# Commission Regulation (EU) No 544/2011 of 10 June 2011 implementing Regulation (EC) No 1107/2009 of the European Parliament and of the Council as regards the data requirements for active substances (Text with EEA relevance) (repealed), Division: Test conditions

Extent: E+W+S+N.I.

A long-term oral toxicity and carcinogenicity study (2 years) of the active substance must be conducted using the rat as test species; these studies can be combined.
A carcinogenicity study of the active substance must be conducted using the mouse as test species.
Where a non-genotoxic mechanism for carcinogenicity is suggested, a well argued case, supported with relevant experimental data, including that necessary to elucidate the possible mechanism involved, must be provided.
While the standard reference points for treatment responses are concurrent control data, historical control data, may be helpful in the interpretation of particular carcinogenicity studies. Where submitted, historical control data shall be from the same species and strain, maintained under similar conditions and shall be from contemporaneous studies. The information on historical control data provided must include:
identification of species and strain, name of the supplier, and specific colony identification, if the supplier has more than one geographical location,
name of the laboratory and the dates when the study was performed,
description of the general conditions under which animals were maintained, including the type or brand of diet and, where possible, the amount consumed,
approximate age, in days, of the control animals at the beginning of the study and at the time of killing or death,
description of the control group mortality pattern observed during or at the end of the study, and other pertinent observations (e.g. diseases, infections),
name of the laboratory and the examining scientists responsible for gathering and interpreting the pathological data from the study, and
a statement of the nature of the tumours that may have been combined to produce any of the incidence data.
The doses tested, including the highest dose tested, must be selected on the basis of the results of short-term testing and where available at the time of planning the studies concerned, on the basis of metabolism and toxicokinetic data. The highest dose level in the carcinogenicity study shall elicit signs of minimal toxicity such as slight depression in body-weight gain (less than 10 %), without causing tissue necrosis or metabolic saturation and without substantially altering normal lifespan due to effects other than tumours. If the long-term toxicity study is carried out separately, the highest dose level shall elicit definite signs of toxicity without causing excessive lethality. Higher doses, causing excessive toxicity are not considered relevant to evaluations to be made.
In the collection of data and compilation of reports, incidence of benign and malignant tumours must not be combined, unless there is clear evidence of benign tumours becoming malignant with time. Similarly, dissimilar, un-associated tumours, whether benign or malignant, occurring in the same organ, must not be combined, for reporting purposes. In the interests of avoiding confusion, terminology such as that developed by the American Society of Toxicologic Pathologists, or the Hannover Tumour Registry (RENI) shall be used in the nomenclature and reporting of tumours. The system used must be identified.
It is essential that biological material selected for histopathological examination includes material selected to provide further information on lesions identified during gross pathological examination. Where relevant to the elucidation of mechanism of action and available, special histological (staining) techniques, histochemical techniques and electron microscopic examinations, must be conducted and reported.

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Source: https://www.legislation.gov.uk/eur/2011/544/annex/part/A/division/5/division/5.5/division/3 (the official version)
Page: https://openlegislation.uk/eu-regulation-2011-544/annex/part-A/division-5/division-5.5/division-3
Contains public sector information licensed under the Open Government Licence v3.0. Source: legislation.gov.uk, The National Archives.