N,N-dimethylpyridin-4-amine

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:

2011

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

Test material information

Constituent 1

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.

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.