1-methylpiperidine

Endpoint summary

Additional information

Assessment of the Toxicokinetic Behaviour

 

There is one study available concerning the cleavage of N-Methylpiperidine by the 9000 x g supernatant of mouse and rat liver in vitro (Kimura et al., 1979; see below). No other studies were available in which the toxicokinetic properties of N-Methylpiperidine were investigated.

 

N-Methylpiperidine (molecular weight of 99.17 g/mol) is a colourless liquid with an amine-like odor, pH value of 12 at a concentration of 100 g/L and 20 °C, high water solubility of 167 g/L at 20 °C (GESTIS, 2011) and a vapour pressure of 25.81 hPa at 20 °C (BASF, 1990; extrapolated value). The log Pow for the molecule was determined to be -1.8 at 25 °C and pH 7.1 (BASF, 1990), indicating no accumulation of the substance.

 

Absorption

Data for absorption can only be taken from acute (oral, inhalative and dermal) studies.

In an acute oral toxicity study, rats were administered the substance by gavage at doses of 163 to 1306 mg/kg bw., a LD50 of ca. 490 mg/kg bw was determined, clinical signs such as accelerated respiration, dyspnoea, convulsions and gross pathological effects such as bloody erosion and oedema at the stomach in deceased rats were observed. These effects at the site of action and mortality are caused primarily by the strong corrosive mode of action of the substance (BASF, XX/37, 1970). Absorption of the test compound in the gastrointestinal tract by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid due to the water solubility, but may be facilitated by the low molecular weight of the test substance and the moderate log P (ECHA Guidance 7c, 2008).

 

The test compound has a high vapour pressure. Accordingly, in an inhalation hazard exposure for 10 min to an atmosphere that had been saturated at 20 degrees centigrade with the volatile parts of the compound all animals died within 10 min (BASF, XX/37, 1970). Clinical signs were strong agitation, strong mucosal irritation, gasping, bloody crusts of the eyes and nose and respiratory sounds, pointing to irritation as the primary mode of action. In an acute inhalation study, clinical signs observed were restlessness, intermittent respiration, gasping, salivation, epistaxis, paroxysmal clonic convulsions, respiratory sounds, mouth breathing, serous discharge at the nose, bloody discharge of the eyes, mucosal irritation after inhalation of an aerosol for 1 hour (BASF/Fraunhofer Gesellschaft, 1979). Due to the moderate water solubility, the test substance is expected to be retained within the mucus after inhalation followed by local irritation and may pass across the respiratory epithelium. However, the main effects are local effects due to the corrosive potential of the test substance.

 

In an acute dermal study the LD50 for male and female rabbits was > 1000 - < 2000 mg/kg bw. Clinical signs were severe dermal irritation at the dosing site, lethargy, irregular respiration and pale skin pointing to resorption through the skin (Reilly Industries/Product Safety Labs, 1994). Nevertheless, the primary effect was the local effect which led to destruction of membrane barriers.

 

Metabolism

In rat and mouse rat liver in vitro N-C-cleavage was investigated and demethylation of N-Methylpiperidine to piperidine was shown (Kimura et al., 1979). Piperidine is N-oxidized to the corresponding N-Hydroxylamine. Other metabolites are 2,3,4,5-tetrahydropyridine-1-oxide, 3-hydroxy piperidine, 4-hydroxy piperidine and Piperidone-2 (Wang et al., 1989, Acta Pharmacol. Sin. 10, 252-256 and Okano et al., 1978, Japan. J. Pharmacol. 28: 41-47).

Studies on genotoxicity, i.e. Ames assay gave indications of a reactivity of the substance or its metabolites under the test conditions as shown by cytotoxicity in treatments with or without metabolic activation. No increased Mutagenicity was observed.

 

Excretion

1-Methylpiperidine has a molecular weight of 90 g/mol and has moderate water solubility and is therefore likely to be excreted predominantly via the urine (ECHA GD 7c, 2008). The metabolite piperidine is excreted by the kidneys. Okano et al., 1978 (J. Pharmacol. 28: 41-47) found unchanged piperidine, 3-hydroxypiperidine, 4-hydroxypiperidine, and two unidentified metabolites in urine collected over 72 hours after i.p. injection of rats with [³H]piperidine.