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

Abstract

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.

Keywords

skin irritation/corrosion eye irritation/corrosion structure-activity relationships electronic database decision support systems alternative methods

Get full access to this article

View all access options for this article.

References

EC (1993). Commission Directive 93/67/EEC of 20 July 1993 laying down the principles for the assessment of risks to man and the environment of substances notified in accordance with Council Directive 67/548/EEC. Official Journal of the European Communities L227, 9–18.

EC (1992). Council Directive 92/69/EEC adapting to technical progress for the seventeenth time Council Directive 67/548/EEC on the approximation of laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances: Annex V. Official Journal of the European Communities L 383A, 113–235.

OECD (2000). OECD Guidelines for Testing of Chemicals. http://www.oecd.org/ehs/test/teslist.htm.

OECD (1998). Revised Proposal for a Harmonized Integrated Classification System for Human Health and Environmental Effects of Chemicals, ENV/MC/CHEM/HCL(98)15, 64 pp. Paris, France: OECD.

Barratt

M.D.

, Castell

J.V.

, Chamberlain

, Combes

R.D.

, Dearden

J.C.

, Fentem

J.H.

, Gerner

, Giuliani

, Gray

T.J.B.

, Livingstone

D.J.

, Provan

W.M.

, Rutten

F.A.J.J.L.

, Verhaar

H.J.M.

, & Zbinden

(1995). The integrated use of alternative approaches for predicting toxic hazard. The report and recommendations of ECVAM workshop 8. ATLA 23, 410–429.

EC (1992). Commission Directive 92/32/EEC of 30 April 1992 amending for the seventh time Directive 67/548/EEC on the approximation of the laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances. Official Journal of the European Communities L154, 1–28.

Gerner

, Graetschel

, Kahl

, & Schlede

(2000). Development of a decision support system for the introduction of alternative methods into local irritatancy/corrosivity testing strategies. Development of a relational database. ATLA 28, 11–28.

Becker

(1961). Einführung in die Elektronentheorie organisch-chemischer Reaktionen, pp. 49–118. Berlin, Germany: VEB Deutscher Verlag der Wissenschaften.

Elias

P.M.

(1988). Structure and function of the stratum corneum permeability barrier. Drug Development Research 13, 97–105.

10.

Anderson

B.D.

, Higuchi

W.I.

, & Raykar

P. V.

(1988). Heterogeneity effects on permeability–partition coefficient relationships in human stratum corneum. Pharmaceutical Research 5, 566–573.

11.

Schaefer

, & Redelmeier

T.E.

(1996). Relationships between the structure of compounds and their diffusion across membranes. In Skin Barrier. Principles of Percutaneous Absorption (ed. Karser

), pp. 87–152. Basel, Switzerland: S. Karger AG

12.

Schultz

T.W.

, Jain

, Cajina-Quezada

, & Lin

D.T.

(1988). Structure–toxicity relationships for selected benzyl alcohols and the polar mechanism of toxicity. Ecotoxicology and Environmental Safety 16, 57–64.

13.

Schultz

T.W.

, Wesley

S.K.

, & Baker

L.L.

(1989). Structure-activity relationships for di- and trialkyl and/or halogen substituted phenols. Bulletin of Environmental Contamination and Toxicology 43, 192–198.

14.

Schultz

T.W.

, Cajina-Quezada

, & Wesley

S.K.

(1989). Structure-toxicity relationships for mono alkyl- or halogen-substituted anilines. Bulletin of Environmental Contamination and Toxicology 43, 564–569.

15.

Schultz

T.W.

, Arnold

L.M.

, Wilke

T.S.

, & Moulton

M.P.

(1990). Relationships of quantitative structure-activity for normal aliphatic alcohols. Ecotoxicology and Environmental Safety 19, 243–253.

16.

Jaworska

J.S.

, & Schultz

T.W.

(1991). Comparative toxicity and structure-activity in Chlorella and Tetrahymena: monosubstituted phenols. Bulletin of Environmental Contamination and Toxicology 47, 57–62.

17.

Schultz

T.W.

, Lin

D.T.

, & Culberson

R.W.

(1993). Predicted toxicities of aryl alkanols and related compounds. Journal of Applied Toxicology 13, 429–434.

18.

Niimi

A.J.

, Lee

H.B.

, & Kissoon

G.P.

(1989). Octanol/water partition coefficients and bioconcentration factors of chloronitrobenzenes in rainbow trout (Salmo Gairdneri). Environmental Toxicology and Chemistry 8, 817–823

19.

Potts

R.O.

, & Guy

R.H.

(1992). Predicting skin permeability. Pharmaceutical Research 9, 663–669.

20.

Jackson

J.A.

, Diliberto

J.J.

, & Birnbaum

L.S.

(1993). Estimation of octanol-water partition coefficients and correlation with dermal absorption for several polyhalogenated aromatic hydrocarbons. Fundamental and Applied Toxicology 21, 334–344.

21.

Staab

H.A.

(1960). Kohaesionseigenschaften. In Einführung in die theoretische organische Chemie (ed. Staab

H. A.

), pp. 655–666. Weinheim, Germany: Verlag Chemie.

22.

Zinke

, & Gerner

(2000). A computer-based structure-activity relationship method for predicting the toxic effects of organic chemicals from one-dimensional representations of their molecular structures. ATLA 28, 609–620.

23.

Zinke

, Gerner

, Graetschel

, & Schlede

(2000). Local irritation/corrosion testing strategies: development of a decision support system for the introduction of alternative methods. ATLA 28, 29–40.

24.

Hansch

, & Fujita

(1964). p-σ-π Analysis: a method for the correlation of biological activity and chemical structure. Journal of the American Chemical Society 86, 1616–1626.

25.

EC (1996). Technical Guidance Documents in Support of the Commission Directive 93/67/EEC on Risk Assessment for New Notified Substances and the Commission Regulation (EC) 1488/94 on Risk Assessment for Existing Substances. 735 pp. Luxembourg, Luxembourg: Publication Office European Community.

26.

Hansen

, Loonen

, & Karcher

(1996). Use of QSARs for risk assessment of chemicals in the European Union. In Qualitative Structure-Activity Relationships in Environmental Sciences, Vol. 7. (ed. Chen

, & Schüürmann

), pp. 413–424. Pensacola, FL, USA: SETAC Press.

27.

Hansch

, Kim

, Leo

A.J.

, Novellino

, Silipo

, & Vittoria

(1989). Towards a quantitative comparative toxicology of organic compounds. CRC Critical Reviews in Toxicology 19, 185–226.

28.

Enslein

(1988). An overview of structure–activity relationships as an alternative to testing in animals for carcinogenicity, mutagenicity, dermal and eye irritation, and acute oral toxicity. Toxicology and Industrial Health 4, 479–498.

29.

Héberger

, & Rajkó

(1996). Discrimination of statistically equivalent variables in quantitative structure-activity relationships. In Quantitative structure-Activity Relationships in Environmental Sciences, Vol. 7 (ed. Chen

, & Schüümann

), pp. 425–433. Pensacola, FL, USA: SETAC Press.

30.

Gombar

V.K.

, Enslein

, Blake

B.W.

, & Reid

D.A.

(1996). Quantitative structure-activity relationships in predicting chemical toxicity: when is the prediction reliable? In Quantitative Structure-Activity Relationships in Environmental Sciences, Vol. 7 (ed. Chen

, & Schüürmann

), pp. 399–411. Pensacola, FL, USA: SETAC Press.

31.

Whittle

, Barratt

M.D.

, Carter

J.A.

, Basketter

D.A.

, & Chamberlain

(1996). Skin corrosivity potential of fatty acids: in vitro rat and human skin testing and QSAR studies. Toxicology in Vitro 10, 95–100.

32.

Barratt

M.D.

(1996). Quantitative structure-activity relationships (QSAR) for skin corrosivity of organic acids, bases and phenols: principal components and neural network analysis of extended datasets. Toxicology in Vitro 10, 85–94.

33.

Koehler

M.G.

, Grigoras

, & Dunn

W.J.

(1988). The relationships between chemical structure and the logarithm of the partition coefficient. Quantitative Structure–Activity Relationships 7, 150–159.

34.

Isnard

, & Lambert

(1989). Aqueous solubility and n-octanol/water partition coefficient correlations. Chemosphere 18, 1837–1853.

35.

Sasaki

, Kubodera

, Matuszaki

, & Umeyama

(1991). Prediction of octanol/water partition coefficients using parameters derived from molecular structures. Journal of Pharmacobiodynamics 14, 207–214.

36.

Makino

(1998). Prediction of n-octanol/water partition coefficients of polychlorinated biphenyls by use of computer calculated molecular properties. Chemosphere 37, 13–26.

37.

Patil

G.S.

(1991). Correlation of aqueous solubility and octanol-water partition coefficient based on molecular structure. Chemosphere 22, 723–738.

38.

Banerjee

, Howard

P.H.

, & Lande

S.S.

(1990). General structure-vapour pressure relationships for organics. Chemosphere 21, 1173–1180.

39.

Benfenati

, & Gini

(1997). Computational predictive programs (expert systems) in toxicology. Toxicology 119, 213–225.

40.

EC (2000). Commission Directive 2000/33/EC of 25 April 2000 adapting to technical progress for the 27th time Council Directive 67/548/EEC on the approximation of laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances. Official Journal of the European Communities. Annex 1. B.40. Skin Corrosion. L136, 90–107.

41.

OECD (2000). OECD Guidelines for the Testing of Chemicals. Draft Proposal for a New Guideline: In Vitro Skin Corrosion Tests. Draft to be commented with deadline 30 June 2000. Paris, France: OECD.