In August 2016, the OECD issued new Testing and Assessment Guidance No. 237, which focuses on waiving or bridging (read-across) of in vivo mammalian acute toxicity testing via skin, eye, oral and inhalation routes. The updated guidance essentially recommends processes to replace the US EPA “six pack” testing with potential waivers based on existing in vitro and physicochemical data, read-across and weight-of-evidence approaches with the stated intent of “reducing or eliminating animal testing.”
Broadly, waivers for additional testing are a consideration when human exposure via oral, dermal or inhalation routes is unlikely, or when a substance is already known to have an acute toxic response such as corrosivity. In other words, in vivo testing should not be performed and a waiver issued when validated in vitro tests or physicochemical-based approaches such as QSAR modelling and read-across methods are considered adequate to draw a conclusion regarding acute hazard classification.
Each endpoint has its own specific waiver requirements. Testing waivers may be available under the following guidelines:
- Acute Oral Toxicity
- If the chemical is GHS Category 1 for skin corrosion, or if the pH of the test article is ≤2 or ≥11.5 (toxicity is assumed based on the corrosive nature of the chemical) OR
- If the oral LD50 is predicted to be over 2000 mg/kg (indicating limited oral toxicity) OR
- If the end-product is composed of non-friable material and is too large to be ingested or where the product design prevents oral exposure.
- Acute Dermal Toxicity
- If a chemical is classified as GHS Category 1 for skin corrosion or if the pH of the chemical is ≤2 or ≥11.5 OR
- If a chemical shows no acute oral toxicity up to 2000 mg/kg OR
- If the oral LD50 falls below 300 mg/kg (the dermal toxicity would be classified within the same GHS category as the oral hazard) OR
- The oral LD50 falls between 300-2000 mg/kg and dermal penetration is low (<10%) compared to oral absorption.
- Acute Inhalation Toxicity
- A test article exhibits low volatility, is not aerosolised, or otherwise made inhalable through heating, evaporation or other method OR
- If test articles are solids that are too large to be inhaled, do not easily crumble into inhalable particles or are aerosols with a certain particle size OR
- If a test article cannot be produced in an inhalable state (e.g., gas or vapor) to elicit toxic response under ideal conditions OR
- Test articles which are classified as GHS Category 1 or 2 for acute oral or dermal toxicity (test article would be classified as GHS Category 1 inhalation hazard in this instance).
- Skin Corrosion and Irritation
- If validated and/or accepted in vitro tests are considered adequate for the classification and labelling of skin irritation or corrosion OR
- If chemicals are classified as either GHS Category 1 or 2 acute dermal hazard OR
- pH-metric (≤2 or ≥11.5) properties and high buffering capacity are sufficient to determine a substance as GHS Category 1 OR
- If the test chemical is spontaneously flammable in air or water.
- Serious Eye Damage and Irritation
- If validated and/or accepted in vitro tests are considered adequate for the classification and labelling of serious eye damage or eye irritation OR
- If a compound has already been classified as corrosive to skin (GHS Category 1) OR
- pH-metric (<2 or >11.5) properties and high buffering capacity are sufficient to determine a substance as GHS Category 1 OR
- The test article has been found to be spontaneously flammable in air at room temperature OR
- If the chemical is already classified as a Category 1 or 2 acute dermal hazard (chemicals would be classified as GHS Category 1 for serious eye damage in this instance).
- If the test article is a granular solid composed of particles too large to be retained in the eye.
- Dermal Sensitisation
- If in vitro or in chemico tests covering the necessary key mechanistic events of the skin sensitization AOP are adequate to classify a test substance. If potency data is required, addition in vitro testing may be needed.
- If test article is corrosive to skin at the most dilute concentration on the product label or if the test chemical has a pH <2 or >11.5 together with a high buffering capacity.
- If the test chemical is spontaneously flammable in air at room temperature.
Cyprotex have a panel of validated and accepted in vitro methods which can be used to waiver mammalian acute toxicity tests and the EPA Six Pack testing strategy.
Contact us to find out more