Alternative acute oral toxicity assessment under REACH based on sub-acute toxicity values.

Andrea Gissi

doi:10.14573/altex.1609121

Abstract

The REACH Regulation requires information on acute oral toxicity for substances produced or imported in quantities greater than one ton per year. When registering, animal testing should be used as last resort. The standard acute oral toxicity test requires use of animals. Therefore, the European Chemicals Agency examined whether alternative ways exist to generate information on acute oral toxicity. The starting hypothesis was that low acute oral toxicity can be predicted from the results of low toxicity in oral sub-acute toxicity studies. Proving this hypothesis would allow avoiding acute toxicity oral testing whenever a sub-acute oral toxicity study is required or available and indicates low toxicity. ECHA conducted an analysis of the REACH database and found suitable studies on both acute oral and sub-acute oral toxicities for 1,256 substances. 415 of these substances had low toxicity in the sub-acute toxicity study (i.e., NO(A)EL at or above the limit test threshold of 1,000 mg/kg). For 98% of these substances, low acute oral toxicity was also reported (i.e., LD50 above the classification threshold of 2,000 mg/kg). On the other hand, no correlation was found between lower NO(A)ELs and LD50. According to the REACH Regulation, this approach for predicting acute oral toxicity needs to be considered as part of a weight of evidence analysis. Therefore, additional sources of information to support this approach are presented. Ahead of the last REACH registration deadline, in 2018, ECHA estimates that registrants of about 550 substances can omit the in vivo acute oral toxicity study by using this adaptation.

Highlights

1.1 Acute and sub-acute toxicity under REACH Information on acute oral toxicity is required under the REACH Regulation (EU, 2006) for substances that are manufactured or imported in quantities above 1 ton per year
Step 1: 25,055 studies were retained for acute toxicity and 8,950 for sub-acute toxicity; Step 2: 18,804 studies were retained for acute toxicity and 3,308 for sub-acute toxicity; Step 3: multiple studies were aggregated resulting in 4,418 different substances with acute toxicity studies reported and 1,759 substances with sub-acute studies; Step 4: 1,336 substances with both acute and sub-acute studies were selected; Step 5: 1,261 substances were selected for the analysis
Information on acute oral toxicity is required under the REACH Regulation for substances registered at tonnages greater than 1 ton per year (EU, 2006)

Summary

Introduction

1.1 Acute and sub-acute toxicity under REACH Information on acute oral toxicity is required under the REACH Regulation (EU, 2006) for substances that are manufactured or imported in quantities above 1 ton per year. This information is obtained from an animal study performed according to an OECD Test Guideline (TG) or a corresponding EU test method. The currently used OECD TGs are: OECD TG 420 (Fixed Dose Procedure), OECD TG 423 (Acute Toxic Class Method), OECD TG 425 (Up-and-down procedure) These test guidelines use fewer animals than the old OECD TG 401, are likely to induce less suffering of the test animals, and provide more information on possible target organs and possible mechanisms of toxicity. TG 423 requires that animals be humanely killed when showing signs of evident toxicity, i.e., “animals obviously in pain or showing signs of severe and enduring distress”

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Conclusion