg bw/d. Neurological effects (central nervous system) were noted and attributed to the pharmacology of the substance; and there were decreases in body weights at the mid and high dose. The NOAEL for toxicity effects was less than 2 mg/kg bw/d. An analogue approach between DMAP and 4-aminopyridine, based on a common functional group (4-aminopyridine), is used for filling the registration requirement of this endpoint. This approach is adequate for the purposes of classification and labelling, and for risk assessment.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.