ANNEX 3 U.K.
CRITERIA FOR CLASSIFICATION OF TEST SUBSTANCES WITH EXPECTED LD50 VALUES EXCEEDING 2000 MG/KG WITHOUT THE NEED FOR TESTING. U.K.
Criteria for hazard Category 5 are intended to enable the identification of test substances which are of relatively low acute toxicity hazard but which, under certain circumstances may present a danger to vulnerable populations. These substances are anticipated to have an oral or dermal LD50 in the range of 2000-5000 mg/kg or equivalent doses for other routes. Test substances could be classified in the hazard category defined by: 2000mg/kg <LD50 < 5000mg/kg (Category 5 in the GHS) in the following cases:
if directed to this category by any of the testing schemes of Annex 2, based on mortality incidences
if reliable evidence is already available that indicates the LD50 to be in the range of Category 5 values; or other animal studies or toxic effects in humans indicate a concern for human health of an acute nature.
through extrapolation, estimation or measurement of data if assignment to a more hazardous class is not warranted, and
reliable information is available indicating significant toxic effects in humans, or
any mortality is observed when tested up to Category 4 values by the oral route, or
where expert judgement confirms significant clinical signs of toxicity, when tested up to Category 4 values, except for diarrhoea, piloerection or an ungroomed appearance, or
where expert judgement confirms reliable information indicating the potential for significant acute effects from the other animal studies.
TESTING AT DOSES ABOVE 2000 MG/KG U.K.
Exceptionally, and only when justified by specific regulatory needs, the use of an additional upper fixed dose level of 5000 mg/kg may be considered. Recognising the need to protect animal welfare, testing at 5000 mg/kg is discouraged and should only be considered when there is a strong likelihood that the results of such a test would have a direct relevance for protecting animal or human health (9).
Sighting Study U.K.
The decision rules governing the sequential procedure presented in Annex 1 are extended to include a 5000 mg/kg dose level. Thus, when a sighting study starting dose of 5000 mg/kg is used outcome A (death) will require a second animal to be tested at 2000 mg/kg; outcomes B and C (evident toxicity or no toxicity) will allow the selection of 5000 mg/kg as the main study starting dose. Similarly, if a starting dose other than 5000 mg/kg is used then testing will progress to 5000 mg/kg in the event of outcomes B or C at 2000 mg/kg; a subsequent 5000 mg/kg outcome A will dictate a main study starting dose of 2000 mg/kg and outcomes B and C will dictate a main study starting dose of 5000 mg/kg.
Main Study U.K.
The decision rules governing the sequential procedure presented in Annex 2 are extended to include a 5000 mg/kg dose level. Thus, when a main study starting dose of 5000 mg/kg is used, outcome A (≥2 deaths) will require the testing of a second group at 2000 mg/kg; outcome B (evident toxicity and/or ≤1 death) or C (no toxicity) will result in the substance being unclassified according to GHS. Similarly, if a starting dose other than 5000 mg/kg is used then testing will progress to 5000 mg/kg in the event of outcome C at 2000 mg/kg; a subsequent 5000 mg/kg outcome A will result in the substance being assigned to GHS Category 5 and outcomes B or C will lead to the substance being unclassified.