Structure-toxicity relationships for mono alkyl- or halogen-substituted anilines

Schultz, T.W.; Cajina-Quezada, M; Wesley, S K

doi:10.1007/bf01701936

Cited by 18 publications

(6 citation statements)

References 7 publications

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“…From the original set of 93 chemicals common to both test systems, four compounds were not toxic at amounts that saturate the protozoan growth media and were excluded from further analyses. Previous studies [20,21] have noted that para-position halogen-substituted anilines are excessively toxic in the Tetrahymena assay. Seven of these anilines were removed from the data set in further analyses, as no explanation can be made at this time for their toxicity.…”

Section: Resultsmentioning

confidence: 90%

Structure–activity Relationships for Pimephales and Tetrahymena: A Mechanism of Action Approach

Bearden¹,

Schultz²

1997

Environ Toxicol Chem

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Abstract-The toxicity data of 74 chemicals tested in both the 96-h fathead minnow (Pimephales promelas) mortality assay and the 2-d Tetrahymena pyriformis (a protozoan) growth inhibition assay were evaluated using quantitative structure-activity relationships (QSARs). Each chemical was a priori assigned a mechanism of acute toxic action from either nonpolar narcosis, polar narcosis, weak acid respiratory uncoupling, soft electrophilicity, or proelectrophilicity. The polar narcotics were further split into a phenol group and an aniline group. The relationship between bioreactivity and the importance of penetration to the site of action in both systems was studied. Bioreactivity showed a trend to be inversely proportional to the value of the hydrophobicity term. The data were examined to investigate how different molecular descriptors modeled the mechanisms of action. Models were produced for nonpolar narcotics and anilines for both species with the 1-octanol/water partition coefficient (log K ow ) alone. Soft electrophiles were best predicted by the average acceptor superdelocalizability ( ), whereas proelectrophiles were modeled by log K ow and n S av . The weak acid uncouplers modeled with either log K ow or log K ow plus the ionization constant (pK a ) for Pimephales and n S av Tetrahymena, respectively. Phenols yielded predictive models using a either a combination of log K ow with or lowest unoccupied n S av molecular orbital, for fathead minnow and protozoan, respectively.

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Section: Resultsmentioning

confidence: 90%

Structure–activity Relationships for Pimephales and Tetrahymena: A Mechanism of Action Approach

Bearden¹,

Schultz²

1997

Environ Toxicol Chem

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“…On the basis of these preliminary evaluations, it was decided to examine all relationships between physicochemical properties and acute local effects separately for lesions on skin and for lesions on eyes and, in addition, to examine relationships between n-octanol/ water partition coefficient and local irritation/corrosion, because this parameter correlating hydrophilic and hydrophobic substance properties has proved to be predictive for ecotoxicokinetic substance properties (12)(13)(14)(15)(16)(17)(18), and thus may also be predictive for specific local toxic effects (11,19,20). It was also decided to examine the relationship between surface tension and local irritation/corrosion, because surface activity alters the effects of aqueous solubility and lipid solubility on the capacity of a chemical to penetrate membranes.…”

Section: Calculation Of Sar Algorithms: Evaluation Of Physical Datamentioning

confidence: 99%

“…The logarithm of the octanol/water partition coefficient (log P ow ) for the partition of a chemical between a hydrophilic solvent phase (water) and a hydrophobic solvent phase (n-octanol) is correlated with the aqueous solubility (21). Log P ow has proved to be a good parameter for considerations relating to the possible kinetic fate of a chemical in the environment, and as represented by percutaneous absorption of chemicals from natural waters, from ambient air, and from soil (12)(13)(14)(15)(16)(17)(18). SAR considerations relating to local irritation/corrosion can also be based on this partition coefficient (11,19,20).…”

Section: Relationships Between Octanol/water Partition Coefficient Anmentioning

confidence: 99%

Development of a Decision Support System for the Introduction of Alternative Methods into Local Irritancy/Corrosivity Testing Strategies. Creation of Fundamental Rules for a Decision Support System

et al. 2000

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The notification procedure of the European Union (EU) for new chemicals requires the application of protocols on physicochemical and toxicological tests for the evaluation of physicochemical properties and probable toxic effects of each notified substance. A computerised database was developed from data sets and toxicological test protocols relating to substance properties responsible for skin and eye irritation/corrosion. To develop specific structure-activity relationship (SAR) models and to find rules for a decision support system (DSS) to predict local irritation/corrosion, physical property data, chemical structure data and toxicological data for approximately 1300 chemicals, each having a purity of 95% or more, were evaluated. The evaluation demonstrated that the lipid solubility and aqueous solubility of a chemical are relevant to, or — in some cases — responsible for, the observed local effects of a substance on the skins and eyes of rabbits. The octanol/water partition coefficient and the measured value of the surface tension of a saturated aqueous solution of the substance give additional information that permits the definition of detailed SAR algorithms that use measured solubility values. Data on melting points and vapour pressure can be used to assess the intensity and duration of local contact with a chemical. Considerations relating to the reactivity of a pure chemical can be based on molecular weight and the nature of the heteroatoms present. With respect to local lesions produced following contact with the skin and eyes of rabbits, the data evaluation revealed that no general “local irritation/corrosion potential” of a chemical can be defined. A variety of mechanisms are responsible for the formation of local lesions on the skin or in the eyes: serious lesions are produced by mechanisms different from those that cause moderate irritation in these organs. In order to develop a DSS that uses the information extracted from the database, chemical main groups were categorised on the basis of their empirical formulae, and rules were defined of the type IF (physicochemical property) A, THEN not (toxic) effect B, based on correlations between specific local effects and measured physicochemical values. Other rules of the type IF substructure A, THEN effect B were developed based on correlations between specific local effects and the submitted structural formulae. Reactive chemical substructures relevant to the formation of local lesions and rules for the prediction of the absence of any skin irritation potential were identified. Proposals are made relating to the development of alternatives to eye irritation testing with rabbits.

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“…From the original set of 93 chemicals common to both test systems, four compounds were not toxic at amounts that saturate the protozoan growth media and were excluded from further analyses. Previous studies [20,21] have noted that para‐position halogen‐substituted anilines are excessively toxic in the Tetrahymena assay. Seven of these anilines were removed from the data set in further analyses, as no explanation can be made at this time for their toxicity.…”

Section: Resultsmentioning

confidence: 99%

Structure‐activity relationships for Pimephales and Tetrahymena: A mechanism of action approach

Bearden

Schultz

1997

Enviro Toxic and Chemistry

Self Cite

View full text Add to dashboard Cite

The toxicity data of 74 chemicals tested in both the 96‐h fathead minnow (Pimephales promelas) mortality assay and the 2‐d Tetrahymena pyriformis (a protozoan) growth inhibition assay were evaluated using quantitative structure‐activity relationships (QSARs). Each chemical was a priori assigned a mechanism of acute toxic action from either nonpolar narcosis, polar narcosis, weak acid respiratory uncoupling, soft electrophilicity, or proelectrophilicity. The polar narcotics were further split into a phenol group and an aniline group. The relationship between bioreactivity and the importance of penetration to the site of action in both systems was studied. Bioreactivity showed a trend to be inversely proportional to the value of the hydrophobicity term. The data were examined to investigate how different molecular descriptors modeled the mechanisms of action. Models were produced for nonpolar narcotics and anilines for both species with the 1‐octanol/water partition coefficient (log Kow) alone. Soft electrophiles were best predicted by the average acceptor superdelocalizability (Snav), whereas proelectrophiles were modeled by log Kow and Snav. The weak acid uncouplers modeled with either log Kow or log Kow plus the ionization constant (pKa) for Pimephales and Tetrahymena, respectively. Phenols yielded predictive models using a either a combination of log Kow with Snav or lowest unoccupied molecular orbital, for fathead minnow and protozoan, respectively.

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Structure-toxicity relationships for mono alkyl- or halogen-substituted anilines

Cited by 18 publications

References 7 publications

Structure–activity Relationships for Pimephales and Tetrahymena: A Mechanism of Action Approach

Structure–activity Relationships for Pimephales and Tetrahymena: A Mechanism of Action Approach

Development of a Decision Support System for the Introduction of Alternative Methods into Local Irritancy/Corrosivity Testing Strategies. Creation of Fundamental Rules for a Decision Support System

Structure‐activity relationships for Pimephales and Tetrahymena: A mechanism of action approach

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