Use of the GHS Mixtures Equation to predict acute toxicity

Background

The Globally Harmonized System of Classification and Labelling of Chemicals (GHS)1 was developed through a United Nations-led initiative beginning at the 1992 Rio Earth Summit and formally adopted in 2003. The GHS establishes harmonised criteria for identifying physical, health, and environmental hazards and standardises hazard communication elements such as labels, pictograms, and safety data sheets, making it the primary global framework for communicating chemical hazards to workers, regulators, and downstream users. The GHS itself is not a legally binding regulation; rather, it is a non-binding framework that countries implement through their own national or regional legislation by adopting selected “building blocks” based on regulatory needs (as one example, an agency may adopt a five-category hazard classification system for acute systemic toxicity).

As a result, while implementation may vary across jurisdictions, the core hazard communication elements remain broadly consistent. Examples of regulatory agencies that have integrated the GHS into their hazard communication requirements for industrial chemicals include the United States Occupational Safety and Health Administration (OSHA) Hazard Communication Standard (HCS)2, the European Union’s Classification, Labelling and Packaging (CLP) Regulation3, and Canada’s Workplace Hazardous Materials Information System (WHMIS) implemented through the Hazardous Products Regulations (HPR)4.

GHS has been implemented or is in the process of implementation in dozens of countries. Therefore, it provides a foundation for regulatory agencies worldwide to use the same tools to predict a chemical’s GHS hazard classification; for example, use of the mixtures equation for estimating acute toxicity. In support, the Organisation for Economic Co-operation and Development (OECD) has guidance that allows for the use of recognised calculation approaches.2

GHS Mixtures Equation

The GHS mixtures equation (also known as the additivity formula or calculation method) is a computational approach used to predict acute toxicity classifications for mixtures based on the concentration and acute toxicity estimate (ATE) of relevant individual components.

The ATE of the mixture is determined from the ATE values for all relevant ingredients using the following equation:


where: Ci = concentration of ingredient i
with: n ingredients, and i inclusive of integer numbers from 1 to n
ATEmix  = Acute Toxicity Estimate of mixture
ATEi  = Acute Toxicity Estimate of ingredient i

To calculate ATEmix the following inclusions and exclusions are applied:
(a) include ingredients with a known acute toxicity estimate that falls into any of the UN GHS acute toxicity hazard categories
(b) exclude ingredients that are presumed not acutely toxic (e.g., water or sugar)
(c) exclude ingredients if the data available are from a limit dose test (at the upper threshold for Category 4 for the appropriate route of exposure) and do not show acute toxicity

The GHS also provides guidance on how the equation may be applied if data are not available for one or more ingredients of the mixture.1

Expanding use of the GHS Mixtures Equation to pesticides

In addition to its use for industrial chemicals, use of the GHS mixtures equation has been expanded to inform acute toxicity hazard characterisation of pesticide formulations across multiple regulatory frameworks.

  • European Union: EU plant protection product (PPP) data requirements specify that the relevant calculation methods for classifying mixtures under CLP, “shall, where appropriate, be applied in the hazard assessment of the plant protection product.” Therefore, this approach should be applied when conducting PPP hazard assessments as Member States consider the mixtures equation in scientific risk assessment and the European Commission uses it in its regulatory decisions.5
  • United Kingdom: The Health and Safety Executive (HSE) states that the GB/NI CLP calculation method for mixtures may be used to fulfil the PPP toxicology data requirement for acute toxicity (including skin/eye irritation and skin sensitisation), and that it should be considered before any vertebrate animal testing. It should be noted that HSE will not accept vertebrate animal testing for formulations commissioned after June 2011 when the calculation method (or other valid alternatives) could reliably have been used.6
  • United States: The US Environmental Protection Agency (EPA) evaluated the acceptability of the GHS mixtures equation as an approach for estimating the acute oral toxicity of pesticide formulations via a pilot program and publication.7 Additional guidance is expected to be published in 2026.

For questions about using the GHS mixtures equation, please contact [email protected].