Council Directive of 15 July 1991 concerning the placing of plant protection products on the market (91/414/EEC) (repealed)

[F1 5.5. Long term toxicity and carcinogenicity U.K.

Aim of the test U.K.

The long-term studies conducted and reported, taken together with other relevant data and information on the active substance, must be sufficient to permit the identification of effects, following repeated exposure to the active substance, and in particular must be sufficient to:

• identify adverse effects resulting from exposure to the active substance,

• identify target organs, where relevant,

• establish the dose-response relationship,

• identify changes in toxic signs and manifestations observed, and

• establish the Noael.

Similarly, the carcinogenicity studies taken together with other relevant data and information on the active substance, must be sufficient to permit the hazards for humans, following repeated exposure to the active substance, to be assessed, and in particular must be sufficient:

• to identify carcinogenic effects resulting from exposure to the active substance,

• to establish the species and organ specificity of tumours induced,

• to establish the dose-response relationship, and

• for non-genotoxic carcinogens, to identify the maximum dose eliciting no adverse effect (threshold dose).

Circumstances in which required U.K.

The long-term toxicity and carcinogenicity of all active substances must be determined. If in exceptional circumstances, it is claimed that such testing is unnecessary, that claim must be fully justified, viz. toxicokinetic data demonstrates that absorption of the active substance does not occur from the gut, through the skin or via the pulmonary system.

Test conditions U.K.

A long-term oral toxicity and carcinogenicity study (two 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 should be from the same species and strain, maintained under similar conditions and should 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 should 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 should 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 American Society of Toxicologic Pathologists (2) , or the Hannover Tumour Registry (RENI) should 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.

Test guideline U.K.

The studies must be carried out in accordance with Directive 87/302/EEC, part B, Chronic toxicity test, Carcinogenicity test or combined chronic toxicity/carcinogenicity test.]

Textual Amendments

F1 Substituted by Commission Directive 94/79/EC of 21 December 1994 amending Council Directive 91/414/EEC concerning the placing of plant protection products on the market.

(1)

Substance within the meaning of the definition of Article 2, point 3.

(2)

[F1 Standardized System of Nomenclature and Diagnostic Criteria — Guides for Toxicologic Pathology]

Textual Amendments

F1 Substituted by Commission Directive 94/79/EC of 21 December 1994 amending Council Directive 91/414/EEC concerning the placing of plant protection products on the market.