Examining the Regulatory Value of Multi-route Mammalian Acute Systemic Toxicity Studies

Troy Seidle, Humane Society International
Pilar Prieto, European Centre for the Validation of Alternative Methods
Anna Bulgheroni, European Centre for the Validation of Alternative Methods

The authors acknowledge members of the European Partnership for Alternative Approaches to Animal Testing (EPAA) Acute Toxicity Task Force for their advice. This work was supported by the authors’ affiliated institutions, together with a grant for the lead author from the Doerenkamp-Zbinden Foundation, Switzerland. In addition, we would like to thank Joaquin Baraibar Fentanes from the System Toxicology Unit (IHCP, JRC, Ispra), who helped with data retrieval from the NCD


Regulatory information requirements for pesticides call for submission of acute systemic toxicity data for up to three different exposure routes (oral, dermal, inhalation) for both active ingredients and formulated products. Similar multi-route testing is required in the European Union and elsewhere for industrial chemicals. To determine the value of acute toxicity testing by more than one route, oral-dermal and oralinhalation concordances among regulatory classifications were examined for large data sets of chemicals and pesticide active ingredients. Across all sectors examined, oral acute toxicity classifications for pure active substances were more severe than those derived from dermal data in more than 98% of cases, which calls into question the value of routine dermal route testing for acute toxicity. Oral classifications were equivalent to or more severe than for the inhalation route for 83% of industrial chemicals and for 48% of pesticides examined.