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Review Article

Acute toxicity testing of chemicals—Opportunities to avoid redundant testing and use alternative approaches

, , , , , , , & show all
Pages 50-83 | Received 11 Jun 2009, Accepted 09 Oct 2009, Published online: 16 Dec 2009

References

  • Adriaens E, Bytheway H, De Wever B, Eschrich D, Guest R, Hansen E, Vanparys P, Schoeters G, Warren N, Weltens R, Whittingham A, Remon JP. (2008). Successful prevalidation of the slug mucosal irritation test to assess the eye irritation potency of chemicals. Toxicol In Vitro 22:1285–1296.
  • Aleksic M, Thain E, Roger D, Saib O, Davies M, Li J, Aptula A, Zazzeroni R. (2009). Reactivity profiling: Covalent modification of single nucleophile peptides for skin sensitization risk assessment. Toxicol Sci 108: 401–411.
  • Anon. (2002). Chemicals (Hazard Information and Packaging for Supply) Regulations 2002. Vol. No. 1689.
  • Aufderheide M, Mohr U. (1999). CULTEX—A new system and technique for the cultivation and exposure of cells at the air/liquid interface. Exp Toxicol Pathol 51: 489–90.
  • Aufderheide M, Mohr U. (2000). CULTEX—An alternative technique for cultivation and exposure of cells of the respiratory tract to airborne pollutants at the air/liquid interface. Exp Toxicol Pathol 52: 265–70.
  • Ayehunie S, Snell M, Child M, Klausner M. (2009). A plasmacytoid dendritic cell (CD123+/CD11c−) based assay system to predict contact allergenicity of chemicals. Toxicology 264: 1–9.
  • Bakand S, Winder C, Khalil C, Hayes A. (2006a). An experimental in vitro model for dynamic direct exposure of human cells to airborne contaminants. Toxicol Lett 165: 1–10.
  • Bakand S, Winder C, Khalil C, Hayes A. (2006b). A novel in vitro exposure technique for toxicity testing of selected volatile organic compounds. J Environ Monit 8: 100–5.
  • Balls M. (1991). Why modification of the LD50 test will not be enough. Lab Anim 25: 198–206.
  • Basketter DA, Clapp C, Jefferies D, Safford B, Ryan CA, Gerberick F, Dearman RJ, Kimber I. (2005). Predictive identification of human skin sensitization thresholds. Contact Dermatitis 53: 260–267.
  • Basketter DA, Reynolds FS, York M. (1997). Predictive testing in contact dermatitis. Irritant dermatitis. Clin Dermatol 15: 637–644.
  • Boverhof DR, Wiescinski CM, Botham P, Lees D, Debruyne E, Repetto-Larsay M, Ladics G, Hoban D, Gamer A, Remmele M, Wang-Fan W, Ullmann LG, Mehta J, Billington R, Woolhiser MR. (2008). Interlaboratory validation of 1% pluronic l92 surfactant as a suitable, aqueous vehicle for testing pesticide formulations using the murine local lymph node assay. Toxicol Sci 105: 79–85.
  • BTS (1984). A new approach to the classification of substances and preparations on the basis of their acute toxicity. A report by the British Toxicology Society working party on toxicity. Hum Toxicol 3: 85–92.
  • Bulgheroni A, Kinsner-Ovaskainen A, Hoffmann S, Hartung T, Prieto P. (2009). Estimation of acute oral toxicity using the No Observed Adverse Effect Level (NOAEL) from the 28 day repeated dose toxicity studies in rats. Regul Toxicol Pharmacol 53: 16–19.
  • CFR. (1998). Code of Federal Regulations, Title 40, Part 158, Section 340: Toxicology Data Requirements (Inhalation). Washington, DC: Office of the Rederal Register, National Archives and Records Administration.
  • Chapman K, Robinson S. (2007). Challenging the regulatory requirement for acute toxicity studies in the development of new medicines: A workshop report. NC3Rs, 2007.
  • Cinalli C, Carter C, Clark A, Dixon D. (1992). A laboratory method to determine the retention of liquids on the surface of hands. Washington, DC: US Environmental Protection Agency, Exposure Evaluation Division, Office of Pollution, Prevention and Toxics.
  • Clemedson C. (2008). The European ACuteTox project: A modern integrative in vitro approach to better prediction of acute toxicity. Clin Pharmacol Ther 84: 200–202.
  • Clemedson C, Kolman A, Forsby A. (2007). The integrated acute systemic toxicity project (ACuteTox) for the optimisation and validation of alternative in vitro tests. Altern Lab Anim 35: 33–8.
  • Cormier EM, Parker RD, Henson C, Cruse LW, Merritt AK, Bruce RD, Osborne R. (1996). Determination of the intra- and interlaboratory reproducibility of the low volume eye test and its statistical relationship to the Draize eye test. Regul Toxicol Pharmacol 23: 156–161.
  • Costa DL. (2008). Alternative test methods in inhalation toxicology: Challenges and opportunities. Exp Toxicol Pathol 60: 105–109.
  • Draize JH, Woodard G, Calvery HO. (1944). Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. J Pharmacol Exp Therapeutics 82: 377–390.
  • EC. (1999). Directive 1999/45/EC of the European Parliament and of the Council of May 1999. Concerning the approximation of the laws, regulations and administrative provisions of the Member States relating to the classifications, packaging and labelling of dangerous preparations.
  • EC (2003). Directive 2003/15/EC of the European Parliament and of the Council of 27 Feburary 2003 amending Directive 78/786/EEC on the approximation of the laws of the member states relating to cosmetic products. Off J Eur Union L 66: pp 26–35.
  • EC (2007). Corrigendum to Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending DirECtive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94 as well as Council DirECtive 76/769/EEC and Commission Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC (OJ L 396, 30.12.2006). Off J Eur Union L 136, 50: pp 3–280.
  • EC. (2008a). Council Regulation (EC) No. 440/2008, laying down test methods pursuant to to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH).
  • EC. (2008b). Council Regulation (EC. No 1272/2008 of the European Parliament and of the Council on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC. and amending Regulation (EC) No 1907/2006).
  • EC. (2009). Commission Regulation (EC) No 761/2009 of 23 July 2009 amending, for the purpose of its adaptation to technical progress, Regulation (EC) No 440/2008 laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH).
  • ECHA. (2008). Guidance on Information Requirements and Chemical Safety Assessment. Chapter R6: QSARs and grouping of chemicals. Helsinki, Finland: European Chemicals Agency.
  • ECHA. (2008b). Guidance on Information Requirements and Chemical Safety Assessment. Chapter R7a: Endpoint specific guidance. Helsinki, Finland: European Chemicals Agency.
  • ECVAM. (1998). ESAC Statement, April 3, 1998: Scientific Validity of the EpiSkin Test (an In Vitro test for Skin Corrosivity).
  • ECVAM. (2000). ESAC Statement, March 21, 2000: Statement on the Application of the EpiDerm Human Skin Model for Skin Corrosivity Testing.
  • ECVAM. (2006). ESAC Statement, November 17, 2006: Statement on the Application of the SkinEthic Human Skin Model for Skin Corrosivity Testing.
  • ECVAM. (2007a). ESAC Statement, April 27, 2007: Reduced Local Lymph Node Assay (rLLNA) for Skin Sensitisation.
  • ECVAM. (2007b). ESAC Statement, April 27, 2007: Statement on the conclusions of the ICCVAM retrospective study on Organotypic in vitro assays as screening tests to identify potential ocular corrosives and sever irritants as determined by US EPA, EU (R41) and UN GHS classifications in a tiered testing strategy, as part of a weight of evidence approach.
  • ECVAM. (2007c). ESAC Statement, April 27, 2007: Statement on the Validity of In Vitro Tests for Skin Irritation.
  • ECVAM. (2008). ESAC Statement, November 5, 2008: Statement on the Scientific Validity of In Vitro Tests for Skin Irritation Testing.
  • ECVAM. (2009a). ESAC Statement, April 9, 2009: Statement on the Performance under UN GHS of Three In Vitro Tests for Skin Irritation Testing and the Adaptation of the Reference Chemicals and Defined Accuracy Values of the ECVAM Skin Irritation Performance Standards.
  • ECVAM. (2009b). ESAC Statement, June 12, 2009: Statement on the Scientific Validity of an In-Vitro Test Method for Skin Corrosivity Testing.
  • EEC. (1986). Council Directive 86/609/EEC of 24 November 1986 on the approximation of laws, regulations and administrative provisions of the Member States regarding the protection of animals used for experimental and other scientific purposes.
  • EPA. (2001). Pesticide Registration Notice 2001-2. Acute toxicity data requirements for granular pesticide products, including those with granular fertilizers in the product. Washington, DC: US EPA. Office of Prevention, Pesticides and Toxic Substances.
  • EPA. (2002). Health Effects Test Guidelines. OPPTS 870.1000: Acute Toxicity Testing—Background.
  • EPA. (2004). Status and future directions of the high production volume challenge program. Washington, DC: US EPA, Office of Pollution Prevention and Toxics.
  • Fentem J, Chamberlain M, Sangster B. (2004). The feasibility of replacing animal testing for assessing consumer safety: A suggested future direction. Altern Lab Anim 32: 617–623.
  • Gehen SC, Wiescinski CM, Woolhiser MR, Billington R. (2009). Acceptability of the mouse local lymph node assay for pesticide formulation hazard assessment. Toxicologist 108: pp 316–317.
  • Gerberick GF, Troutman JA, Foertsch LM, Vassallo JD, Quijano M, Dobson RL, Goebel C, Lepoittevin JP. (2009). Investigation of peptide reactivity of pro-hapten skin sensitizers using a peroxidase-peroxide oxidation system. Toxicol Sci 112: pp 164–174.
  • Gerde P. (2008). How do we compare dose to cells in vitro with dose to live animals and humans? Some experiences with inhaled substances. Exp Toxicol Pathol 60: 181–184.
  • Gettings SD, Lordo RA, Demetrulias J, Feder PI, Hintze KL. (1996). Comparison of low-volume, Draize and in vitro eye irritation test data. I. Hydroalcoholic formulations. Food Chem Toxicol 34: 737–749.
  • Gettings SD, Lordo RA, Feder PI, Hintze KL. (1998a). A comparison of low volume, draize and in vitro eye irritation test data. II. Oil/water emulsions. Food Chem Toxicol 36: 47–59.
  • Gettings SD, Lordo RA, Feder PI, Hintze KL. (1998b). A comparison of low volume, Draize and in vitro eye irritation test data. III. Surfactant-based formulations. Food Chem Toxicol 36: 209–231.
  • GHS. (2007). Globally Harmonized System of Classification and Labelling of Chemicals. Second revised edition. Geneva: United Nations.
  • Gildea LA, Ryan CA, Foertsch LM, Kennedy JM, Dearman RJ, Kimber I, Gerberick GF. (2006). Identification of gene expression changes induced by chemical allergens in dendritic cells: Opportunities for skin sensitization testing. J Invest Dermatol 126: 1813–1822.
  • Griffith JF, Nixon GA, Bruce RD, Reer PJ, Bannan EA. (1980). Dose-response studies with chemical irritants in the albino rabbit eye as a basis for selecting optimum testing conditions for predicting hazard to the human eye. Toxicol Appl Pharmacol 55: 501–513.
  • Hanway RH, Evans PF. (2000). Read across of toxicological data in the notification of new chemicals. Toxicol Lett 116: 61.
  • Hartung T, Rovida C. (2009). Chemical regulators have overreached. Nature 460: 1080–1081.
  • Hood E. (2008). Alternative test models: Ocular safety assays accepted. Environ Health Perspect 116: A381.
  • Hooyberghs J, Schoeters E, Lambrechts N, Nelissen, I, Witters H, Schoeters G, Van Den Heuvel R. (2008). A cell-based in vitro alternative to identify skin sensitizers by gene expression. Toxicol Appl Pharmacol 231: 103–111.
  • ICCVAM. (2001). Report of the International Workshop on In Vitro Methods for Assessing Acute Systemic Toxicity. Bethesda, MD: NIH.
  • ICCVAM. (2006a). ICCVAM Test Method Evaluation Report (TMER): In Vitro Cytotoxicity Test Methods for Estimating Starting Doses For Acute Oral Systemic Toxicity Testing. Research Triangle Park, NC: National Institute of Environmental Health Sciences.
  • ICCVAM. (2006b). ICCVAM Test Method Evaluation Report (TMER): In Vitro ocular toxicity test methods for identifying severe irritants and corrosives. Research Triangle Park, NC: National Institute of Environmental Health Sciences.
  • ICCVAM. (2009a). Independent Scientific Peer Review Panel Report: Evaluation of the Validation Status of Alternative Ocular Safety Testing Methods and Approaches. Research Triangle Park, NC: National Institute of Environmental Health Sciences.
  • ICCVAM. (2009b). Independent Scientific Peer Review Panel Report: Updated Validation Status of New Versions and Applications of the Murine Local Lymph Node Assay: A Test Method for Assessing the Allergic Contact Dermatitis Potential of Chemicals and Products. Research Triangle Park. NC: National Institute of Environmental Health Sciences, Research Triangle Park.
  • ICH. (2009). International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and marketing authorization for Pharmaceuticals M3(R2). Recommended for adoption at step 4 of the ICH process on June 11, 2009.
  • Indans I, Fry T, Parsons P, Evans P. (1998). Classification and labelling of new industrial chemicals for acute toxicity, skin and eye irritation. Hum Exp Toxicol 17: 529.
  • Kesimer M, Kirkham S, Pickles RJ, Henderson AG, Alexis NE, Demaria G, Knight D, Thornton DJ, Sheehan JK. (2008). Tracheobronchial air-liquid interface cell culture: A model for innate mucosal defense of the upper airways? Am J Physiol Lung Cell Mol Physiol 296: pp L92–L100.
  • Kimber I, Cumberbatch M, Betts CJ, Dearman RJ. (2004). Dendritic cells and skin sensitisation hazard assessment. Toxicol In Vitro 18: 195–202.
  • Kinsner-Ovaskainen A, Bulgheroni A, Hartung T, Prieto P. (2009). ECVAM’s ongoing activities in the area of acute oral toxicity. Toxicol In Vitro 23: pp 1535–1540.
  • Lambre CR, Auftherheide M, Bolton RE, Fubini B, Haagsman HP, Hext PM, Jorissen M, Landry Y, Morin JP, Nemery B, Nettesheim P, Pauluhn J, Richards RJ, Vickers AEM, Wu R. (1996). In vitro tests for respiratory toxicity. The report and recommendations of ECVAM workshop 18. Altern Lab Anim J 24: 671–681.
  • Langley G. (2005). European Coalition to End Animal Experiments: Acute Toxicity Testing Without Animals. London: ECEAE.
  • Lee MK, Yoo JW, Lin H, Kim YS, Kim DD, Choi YM, Park SK, Lee CH, Roh HJ. (2005). Air-liquid interface culture of serially passaged human nasal epithelial cell monolayer for in vitro drug transport studies. Drug Deliv 12: 305–311.
  • Lin H, Li H, Cho HJ, Bian S, Roh HJ, Lee MK, Kim JS, Chung SJ, Shim CK, Kim DD. (2007). Air-liquid interface (ALI) culture of human bronchial epithelial cell monolayers as an in vitro model for airway drug transport studies. J Pharm Sci 96: 341–350.
  • Macfarlane M, Jones P, Goebel C, Dufour E, Rowland J, Araki D, Costabel-Farkas M, Hewitt NJ, Hibatallah J, Kirst A, McNamee P, Schellauf F, Scheel J. (2009). A tiered approach to the use of alternative approaches for the safety assessment of cosmetics: Skin irritation. Regul Toxicol Pharmacol 54: pp 188–196.
  • Maxwell G, Aleksic M, Aptula A, Carmichael P, Fentem J, Gilmour N, Mackay C, Pease C, Pendlington R, Reynolds F, Scott D, Warner G, Westmoreland C. (2008). Assuring consumer safety without animal testing: A feasibility case study for skin sensitisation. Altern Lab Anim 36: 557–68.
  • McNamee P, Hibatallah J, Costabel-Farkas M, Goebel C, Araki D, Dufour E, Hewitt NJ, Jones P, Kirst A, Varlet BL, Macfarlane M, Marrec-Fairley M, Rowland J, Schellauf F, Scheel J. (2009). A tiered approach to the use of Alternatives to Animal Testing for the safety assessment of cosmetics: Eye irritation. Regul Toxicol Pharmacol 54: pp 197–209.
  • Mishima S. (1981). Clinical pharmacokinetics of the eye. Opthalmol Vis Sci 21: 504–541.
  • Mutschler J, Gimenez-Arnau E, Foertsch L, Gerberick GF, Lepoittevin JP. (2009). Mechanistic assessment of peptide reactivity assay to predict skin allergens with Kathon CG isothiazolinones. Toxicol In Vitro 23: 439–446.
  • Natsch A, Emter R. (2008). Skin sensitizers induce antioxidant response element dependent genes: Application to the in vitro testing of the sensitization potential of chemicals. Toxicol Sci 102: 110–119.
  • Natsch A, Emter R, Ellis G. (2009). Filling the concept with data: Integrating data from different in vitro and in silico assays on skin sensitizers to explore the battery approach for animal-free skin sensitization testing. Toxicol Sci 107: 106–121.
  • NIEHS. (1999). National Institutes of Environmental and Health Sciences. The murine LLNA: A test for assessing the allergic contact dermatitis potential of chemicals/compounds. Fed Register 64:14006–14007.
  • NRC. (2001). Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press.
  • OECD. (1981a). Test Guideline 401: Acute Oral Toxicity. OECD Guidelines for Testing of Chemicals.
  • OECD. (1981b). Test Guideline 403: Acute Inhalation Toxicity. OECD Guidelines for the Testing of Chemicals.
  • OECD. (1992). Test Guideline 406: Skin Sensitisation. OECD Guidelines for the Testing of Chemicals.
  • OECD. (2000). Guidance document on the recognition, assessment, and use of clinical signs as humane endpoints for experimental animals used in safety evaluation. Series on Testing and Assessment.
  • OECD. (2001). Guidance document on acute oral toxicity testing. Series on Testing and Assessment.
  • OECD. (2001b). Test Guideline 420: Acute Oral Toxicity—Fixed Dose Procedure. OECD Guidelines for the Testing of Chemicals.
  • OECD. (2001c). Test Guideline 423: Acute Oral Toxicity—Acute Toxic Class Method. OECD Guidelines for the Testing of Chemicals.
  • OECD. (2002a). Test Guideline 404: Acute Dermal Irritation/Corrosion. OECD Guidelines for Testing of Chemicals.
  • OECD. (2002b). Test Guideline 405: Acute Eye Irritation/Corrosion. OECD Guidelines for the Testing of Chemicals.
  • OECD. (2002c). Test Guideline 429: Skin Sensitisation: Local Lymph Node Assay. OECD.Guidelines for the Testing of Chemicals.
  • OECD. (2004a). Test Guideline 428: Skin Absorption: In Vitro Method. OECD Guidelines for the Testing of Chemicals.
  • OECD. (2004b). Test Guideline 430: In Vitro Skin Corrosion: Transcutaneous Electrical Resistance Test (TER). OECD.Guidelines for the Testing of Chemicals.
  • OECD. (2004c). Test Guideline 431: In Vitro Skin Corrosion: Human Skin Model Test. OECD Guidelines for the Testing of Chemicals.
  • OECD. (2006). Test guideline 435: In Vitro Membrane Barrier Test Method for Skin Corrosion. OECD.Guidelines for the Testing of Chemicals.
  • OECD. (2007). Guidance document on the validation of (quantitative) structure-activity relationship (QSAR) models. Series on Testing and Assessment.
  • OECD. (2008a). Guidance document on acute inhalation toxicity testing. Series on Testing and Assessment.
  • OECD. (2008b). Test Guideline 425: Acute Oral Toxicity: Up-and-Down Procedure. OECD Guidelines for the Testing of Chemicals.
  • OECD. (2009a). Guidance document on acute inhalation toxicity testing. Series on Testing and Assessment.
  • OECD. (2009b). Test guideline 403: Acute Inhalation Toxicity. OECD Guidelines for the Testing of Chemicals.
  • OECD. (2009c). Test Guideline 436: Acute Inhalation Toxicity—Acute Toxic Class (ATC) Method. OECD Guidelines for the Testing of Chemicals.
  • OECD. (2009d). Test Guideline 437: Bovine Corneal Opacity and Permeability (BCOP) Test Method for Identifying Ocular Corrosives and Severe Irritants. OECD Guidelines for the Testing of Chemicals.
  • OECD. (2009e). Test Guideline 438: Isolated Chicken Eye (ICE) Test Method for Identifying Ocular Corrosives and Severe Irritants. OECD Guidelines for the Testing of Chemicals.
  • Park SK, Lee WJ, Yang YI. (2007). Organ culture at the air-liquid interface maintains structural and functional integrities of inflammatory and fibrovascular cells of nasal polyps. Am J Rhinol 21: 402–407.
  • Pedersen F, de Bruijn J, Munn S, van Leeuwen K. (2003). Assessment of additional testing needs under REACH. Effects of (Q)SARs, risk based testing and voluntary industry initiatives. Brussels: European Commission, Joint Research centre. Report EUR 20863 EN.
  • Python F, Goebel C, Aeby P. (2009). Comparative DNA microarray analysis of human monocyte derived dendritic cells and MUTZ-3 cells exposed to the moderate skin sensitizer cinnamaldehyde. Toxicol Appl Pharmacol 239: 273–283.
  • Robinson S, Delongeas JL, Donald E, Dreher D, Festag M, Kervyn S, Lampo A, Nahas K, Nogues V, Ockert D, Quinn K, Old S, Pickersgill N, Somers K, Stark C, Stei P, Waterson L, Chapman K. (2008). A European pharmaceutical company initiative challenging the regulatory requirement for acute toxicity studies in pharmaceutical drug development. Regul Toxicol Pharmacol 50: 345–352.
  • Rovida C, Basketter D, Casati S, de Silva O, Hermans H, Kimber I, Manou I, Weltzien HU, Roggen E. (2007). Management of an integrated project (Sens-it-iv) to develop in vitro tests to assess sensitisation. Altern Lab Anim 35: 317–322.
  • Ryan CA, Kimber I, Basketter DA, Pallardy M, Gildea LA, Gerberick GF. (2007). Dendritic cells and skin sensitization: Biological roles and uses in hazard identification. Toxicol Appl Pharmacol 221: 384–394.
  • Schaafsma G, Kroese ED, Tielemans EL, Van de Sandt JJ, Van Leeuwen CJ. (2009). REACH, non-testing approaches and the urgent need for a change in mind set. Regul Toxicol Pharmacol 53: 70–80.
  • Scott L, Eskes C, Hoffmann S, Adriaens E, Alepee N, Bufo M, Clothier R, Facchini D, Faller C, Guest R, Harbell J, Hartung T, Kamp H, Varlet B. L, Meloni M, McNamee P, Osborne R, Pape W, Pfannenbecker U, Prinsen M, Seaman C, Spielmann H, Stokes W, Trouba K, Berghe CV, Goethem FV, Vassallo M, Vinardell P, Zuang V. (2009). A proposed eye irritation testing strategy to reduce and replace in vivo studies using Bottom-Up and Top-Down approaches. Toxicol In Vitro (In e-publishing: Ahead of print).
  • Seagrave J, Dunaway S, McDonald JD, Mauderly JL, Hayden P, Stidley C. (2007). Responses of differentiated primary human lung epithelial cells to exposure to diesel exhaust at an air-liquid interface. Exp Lung Res 33: 27–51.
  • Semple S. (2004). Dermal exposure to chemicals in the workplace: Just how important is skin absorption? Occup Environ Med 61: 376–82.
  • Stokes W, Casati S, Strickland J, Paris M. (2008). Neutral red uptake cytotoxicity tests for estimating starting doses for acute oral toxicity tests. Curr Protoc Toxicol 36: 20.4.1–20.4.20.
  • Thomas HD, Dewhurst IC. (2007). What does a dermal acute toxicity study add to the information on a plant protection pesticide? Toxicology 231: 114–115.
  • Ukelis U, Kramer PJ, Olejniczak K, Mueller SO. (2008). Replacement of in vivo acute oral toxicity studies by in vitro cytotoxicity methods: Opportunities, limits and regulatory status. Regul Toxicol Pharmacol 51: 108–118.
  • van den Heuvel MJ, Clark DG, Fielder RJ, Koundakjian PP, Oliver GJ, Pelling D, Tomlinson NJ, Walker, AP. (1990). The international validation of a fixed-dose procedure as an alternative to the classical LD50 test. Food Chem Toxicol 28: 469–482.
  • van der Jagt K, Munn S, Torslov J, de Bruijn J. (2004). Alternative approaches can reduce the use of test animals under REACH. Burssels: European Commission, Joint Research Centre. Report EUR 21405 EN.
  • Walum E. (1998). Acute oral toxicity. Environ Health Perspect 106(Suppl 2): 497–503.
  • WHO. (2005). The WHO Recommended Classification of Pesticides by Hazard and Guidelines to Classification: 2004. Geneva: WHO, International Programme on Chemical Safety.
  • York M, Griffiths HA, Whittle E, Basketter DA. (1996). Evaluation of a human patch test for the identification and classification of skin irritation potential. Contact Dermatitis 34: 204–212.
  • York M, Steiling W. (1998). A critical review of the assessment of eye irritation potential using the Draize rabbit eye test. J Appl Toxicol 18: 233–240.
  • Zbinden G, Flury-Roversi M. (1981). Significance of the LD50-test for the toxicological evaluation of chemical substances. Arch Toxicol 47: 77–99.

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