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Chemical reactivity of paraquat with the previously validated antidote, sodium salicylate
S166
Abstracts / Toxicology Letters 180S (2008) S32–S246
S06 Chemical reactivity of paraquat with the previously validated antidote, sodium salicylate Ricardo Dinis-Oliveira 2,3,∗ , Paula Guedes de Pinho 1,3 , António César Silva Ferreira 3,4 , Artur Silva 3,5 , Carlos Afonso 3,6 , Maria de Lourdes Bastos 1,3 , Fernando Remião 1,3 , José Alberto Duarte 1,3 , Félix Carvalho 3,7 1
REQUIMTE, Departamento de Toxicologia, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal, 2 Departamento de Análises Clínicas e Saúde Pública, Cooperativa de Ensino Superior, Politécnico e Universitário, Vila Nova de Famalicão, Portugal, 3 Instituto de Medicina Legal, Faculdade de Medicina, Universidade do Porto, Porto, Portugal, 4 Interface A4, Escola Superior de Biotecnologia, Universidade Católica Portuguesa, Porto, Portugal 5 Departamento de Química, Universidade de Aveiro, Aveiro, Portugal 6 Departamento de Química Orgânica, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal 7 CIAFEL, Faculdade de Desporto, Universidade do Porto, Porto, Portugal Sodium salicylate (NaSAL) has been showing to be a promising antidote for the treatment of paraquat (PQ) poisonings. The modulation of the pro-oxidant and pro-inflammatory pathways, as well as the anti-thrombogenic properties of NaSAL are probably essential features for the healing effects provided by this drug. Nevertheless, a possible direct chemical reactivity between PQ and NaSAL is also a putative pathway to be considered, this hypothesis being the objective of the present study. In accordance, it is shown, for the first time that PQ and NaSAL react immediately in aqueous medium and within 2–3 min in the solid state. Photographs and scanning electron photomicrographs indicated that a new chemical entity is formed when both compounds are mixed. This assumption was corroborated by the evaluation of the melting point, and through several analytical techniques, namely ultraviolet/visible spectroscopy, nuclear magnetic resonance spectroscopy, gas chromatography/mass spectrometry/mass spectrometry (GC/MS/MS), liquid chromatography/electrospray ionization/mass spectrometry/mass spectrometry (LC/ESI/MS/MS) and infrared spectroscopy, which revealed that stable charge-transfer complexes are formed when PQ is mixed with NaSAL. LC/ESI/MS/MS allowed obtaining the stoichiometry of the charge-transfer complexes. In order to increase resolution, single value decomposition, acting as a filter, showed that the charge-transfer complexes with m/z 483, 643 and 803 correspond to the pseudo-molecular ions, respectively 1:2, 1:3 and 1:4 (PQ:NaSAL). In conclusion, these results provided a new and important mechanism of action of NaSAL against the toxicity mediated by PQ. doi:10.1016/j.toxlet.2008.06.260 S07 Developmental toxicity of dinoseb, nitrophenolic herbicide, in laboratory animals Makoto Ema 2,∗ , Mariko Matsumoto 1 , Carlo Poncipe 3 , Akihiko Hirose 1 1 Division of Risk Assessment, Biological Safety Research Center, National Institute of Health Sciences, Tokyo, Japan, 2 Research Institute of Science for Safety and Sustainability, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan, 3 Biocides/HPV Section of the Registration Services Department, SafePharm Laboratories Ltd., Derby, United Kingdom, Derby, United Kingdom
Dinoseb, 2-sec-butyl-4,6-dinitrophenol, is used as a nitrophenolic herbicide in soybeans, vegetables, fruits, nuts, citrus and other field crops for the selective control of grass and broadleaf weeds. It is also used as an insecticide in grapes and as a seed crop drying agent. We summarized the data available in the literature concerning prenatal exposure to dinoseb evaluating reported developmental toxicity in laboratory animals. We have particularly focused on the variable factors in the manifestation of the developmental toxicity of dinoseb. Developmental toxicity of dinoseb was remarkably deferent by experimental conditions including animal species used in experiments. Teratogenicity was detected in rats given dinoseb by gavage and fed a certain diet, rats fed a diet containing dinoseb, mice given dinoseb by gavage, intraperitoneally or subcutaneously, and rabbits given dinoseb by gavage or dermally. Compositions of diet used in experiments, genetic difference in strains of rats, and routes or modes of administration may influence developmental toxicity of dinoseb. Susceptibility of developmental toxicity of dinoseb was greater in rabbits than in rats and mice. It is essential that the relevant mode of administration to human intake be used in laboratory studies for human risk assessment. Human exposure to dinoseb is anticipated to occur by direct contact, ingestion and inhalation for users and producers. Confirmation of the adverse effects on reproduction and development in other species of mammals exposed by anticipated routes of human exposure would be important for risk assessment in humans. doi:10.1016/j.toxlet.2008.06.261 S08 Determination of paclobutrazol in mango by LC/MS/MS system Vera Lúcia Ferracini ∗ , Sonia Claudia Nascimento de Queiroz, Maria Aparecida Rosa Embrapa Meio Ambiente, Jaguariuna, São Paulo, Brazil The mango is the tropical fruit that is most produced in the world, being approximately 50% of all tropical fruits produced. It is an important agricultural product for the economy of the developing countries in the tropics and Brazil is the third largest mango exporter, after Mexico and India. A large percentage of Brazilian mangos is produced in the semiarid zone of the northeast region of Brazil, in the irrigated fruit agriculture of the São Francisco River Valley. Paclobutrazol is used in the irrigated mango generally applied annually as root for the enhancement of a plants reproductive growth. The aim of this work was to develop and validate method for the determination of paclobutrazol in mango. The extraction was made with methanol and the analyses by LC/MS/MS triple quadrupole. The following validation parameters were obtained: limit of detection of method 0.25 g kg−1 , limit of quantification of method 1.25 g kg−1 ; r2 ≥ 0.995; recoveries from 82 to 94%; intermediary precision (%R.S.D.) <15%. The method showed efficient and reliable for determination of the pesticide in mango. LCMSMS analysis no showed presence of paclobutrazol residues in mango. Thus these results indicated that use of paclobutrazol in mango continuously at recommended doses may not result in its residues in mango fruits at harvest at levels which may pose any risk to human health. However, in areas where paclobutrazol is applied regularly, there may be risk of environmental contamination due to its residues persisting in soil for a very long time. doi:10.1016/j.toxlet.2008.06.262
Abstracts / Toxicology Letters 180S (2008) S32–S246
S06 Chemical reactivity of paraquat with the previously validated antidote, sodium salicylate Ricardo Dinis-Oliveira 2,3,∗ , Paula Guedes de Pinho 1,3 , António César Silva Ferreira 3,4 , Artur Silva 3,5 , Carlos Afonso 3,6 , Maria de Lourdes Bastos 1,3 , Fernando Remião 1,3 , José Alberto Duarte 1,3 , Félix Carvalho 3,7 1
REQUIMTE, Departamento de Toxicologia, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal, 2 Departamento de Análises Clínicas e Saúde Pública, Cooperativa de Ensino Superior, Politécnico e Universitário, Vila Nova de Famalicão, Portugal, 3 Instituto de Medicina Legal, Faculdade de Medicina, Universidade do Porto, Porto, Portugal, 4 Interface A4, Escola Superior de Biotecnologia, Universidade Católica Portuguesa, Porto, Portugal 5 Departamento de Química, Universidade de Aveiro, Aveiro, Portugal 6 Departamento de Química Orgânica, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal 7 CIAFEL, Faculdade de Desporto, Universidade do Porto, Porto, Portugal Sodium salicylate (NaSAL) has been showing to be a promising antidote for the treatment of paraquat (PQ) poisonings. The modulation of the pro-oxidant and pro-inflammatory pathways, as well as the anti-thrombogenic properties of NaSAL are probably essential features for the healing effects provided by this drug. Nevertheless, a possible direct chemical reactivity between PQ and NaSAL is also a putative pathway to be considered, this hypothesis being the objective of the present study. In accordance, it is shown, for the first time that PQ and NaSAL react immediately in aqueous medium and within 2–3 min in the solid state. Photographs and scanning electron photomicrographs indicated that a new chemical entity is formed when both compounds are mixed. This assumption was corroborated by the evaluation of the melting point, and through several analytical techniques, namely ultraviolet/visible spectroscopy, nuclear magnetic resonance spectroscopy, gas chromatography/mass spectrometry/mass spectrometry (GC/MS/MS), liquid chromatography/electrospray ionization/mass spectrometry/mass spectrometry (LC/ESI/MS/MS) and infrared spectroscopy, which revealed that stable charge-transfer complexes are formed when PQ is mixed with NaSAL. LC/ESI/MS/MS allowed obtaining the stoichiometry of the charge-transfer complexes. In order to increase resolution, single value decomposition, acting as a filter, showed that the charge-transfer complexes with m/z 483, 643 and 803 correspond to the pseudo-molecular ions, respectively 1:2, 1:3 and 1:4 (PQ:NaSAL). In conclusion, these results provided a new and important mechanism of action of NaSAL against the toxicity mediated by PQ. doi:10.1016/j.toxlet.2008.06.260 S07 Developmental toxicity of dinoseb, nitrophenolic herbicide, in laboratory animals Makoto Ema 2,∗ , Mariko Matsumoto 1 , Carlo Poncipe 3 , Akihiko Hirose 1 1 Division of Risk Assessment, Biological Safety Research Center, National Institute of Health Sciences, Tokyo, Japan, 2 Research Institute of Science for Safety and Sustainability, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan, 3 Biocides/HPV Section of the Registration Services Department, SafePharm Laboratories Ltd., Derby, United Kingdom, Derby, United Kingdom
Dinoseb, 2-sec-butyl-4,6-dinitrophenol, is used as a nitrophenolic herbicide in soybeans, vegetables, fruits, nuts, citrus and other field crops for the selective control of grass and broadleaf weeds. It is also used as an insecticide in grapes and as a seed crop drying agent. We summarized the data available in the literature concerning prenatal exposure to dinoseb evaluating reported developmental toxicity in laboratory animals. We have particularly focused on the variable factors in the manifestation of the developmental toxicity of dinoseb. Developmental toxicity of dinoseb was remarkably deferent by experimental conditions including animal species used in experiments. Teratogenicity was detected in rats given dinoseb by gavage and fed a certain diet, rats fed a diet containing dinoseb, mice given dinoseb by gavage, intraperitoneally or subcutaneously, and rabbits given dinoseb by gavage or dermally. Compositions of diet used in experiments, genetic difference in strains of rats, and routes or modes of administration may influence developmental toxicity of dinoseb. Susceptibility of developmental toxicity of dinoseb was greater in rabbits than in rats and mice. It is essential that the relevant mode of administration to human intake be used in laboratory studies for human risk assessment. Human exposure to dinoseb is anticipated to occur by direct contact, ingestion and inhalation for users and producers. Confirmation of the adverse effects on reproduction and development in other species of mammals exposed by anticipated routes of human exposure would be important for risk assessment in humans. doi:10.1016/j.toxlet.2008.06.261 S08 Determination of paclobutrazol in mango by LC/MS/MS system Vera Lúcia Ferracini ∗ , Sonia Claudia Nascimento de Queiroz, Maria Aparecida Rosa Embrapa Meio Ambiente, Jaguariuna, São Paulo, Brazil The mango is the tropical fruit that is most produced in the world, being approximately 50% of all tropical fruits produced. It is an important agricultural product for the economy of the developing countries in the tropics and Brazil is the third largest mango exporter, after Mexico and India. A large percentage of Brazilian mangos is produced in the semiarid zone of the northeast region of Brazil, in the irrigated fruit agriculture of the São Francisco River Valley. Paclobutrazol is used in the irrigated mango generally applied annually as root for the enhancement of a plants reproductive growth. The aim of this work was to develop and validate method for the determination of paclobutrazol in mango. The extraction was made with methanol and the analyses by LC/MS/MS triple quadrupole. The following validation parameters were obtained: limit of detection of method 0.25 g kg−1 , limit of quantification of method 1.25 g kg−1 ; r2 ≥ 0.995; recoveries from 82 to 94%; intermediary precision (%R.S.D.) <15%. The method showed efficient and reliable for determination of the pesticide in mango. LCMSMS analysis no showed presence of paclobutrazol residues in mango. Thus these results indicated that use of paclobutrazol in mango continuously at recommended doses may not result in its residues in mango fruits at harvest at levels which may pose any risk to human health. However, in areas where paclobutrazol is applied regularly, there may be risk of environmental contamination due to its residues persisting in soil for a very long time. doi:10.1016/j.toxlet.2008.06.262