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Replacing Animals for Acute Systemic Toxicity Testing

ICCVAM, with support from NICEATM, is developing a U.S. strategy and roadmap for implementing alternative approaches for required acute systemic toxicity testing. Development and implementation of these approaches will involve four key steps: (1) defining testing needs, (2) identifying available alternatives, (3) developing integrated approaches to testing and assessment, and (4) addressing both scientific and non-scientific challenges.

The ICCVAM Acute Toxicity Workgroup is coordinating activities relevant to these goals. Initial efforts focused on identifying existing alternatives and activities needed to advance their development and utilization. The working group will then use this information to develop an implementation plan for addressing the roadmap goals in the area of acute systemic toxicity testing. Current activities supporting this effort include:

  • Assessing the usefulness of additivity formulas (as used by the GHS) for classifying formulations and mixtures for acute systemic toxicity
  • Evaluating in vitro and in silico approaches for predicting acute systemic toxicity, including approaches using high throughput screening data and quantitative structure-activity relationship models
  • Developing a scoping document that outlines the current requirements and testing needs for U.S. and international government agencies
    Strickland J, Clippinger AJ, Brown J, Allen D, Jacobs A, Matheson J, Lowit A, Reinke EN, Johnson MS, Quinn MJ. 2018. Status of acute toxicity testing requirements and data uses by U.S. regulatory agencies [published online ahead of print 3 February 2018]. Reg Toxicol Pharmacol

Other past and ongoing NICEATM and ICCVAM activities relevant to this effort are described on this page and elsewhere in this website.

NICEATM Evaluation of Use of Acute Oral Hazard Classification to Predict EPA Acute Dermal Hazard Classification

Acute oral and dermal systemic toxicity test data are used to determine hazard label requirements needed to protect pesticide users, workers, and handlers, and to establish the type of personal protective equipment required for occupational pesticide users.

NICEATM conducted a retrospective data analysis that was used to support EPA guidance on waiving acute dermal toxicity tests for pesticide formulations. This guidance is expected to substantially reduce laboratory animal use for acute toxicity testing.

The NICEATM analysis used acute oral toxicity data for pesticide active ingredients and similar information for pesticide formulations provided by EPA. NICEATM reviewed the data to ensure that only high quality data were used to evaluate the usefulness and limitations of the acute oral hazard classifications in estimating dermal hazard classifications. The analysis was summarized in a poster (Paris et al.) presented at the 2016 SOT annual meeting. A manuscript currently in preparation will provide a more detailed description of the analysis.

Workshops on Alternatives for Acute Toxicity Testing

Two recent NICEATM workshops assessed the state of the science of replacements for animal use for acute systemic toxicity testing.

  • Attendees at a 2015 workshop on Alternative Approaches for Identifying Acute Systemic Toxicity: Moving from Research to Regulatory Testing developed strategies to advance alternative methods for product safety testing that meet the needs of regulatory agencies (workshop organized by NICEATM, PISC, and PCRM.
    Workshop report: Hamm et al. 2017. Alternative approaches for identifying acute systemic toxicity: moving from research to regulatory testing. Toxicol In Vitro 41:245-259.
  • A 2016 workshop and webinar series focused on needs to replace animals for acute inhalation toxicity testing (workshop and webinars organized by NICEATM and PISC).
    Summary of webinar series and workshop: Clippinger AJ et al. 2018. Alternative approaches for acute inhalation toxicity testing to address global regulatory and non-regulatory data requirements: An international workshop report. Toxicology In Vitro 48:53-70
Use of High-Throughput Screening Data to Reduce Animal Use for Acute Oral Toxicity Testing

NICEATM evaluated the use of HTS data from the interagency Tox21 and the EPA ToxCast programs to reduce animal use for acute oral toxicity testing. The HTS data were analyzed for correlation and model fit to rat oral LD50 data to determine which tests or combinations of tests best characterized the rat oral toxicity data. The analysis suggested that, for some substances, combinations of in vitro assays and data from small model organisms such as zebrafish offer promise for predicting outcomes of rat acute oral toxicity tests. This project was described in a poster presentation (Polk et al.) at the 2015 SOT annual meeting .

Request for Data and Information on Technologies Used to Identify Substances With the Potential To Cause Acute Systemic Toxicity

NICEATM requests available data and information on approaches and/or technologies currently used to identify substances with the potential to cause acute systemic toxicity when swallowed, inhaled, or absorbed through the skin.  Submitted information will be used to assess the state of the science and determine technical needs for non-animal test methods used to evaluate the potential of chemicals to induce acute systemic toxicity.

Guidelines for Submission of Acute Toxicity Data

Acute systemic toxicity tests are conducted to determine the potential for a single or short-term dose of a substance to cause illness or death when inhaled (inhalation toxicity testing), swallowed (oral toxicity testing), or absorbed through the skin (dermal toxicity testing). These tests are required by multiple regulatory agencies and can use large numbers of animals. NICEATM, which fosters the evaluation and promotion of alternative test methods for regulatory use, supports efforts to develop, validate, and implement alternative approaches for acute systemic toxicity testing that replace, reduce, or refine animal use.

Respondents should provide information on any activities relevant to the development or validation of alternatives to in vivo tests currently required by regulatory agencies that assess acute oral, dermal, or inhalation toxicity. Of specific interest are chemical-specific data from non-animal tests for acute systemic toxicity hazard, as well as available data on the same chemicals from in vivo acute systemic toxicity tests, such as ethical human or animal studies or accidental human exposures. Respondents should include their name, affiliation (if applicable), mailing address, telephone, email, and sponsoring organization (if any) with their communications.

Responses to this notice will be posted on this page; therefore, no proprietary, classified, confidential, or sensitive information should be included in responses. View NTP guidelines for public comments.

Federal Register notice announcing data request (July 18, 2016) — View as a webpage

Responses to Federal Register Notice