Pyridine-2-carbaldehyde

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Evaluation of toxicokinietcs based on literature data

Adequacy of study:

key study

Study period:

NA

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

ORAL: According to the ECHA Guidelines (2014), molecules with molecular weights of less than 500 g/mol are small enough to be candidates for absorption by passive diffusion from the GI tract. The molecular weight of the substance is 107 g/mol, it is water soluble (50 g/L) and has an octanol-water partition coefficient (log Pow) of 0.714. This combination of aqueous and lipid solubility favours absorption by the oral route. This conclusion is supported by data from two similar compounds, the absorption of a single oral dose of pyridine in humans (0.01 mg/kg bw) was at least 65% (IARC, 2000) and the absorption of a single oral dose of nicotinic acid in rats (2.5 mg/kg bw) was at least 90% (Reddi and Kodicek, 1952).
This hypothesis is substantiated by the classification of 2 PCA as "Acute toxicity (oral), Hazard Catego ry 4", due to the dose response observed for treatment related clinical signs and mortality.

DERMAL: Based on the physicochemical properties, the substance is likely to be absorbed after dermal application. According to the ECHA Guidelines (ECHA 2014) molecules with molecular weights of less than 500 g/mole are capable of migration through the skin into systemic circulation. In addition, both water and lipid solubility influences the potential for dermal penetration. The dermal penetration of pyridine and picoline was studied in vitro using human skin preparations (Wilkins and Williams, 2001). The study showed that both compounds passed through the skin barrier, with the permeability and flux being dependent on concentration of dose and vehicle. The hypothesis for dermal absorption cannot be substantiated by toxicity studies since the substance is not classified for dermal toxicity. However it is noted that the substance is classified as " Skin irritation/corrosion, Hazard Category 2", due to necrosis of the treated skin, and this skin damage may facilitate dermal penetration.

INHALATION: The substance is a liquid at room temperature with limited volatility. The vapor pressure of the substance is 1.2 hPa at 20°C which limits the likelihood of significant systemic exposure by inhalation of vapors. However, if the substance were aerosolized, absorption across the respiratory epithelium would likely be rapid based on its partition coefficient and low molecular weight. This hypothesis is substantiated by the classification of the substance as "Acute toxicity (inhalation), Hazard Category 3", due to mortalities seen at all dose levels utilized in the study.

Details on distribution in tissues:

The distribution of the test item has not been characterized?

Details on excretion:

The polarity and water solubility of the test item would facilitate its rapid excretion in urine. Any of the metabolic steps described above would further increase its polarity and thus enhance urinary excret ion. Following addition of a hydroxy function and a possible glucuronide conjugate to the substance the molecular weight of the compound would increase to 299 g/mol and which is at the lower end of the molecular weight range for elimination via bile (~300 g/mol for the rat, ECHA, 2014). Therefore some of the absorbed dose could be eliminated in faeces via bile.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

The structure of the substance contains a number of sites which could be subject to metabolic transformations . The aromatic ring could be subject to oxidative Phase I metabolism at the nitrogen atom giving pyridine N-oxide and/or at the ring carbon moieties giving hydroxy pyridine carbaldehyde. The nitrogen atom could also be methylated. These biotransformation steps were observed for pyridine (IARC, 2000). The aldehyde moiety on the methyl side chain could also be subject to oxidation giving rise to an acid (a structural isomer of nicotinic acid) or be reduced to an alcohol. Hydroxy and acid groups produced from Phase I metabolism could be subject to Phase II (conjugation) reactions to give the sulphate, glucuronide or amino acid conjugates of the Phase I metabolites. The Phase I metabolic reactions are likely to be catalysed by oxidases in the liver giving rise to a high first pass effect. It is also po ssible that oxidases in the lung and skin could also metabolise the substance following inhalation or dermal exposure.

Any other information on results incl. tables

The toxicokinetics of absorption, distribution metabolism and excretion (ADME) of the substance have not been evaluated in vivo. As a result, this analysis of the toxicokinetics is a qualitative assessment based on physicochemical properties and available information on the substance and 2 structurally related compounds (pyrimidine and nicotinic acid) according to the guidance provided in the ECHA Guidelines (ECHA, 2014).

Mode of Action:

No mode of action for adverse effects has been developed for

Toxicodynamics:

The biological effects of the test item are limited. As a result, no toxicodynamic effects have been described.

Applicant's summary and conclusion

Conclusions:

The substance is a small aromatic heterocycle with a molecular weight of 107 g/mol. It is soluble in water at up to 50 g/L at 20°C with a partition coefficient (Log Pow) of 0.714 at 20°C and a vapour pressure of 1.2 hPa at 20°C. With these physical/chemical (phys/chem) properties, oral, dermal and inhalation exposures are all potential routes of exposure.
Once absorbed, the substance is likely to be rapidly metabolized by Phase I oxidation reactions and possi ble Phase II conjugation. Both unchanged parent and metabolites are likely to be excreted in urine. Therefore bioaccumulation is unlikely.
1. the substance can be assumed to be absorbed by the oral, dermal, and inhalation routes of exposure t herefore systemic exposure is likely.
2. the substance is likely to be rapidly metabolized to hydroxy and acid metabolites which could then be c onjugated.
3. the substance is unlikely to bioaccumulate because of its polarity, extensive metabolism and rapid excretion.