title: GHS additivity formula: A true replacement method for acute systemic toxicity testing of agrochemical formulations.
abstract: Acute systemic (oral, dermal, inhalation) toxicity testing of agrochemical formulations (end-use products) is mainly needed for Classification and Labelling (C&L) and definition of personal protection equipment (PPE). A retrospective analysis of 225 formulations with available in vivo data showed that: A) LD50/LC50values were above limit doses in <20.2% via oral route but only in <1% and <2.4% of cases via dermal and inhalation route, respectively; B) for each formulation the acute oral toxicity is always equal or greater than the Acute Toxicity Estimate (ATE) via the other two routes; C) the GHS (Global Harmonised System) computational method based on ATE, currently of limited acceptance, has very high accuracy and specificity for prediction of agrochemical mixture toxicity according to the internationally established classification thresholds. By integrating this evidence, an exposure- and data-based waiving strategy is proposed to determine classification and adequate PPE and to ensure only triggered animal testing is used. Safety characterisation above 2000 mg/kg body weight or 1.0 mg/L air should not be recommended, based on the agrochemical exposure scenarios. The global implementation of these tools would allow a remarkable reduction (up to 95%) in in vivo testing, often inducing lethality and/or severe toxicity, for agrochemical formulations.
authors.affiliation: Dow AgroSciences Ltd, European Development Centre, Milton Park, Abingdon, OX14 4RN, UK. Electronic address: mcorvaro@dow.com.
authors.forename: M
authors.initials: M
authors.lastname: Corvaro
authors.affiliation: Dow AgroSciences LLC, Headquarters, 9330 Zionsville Road, Indianapolis, IN 46268, USA.
authors.forename: S
authors.initials: S
authors.lastname: Gehen
authors.affiliation: Dow AgroSciences Ltd, European Development Centre, Milton Park, Abingdon, OX14 4RN, UK.
authors.forename: K
authors.initials: K
authors.lastname: Andrews
authors.affiliation: Dow AgroSciences Ltd, European Development Centre, Milton Park, Abingdon, OX14 4RN, UK.
authors.forename: R
authors.initials: R
authors.lastname: Chatfield
authors.affiliation: Dow AgroSciences Ltd, European Development Centre, Milton Park, Abingdon, OX14 4RN, UK.
authors.forename: C
authors.initials: C
authors.lastname: Arasti
authors.affiliation: Dow AgroSciences Ltd, European Development Centre, Milton Park, Abingdon, OX14 4RN, UK.
authors.forename: J
authors.initials: J
authors.lastname: Mehta
mesh_terms: D000279:Administration, Cutaneous; D000280:Administration, Inhalation; D000284:Administration, Oral; D016573:Agrochemicals / Q000737:chemistry / Q000145:classification / Q000633:toxicity*; D000465:Algorithms; D000826:Animal Testing Alternatives / Q000379:methods*; D000818:Animals; D045424:Complex Mixtures / Q000737:chemistry / Q000145:classification / Q000633:toxicity*; D062126:Databases, Chemical; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019570:Inhalation Exposure / Q000009:adverse effects; D007928:Lethal Dose 50; D008962:Models, Theoretical; D015203:Reproducibility of Results; D012189:Retrospective Studies; D018570:Risk Assessment; D013997:Time Factors; D023382:Toxicity Tests, Acute / Q000379:methods*
chemical_list: D016573:Agrochemicals; D045424:Complex Mixtures
keywords: 3Rs; Acute toxicity; GHS; Global policy change; Replacement; Theory of additivity