2-methylpyridine

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: compliant with guidelines from the European Chemical Agency for assessment of toxicokinetic behaviour of the substance to the extent that can be derived from the relevant available information.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2010

Report date:

2010

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Assessment of toxicokinetic behaviour of the substance to the extent that can be derived from the relevant available information.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Pyridine

EC Number:

203-809-9

EC Name:

Pyridine

Cas Number:

110-86-1

Molecular formula:

C5H5N

IUPAC Name:

pyridine

Radiolabelling:

no

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Pyridine and methyl derivatives are all readily absorbed in the respiratory tract, by dermal absorption and through the gastrointestinal tract.

Main ADME results 2

Type:

distribution

Results:

Pyridine and methyl derivatives are widely distributed to tissues with the primary tissues being kidney > liver > plasma > lung. They are not likely distributed to fat or breast milk.

Main ADME results 3

Type:

metabolism

Results:

Pyridine and methyl derivatives all appear to undergo metabolism by cytochrome P450 enzymes. Pyridine-N-oxide and N-methylpyridinium appear to be the primary metabolites in both animal and human studies.

Main ADME results 4

Type:

excretion

Results:

Pyridine, its metabolites and derivatives are excreted primarily in the urine, but also in exhaled air and feces.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Pyridine and its derivatives are all colorless liquids at room temperature with disagreeable odors. Each of the substances exerts a relatively high vapor pressure suggesting that the substance may volatilize and thus be potentially inhaled as a vapor. Pyridine and the picoline derivatives all have very high water solubility, relatively low log octanol water partition coefficients and low molecular weights which suggest greater potential for absorption across the skin and gastrointestinal tract. Acute dermal toxicity studies of 3-picoline confirm that it is absorbed across the skin (Tice and Brevard, 1999) and in animal studies pyridine is reported to be well absorbed across the gastrointestinal tract (IARC, 2000). Pyridine has been demonstrated to be readily absorbed through inhalation ingestion and dermal exposure (Reinhardt and Britell, 1981).

Details on distribution in tissues:

Inhalation of pyridine results in olfactory mucosal lesions in rats. Oral administration to mice in chronic studies results in an increase in hepatic tumors while oral administration to rats results in an increase in renal tumors. Acute and sub-acute oral toxicity studies if 2-picoline do not indicate that the kidney and liver are target organs of toxicity (Til et al., (1975). Subchronic inhalation studies of 3-picoline revealed increased liver weights in exposed rats (Tice and Brevard, 1999). Subchronic studies conducted with pyridine (NTP, 2000) and the three picoline derivatives indicate that the liver and kidney are target organs of toxicity. The primary organs of distribution of pyridine and the picoline derivatives are the olefactory epithelium and the upper respiratory tract, the liver and the kidney. For pyridine following intraperitoneal injection orf inhalation the concentrations distributed to tissues were in the order kidney > liver > plasma > lung (Scholl and Iba, 1997). The high water solubility and low partitioning into octanol of pyridine and the picoline derivatives indicates that each of the substances is unlikely to accumulate in body fats or breast milk.

Details on excretion:

Pyridine and its metabolites are eliminated primarily in the urine. Pyridine is also excreted in exhaled air and in feces to a lesser extent (SCOEL, 2004). The elimination half life of pyridine was 17 hours following a single 100 mg/kg intraperitoneal injection and was 8 hours following the last exposure of a 3-day, 8 hour/day exposure to 200 ppm by inhalation (Scholl and Iba, 1997). The shorter elimination half life is possibly due to induction of metabolic enzymes. Pyridine induces CYP2E1 and CYP1A1 metabolism (Scholl and Iba, 1997). The latter induction has been shown to be sexually dimorphic. There is no gender difference in the plasma elimination rate of pyridine after intraperitoneal administration however (Iba et al., 1999). 3-Picoline administered intraperitoneally to guinea pigs, rabbits, mice and ferrets resulted in urinary excretion of the N-oxide compound (approximately 10% in rats, 40% in mice and in guinea pigs) (Gorrod et al., 1980; AIHA, 1988).

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Pyridine was shown to induce lesions in the olefactory epithelium but not the nasal, respiratory or transitional epithelium, which is explained by a higher rate of metabolism in the olefactory epithelium to N-oxide metabolites (Nikula and Lewis, 1994). Pyridine is metabolized by cytochrome P450 2E1 and 4B (Kim et al., 1990) and has been shown to enhance the expression of several isozymes of cytochrome P450 including 2E1, 1A1, 1A2, 2B1 and 2B2 (Kim and Novak, 1990). Pyridine has been shown to induce CYP1A1 in multiple organs in rats, mice and cultured human lung explants (Iba et al, 2000). N-methyl and N-oxide metabolites of pyridine are also able to induce CYP1A1 metabolism to a similar extent as parent compound (Iba et al., 2000). The primary metabolites of pyridine are pyridine-N-oxide, 2-pyridone, 4-pyridone, 3-hydroxypyridine, and N-methyl pyridinium ion (SCOEL, 2004). While the primary source of metabolism data on pyridine is from animal studies, two healthy human volunteers were given 3.4 mg pyridine in orange juice and the excretion of metabolites was determined. The primary metabolite excreted was pyridine-N-oxide (32% of administered dose) and N-methylpyridinium (12% of the dose) collected in a 24 hour urine sample (D’Souza et al., 1980; SCOEL, 2004).

Pyridine and its metabolites are eliminated primarily in the urine. Pyridine is also excreted in exhaled air and in feces to a lesser extent (SCOEL, 2004). The elimination half life of pyridine was 17 hours following a single 100 mg/kg intraperitoneal injection and was 8 hours following the last exposure of a 3-day, 8 hour/day exposure to 200 ppm by inhalation (Scholl and Iba, 1997). The shorter elimination half life is possibly due to induction of metabolic enzymes. Pyridine induces CYP2E1 and CYP1A1 metabolism (Scholl and Iba, 1997). The latter induction has been shown to be sexually dimorphic. There is no gender difference in the plasma elimination rate of pyridine after intraperitoneal administration however (Iba et al., 1999).
3-Picoline administered intraperitoneally to guinea pigs, rabbits, mice and ferrets resulted in urinary excretion of the N-oxide compound (approximately 10% in rats, 40% in mice and in guinea pigs) (Gorrod et al., 1980; AIHA, 1988).

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
Pyridine and its methyl derivatives are absorbed via inhalation, oral and dermal exposures. They are distributed into the water compartment as evidenced by highest levels in the kidney and eliminated primarily in the urine. Pyridine and its derivatives are metabolised by CYP enzymes in the liver, with primary metabolites being pyridine-N-oxide, 2-pyridone, 4-pyridone, 3-hydroxypyridine, and N-methyl pyridinium ion. These substances have a low risk of bioaccumulating in body fat or milk.