3-[(2S)-ピロリジン-2α-イル]ピリジン

TERRESTRIAL FATE: Based on a classification scheme(1), estimated Koc values of 500 and 14(SRC), determined respectively from a structure estimation method(2) and using a log Kow of 0.17(3) and a regression-derived equation(2), indicates that nornicotine may have very high to moderate mobility in soil(SRC). The estimated pKa of nornicotine is 5.25(4), indicating that this compound will partially exist in cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5). Volatilization of nornicotine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.37X10-9 atm-cu m/mole(SRC), using a fragment constant estimation method(2). Nornicotine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 0.00923 mm Hg at 25 °C(SRC), determined from a fragment constant method(2).

AQUATIC FATE: Based on a classification scheme(1), estimated Koc values of 500 and 14(SRC), determined respectively from a structure estimation method(2) and using a log Kow of 0.17(3) and a regression-derived equation(2), indicates that nornicotine may have no to moderate adsorption to suspended solids and sediment(SRC). The estimated pKa of nornicotine is 5.25(4), indicating that this compound will partially exist in cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5); therefore, moderate adsorption may be more likely to occur with the cation form(SRC). Volatilization from water surfaces is not expected(6) based upon an estimated Henry's Law constant of 1.37X10-9 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). According to a classification scheme(7), an estimated BCF of 3(SRC), from its log Kow of 0.17(3), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Nornicotine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(6).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), nornicotine, which has an estimated vapor pressure of 0.00923 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase nornicotine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 4.4 hours(SRC), calculated from its rate constant of 8.67X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). Nornicotine does not contain chromophores that absorb at wavelengths >290 nm(3), and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

The concentration of nornicotine in cured tobacco leaves grown in an enriched CO2 environment ranged from 0.0091-0.0419 g/100 tissue(1). Nornicotine is an undesirable alkaloid in tobacco because it is a precursor to N'-nitrosonornicotine, a suspected carcinogen(2).

Nornicotine has been detected, not quantified in certain plants(1).[Table#7982]

The Koc of nornicotine is estimated as 14(SRC), using a log Kow of 0.17(1) and a regression-derived equation(2). Using a structure estimation method based on molecular connectivity indices(2), the Koc can be estimated to be 500(SRC). According to a classification scheme(3), these estimated Koc value suggest that nornicotine may have very high to moderate mobility in soil. The estimated pKa of nornicotine is 5.25(4), indicating that this compound will partially exist in cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5).

Nornicotine occurs in tobacco (Nicotiana Tabacum), other species of Nicotiana, and indigenous Australian plants such as Duboisia Hopwoodii and Duboisia Myoporoides(1-3); all these plants are members of the Solanacae family(2,3). Nornicotine has been identified as a chemical component in tobacco(4).

/CASE REPORTS/ Umbilical cord tissue was studied as a means of detecting prenatal exposure to nicotine. ... Between June and September 2009, 19 women with a tobacco exposure history (either first- or second-hand tobacco smoke exposure during pregnancy) were consented for the study. A questionnaire was completed to document nicotine exposure during each trimester of pregnancy. All infants were delivered at term (38 weeks or greater) and paired umbilical cord tissue (10-cm segment or greater) and meconium were obtained. ... Nornicotine was detected only in meconium, at very low concentrations. ... All analyte concentrations were lowest when the mother stated she quit smoking early in pregnancy or had only second-hand exposure, and detection was poor if exposure was limited to the first or second trimesters. ...

Nornicotine has been identified as a chemical component in tobacco smoke and in substituent tobacco smoke(1). Nornicotine's former production and use as an insecticide(2) may have resulted in its direct release to the environment through various waste streams(SRC).

An estimated BCF of 3 was calculated in fish for nornicotine(SRC), using a log Kow of 0.17(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for nornicotine is estimated as 1.37X10-9 atm-cu m/mole at 25 °C(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that nornicotine is expected to be essentially nonvolatile water surfaces(2). Nornicotine's Henry's Law constant indicates that volatilization from moist soil surfaces is not expected to be an important fate process(SRC). Nornicotine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 0.00923 mm Hg at 25 °C(SRC), determined from a fragment constant method(1).

/LABORATORY ANIMALS: Neurotoxicity/ The present study demonstrates that S(-)-nornicotine evoked a concentration-dependent increase in dopamine (DA) release from superfused rat striatal slices. The increase in DA release was indicated by an S(-)-nornicotine-induced overflow of endogenous 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatal superfusate and by an S(-)-nornicotine-induced increase in tritium overflow from striatal slices preloaded with [3H]DA. Low concentrations (0.01-1.0 microM) of S(-)-nornicotine, which did not evoke endogenous DOPAC overflow, also were unable to modulate electrically evoked DOPAC overflow. The increase in DOPAC overflow induced by S(-)-nornicotine was compared with that produced by S(-)-nicotine. Comparing equimolar concentrations (0.1-100 microM) of S(-)-nornicotine and S(-)-nicotine, superfusion with S(-)-nornicotine resulted in a significantly greater DOPAC overflow. In contrast to the effect of S(-)-nicotine, S(-)-nornicotine evoked a sustained increase in DOPAC overflow for the entire period of S(-)-nornicotine exposure. Furthermore, DOPAC overflow evoked by S(-)-nornicotine in control Krebs buffer was inhibited by superfusion with a low-calcium buffer. Moreover, in the low-calcium buffer, DOPAC overflow induced by 30 and 100 microM S(-)-nornicotine was not different from that with no S(-)-nicotine, tobacco products and a known metabolite of S(-)-nicotine, increases DA release in a calcium-dependent manner in superfused rat striatal slices. It is interesting that unlike S(-)-nicotine, there does not appear to be desensitization to this effect of S(-)-nornicotine.

/GENOTOXICITY/ Of five tobacco alkaloids tested, only anatabine led to a dose-dependent enhancement of the number of sister-chromatid exchanges (SCE) in Chinese hamster ovary cells (CHO). Nicotine and nornicotine at high concentrations increased the baseline frequency of SCEs moderately. Anabasine and myosmine had no influence on the spontaneous frequency of SCEs.

/OTHER TOXICITY INFORMATION/ ... Nornicotine was found to covalently alter amyloid beta-peptide, leading to reduced peptide aggregation. Potential consequences of this reaction cascade include reduced plaque formation and/or altered clearance of the peptide, as well as attenuated toxicity of soluble amyloid beta-peptide aggregates. The findings described provide an alternative mechanism for nicotine neuroprotection in AD and a means for the alteration of amyloid folding based on a covalent chemical event.

/OTHER TOXICITY INFORMATION/ ...Nornicotine (N-desmethyl-nicotine) appears to activate different nAChR subtypes, has a better pharmacokinetic profile, and produces less toxicity than nicotine. ... In the present study, the S(-)- and R(+)-enantiomers of nornicotine were characterized with regard to analgesia and side-effects profile. Efficacy was demonstrated in rat models of pain where central sensitization is involved: i.e. the chronic constriction nerve injury model of peripheral neuropathy and the formalin model of tonic inflammatory pain. The desirable (analgesic) properties resided predominantly in the S(-)- rather than the R(+)-enantiomer. In contrast, undesirable effects (motor in-coordination, reduced locomotor activity, ataxia) were more pronounced with the R(+)-enantiomer. This is an interesting finding, which may suggest separation of toxicity from analgesia by utilization of S(-)-enantiomer of nornicotine. Maximum analgesic effectiveness without significant side-effects was achieved when S(-)-nornicotine (sub-analgesic dose) was combined with a low-dose of the micro-opioid, morphine. ...

The rate constant for the vapor-phase reaction of nornicotine with photochemically-produced hydroxyl radicals has been estimated as 8.67X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 4.4 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Nornicotine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2). Nornicotine does not contain chromophores that absorb at wavelengths >290 nm(2) and it is reported to not darkened on exposure to light(3); therefore it is not expected to be susceptible to direct photolysis by sunlight(SRC).