Commission Regulation (EU) No 284/2013Show full title

SECTION 7 U.K. Toxicological studies

Introduction U.K.

1. For the evaluation of the toxicity of the plant protection product information shall be provided on acute toxicity, irritation and sensitisation of the active substance. The relevant calculation methods used for the classification of mixtures as laid down in Regulation (EC) No 1272/2008 shall, where appropriate, be applied in the hazard assessment of the plant protection product. Where available, information on mode of toxic action, toxicological profile and all other known toxicological aspects of the active substance and of substances of concern, shall be submitted. U.K.

2. Consideration shall be given to the possible effects of components on the toxic potential of the total mixture. U.K.

7.1. Acute toxicity U.K.

The studies, data and information to be provided and evaluated, shall be sufficient to permit the identification of effects following a single exposure to the plant protection product, to be assessed, and in particular to establish, or indicate:

(a)

the toxicity of the plant protection product;

(b)

toxicity of the plant protection product relative to the active substance;

(c)

the time course and characteristics of the effect with full details of behavioural changes and possible gross pathological findings at post-mortem;

(d)

where possible the mode of toxic action; and

(e)

the relative hazard associated with the different routes of exposure.

While the emphasis shall be on estimating the toxicity ranges involved, the information generated shall also permit the plant protection product to be classified in accordance with Regulation (EC) No 1272/2008, where applicable.

7.1.1. Oral toxicity U.K.

Circumstances in which required U.K.

A test for acute oral toxicity shall be carried out, unless the applicant can justify an alternative approach under Regulation (EC) No 1272/2008. In the latter case, acute oral toxicity of all components shall be provided or reliably predicted with a validated method. Consideration shall be given to the possible effects of components on the toxic potential of the total mixture.

7.1.2. Dermal toxicity U.K.

Circumstances in which required U.K.

A test for dermal toxicity shall be carried out on a case by case basis, unless the applicant can justify an alternative approach under Regulation (EC) No 1272/2008. In the latter case, acute dermal toxicity of all components shall be provided or reliably predicted with a validated method. Consideration shall be given to the possible effects of components on the toxic potential of the total mixture.

Findings of severe skin irritation or corrosion in the dermal study may be used instead of performing a specific irritation study.

7.1.3. Inhalation toxicity U.K.

The study shall provide the inhalation toxicity to rats of the plant protection product or of the smoke it generates.

Circumstances in which required U.K.

The study shall be carried out where the plant protection product:

(a)

is a gas or liquified gas;

(b)

is a smoke generating plant protection product or fumigant;

(c)

is used with fogging/misting equipment;

(d)

is a vapour releasing plant protection product;

(e)

is supplied in an aerosol dispenser;

(f)

is in a form of a powder or granules containing a significant proportion of particles of diameter < 50 μm (> 1 % on a weight basis);

(g)

is to be applied from aircraft in cases where inhalation exposure is relevant;

(h)

contains an active substance with a vapour pressure > 1 × 10^–2 Pa and is to be used in enclosed spaces such as warehouses or glasshouses;

(i)

is to be applied by spraying.

A study shall not be required if the applicant can justify an alternative approach under Regulation (EC) No 1272/2008, where applicable. For this purpose, acute inhalation toxicity of all components shall be provided or reliably predicted with a validated method. Consideration shall be given to the possible effects of components on the toxic potential of the total mixture.

The head/nose only exposure shall be used, unless whole body exposure can be justified.

7.1.4. Skin irritation U.K.

The results of the study shall provide the potential for skin irritancy of the plant protection product including the potential reversibility of the effects observed.

Before undertaking in vivo studies for corrosion/irritation of the plant protection product, a weight-of-evidence analysis shall be performed on the existing relevant data. Where insufficient data are available, they can be developed through application of sequential testing.

The testing strategy shall follow a tiered approach:

(1)

the assessment of dermal corrosivity using a validated in vitro test method;

(2)

the assessment of dermal irritation using a validated in vitro test method (such as human reconstituted skin models);

(3)

an initial in vivo dermal irritation study using one animal, and where no adverse effects are noted;

(4)

confirmatory testing using one or two additional animals.

Consideration shall be given to use the dermal toxicity study to provide irritancy information.

Findings of severe skin irritation or corrosion in the dermal study may be used instead of performing a specific irritation study.

Circumstances in which required U.K.

The skin irritancy of the plant protection product shall be reported based on the tiered approach, unless the applicant can justify an alternative approach under Regulation (EC) No 1272/2008. In the latter case, skin irritation properties of all components shall be provided or reliably predicted with a validated method. Consideration shall be given to the possible effects of components on the irritant potential of the total mixture.

7.1.5. Eye irritation U.K.

The results of the study shall provide the potential for eye irritation of the plant protection product, including the potential reversibility of the effects observed.

Before undertaking in vivo studies for eye corrosion/irritation of the plant protection product, a weight-of-evidence analysis shall be performed on the existing relevant data. Where available data are considered insufficient, further data may be developed through application of sequential testing.

The testing strategy shall follow a tiered approach:

(1)

the use of an in vitro dermal irritation/corrosion test to predict eye irritation/corrosion;

(2)

the performance of a validated or accepted in vitro eye irritation study to identify severe eye irritants/corrosives (such as BCOP, ICE, IRE, HET-CAM), and where negative results are obtained;

(3)

the assessment of eye irritation using an available, in vitro test method validated for plant protection products for identification of non-irritants or irritants, and when not available;

(4)

an initial in vivo eye irritation study using one animal, and where no adverse effects are noted;

(5)

confirmatory testing using one or two additional animals.

Circumstances in which required U.K.

Eye irritation tests shall be provided, unless it is likely that severe effects on the eyes may be produced or the applicant can justify an alternative approach under Regulation (EC) No 1272/2008. In the latter case, eye irritation properties of all components shall be provided or reliably predicted with a validated method. Consideration shall be given to the possible effects of components on the irritant potential of the total mixture.

7.1.6. Skin sensitisation U.K.

The study shall provide information to assess the potential of the plant protection product to provoke skin sensitisation reactions.

Circumstances in which required U.K.

The skin sensitisation test shall be carried out unless the active substances or co-formulants are known to have sensitising properties or the applicant can justify an alternative approach under Regulation (EC) No 1272/2008. In the latter case, skin sensitisation properties of all components shall be provided or reliably predicted with a validated method. Consideration shall be given to the possible effects of components on the sensitising potential of the total mixture.

The local lymph node assay (LLNA) shall be used, including where appropriate the reduced variant of the assay. In case the LLNA cannot be conducted, a justification shall be provided and the Guinea Pig Maximisation Test shall be performed. Where a guinea pig assay (Maximisation or Buehler), meeting OECD guidelines and providing a clear result, is available, further testing shall not be carried out for animal welfare reasons.

Since a skin sensitiser can potentially induce hypersensitivity reaction, potential respiratory sensitisation shall be taken into account when appropriate tests are available or when there are indications of respiratory sensitisation effects.

7.1.7. Supplementary studies on the plant protection product U.K.

The need to perform supplementary studies on the plant protection product shall be discussed with the national competent authorities on a case by case basis in the light of the particular parameters to be investigated and the objectives to be achieved (for example for plant protection products containing active substances or other components suspected to have synergistic or additive toxicological effects).

The type of the study shall be adapted to the endpoint of concern.

7.1.8. Supplementary studies for combinations of plant protection products U.K.

In cases where the product label includes requirements for use of the plant protection product with other plant protection products or with adjuvants as a tank mix, it may be necessary to carry out studies for a combination of plant protection products or for the plant protection product with adjuvant. The need to perform supplementary studies shall be discussed with the national competent authorities on a case by case basis, taking into account the results of the acute toxicity studies of the individual plant protection products and the toxicological properties of the active substances, the possibility for exposure to the combination of the products concerned, with particular regard to vulnerable groups, and available information or practical experience with the products concerned or similar products.

7.2. Data on exposure U.K.

For the purpose of this Regulation the following definitions apply:

(a)

operators are people who are involved in activities relating to the application of a plant protection product, such as mixing, loading, application, or relating to cleaning and maintenance of equipment containing a plant protection product; operators may be professionals or amateurs;

(b)

workers are people who, as part of their employment, enter an area that has previously been treated with a plant protection product or who handle a crop that has been treated with a plant protection product;

(c)

bystanders are people who casually are located within or directly adjacent to an area where application of a plant protection product is in process or has taken place, but not for the purpose of working on the treated area or with the treated commodity;

(d)

residents are people who live, work or attend any institution near to areas that are treated with plant protection products, but not for the purpose of working on the treated area or with the treated commodity.

In cases where the product label includes requirements for use of the plant protection product with other plant protection products or with adjuvants as a tank mix, the exposure assessment shall cover the combined exposure. Cumulative and synergistic effects shall be taken into account and reported in the dossier.

7.2.1. Operator exposure U.K.

Information shall be provided to permit an assessment of the extent of exposure to the active substances and toxicologically relevant compounds in the plant protection product likely to occur under the proposed conditions of use, taking into account cumulative and synergistic effects. It shall also provide a basis for the selection of the appropriate protective measures including personal protective equipment to be used by operators and to be specified on the label.

7.2.1.1. Estimation of operator exposure U.K.

An estimation shall be made, using where available a suitable calculation model, in order to permit an evaluation of the operator exposure likely to arise under the proposed conditions of use. Where relevant, this estimation shall take into account cumulative and synergistic effects resulting from the exposure to more than one active substance and toxicologically relevant compounds, including those in the product and tank mix.

Circumstances in which required U.K.

An estimation of operator exposure shall always be performed.

Estimation conditions U.K.

An estimation shall be made for each type of application method and application equipment proposed for use of the plant protection product taking account of the requirements resulting from Regulation (EC) No 1272/2008, where applicable, for handling the undiluted or diluted product.

The estimation shall address mixing/loading and application, and shall include clean-up activities and routine maintenance of the application equipment. Specific information on local use conditions (types and sizes of containers to be used, application equipment, typical work rates and application rates, spray concentration, field sizes, crop growing climatic conditions) shall be included.

At first an estimation shall be made with the assumption that the operator is not using any personal protective equipment.

Where appropriate, a further estimation shall be made with the assumption that the operator is using effective and readily obtainable protective equipment, which is feasible to be used in practice. Where protective measures are specified on the label, the estimation shall take these into account.

7.2.1.2. Measurement of operator exposure U.K.

The study shall provide data to permit an evaluation of the operator exposure likely to arise under the specific proposed conditions of use. The study shall be ethically sound.

Circumstances in which required U.K.

Exposure data for the relevant exposure routes shall be reported where there are no representative data in available calculation models or where the model-based risk assessment indicates that the relevant reference value is exceeded.

This will be the case, where the results of the estimation of operator exposure in accordance with point 7.2.1.1 indicate that one or both of the following conditions are fulfilled:

(a)

the AOEL established in the context of approval of the active substance may be exceeded;

(b)

the Limit Values established for the active substance and toxicologically relevant compounds of the plant protection product in accordance with Directive 98/24/EC and Directive 2004/37/EC may be exceeded.

The study shall be done under realistic exposure conditions taking into account the proposed conditions of use.

7.2.2. Bystander and resident exposure U.K.

Information shall be provided to permit an assessment of the extent of exposure to the active substances and toxicologically relevant compounds likely to occur under the proposed conditions of use, taking into account, where relevant, cumulative and synergistic effects. It shall also provide a basis for the selection of appropriate protective measures, including restricted entry intervals, exclusion of residents and bystanders from treatment areas and separation distances.

7.2.2.1 Estimation of bystander and resident exposure U.K.

An estimation shall be made, using where available a suitable calculation model in order to permit an evaluation of the bystander and resident exposure likely to arise under the proposed conditions of use. Where relevant, this estimation shall take into account cumulative and synergistic effects resulting from the exposure to more than one active substance and toxicologically relevant compounds, including those in the product and tank mix.

The applicant shall take into consideration that bystanders can be exposed during or after the application of plant protection products and residents may be exposed to plant protection products, mainly, but not only, by inhalation and dermal route and that infants and toddlers exposure may also occur by the oral route (through hand-mouth transfer).

Circumstances in which required U.K.

An estimation of bystander and resident exposure shall always be performed.

Estimation conditions U.K.

An estimation of bystander and resident exposure shall be made for each relevant type of application method. Specific information including maximum total dose and spray concentration shall be included. The estimation shall be made with the assumption that bystanders and residents do not use any personal protective equipment.

7.2.2.2. Measurement of bystander and resident exposure U.K.

The study shall provide data to permit an evaluation of the bystander and resident exposure likely to arise under the specific proposed conditions of use. The study shall be ethically sound.

Circumstances in which required U.K.

Exposure data for the relevant exposure routes shall be required where the model based risk assessment indicates that the relevant reference value is exceeded or where there are no representative data in available calculation models.

The study shall be done under realistic exposure conditions taking into account the proposed conditions of use.

7.2.3. Worker exposure U.K.

Information shall be provided to permit an assessment of the extent of exposure to the active substances and toxicologically relevant compounds in the plant protection product likely to occur under the proposed conditions of use and agricultural practices, taking into account cumulative and synergistic effects. It shall also provide a basis for the selection of appropriate protective measures, including waiting and re-entry periods.

7.2.3.1. Estimation of worker exposure U.K.

An estimation shall be made using, where available, a suitable calculation model, in order to permit an evaluation of the worker exposure likely to arise under the proposed conditions of use. Where relevant, this estimation shall take into account cumulative and synergistic effects resulting from the exposure to more than one active substance and toxicologically relevant compounds, including those in the product and tank mix.

Circumstances in which required U.K.

The estimation of worker exposure shall be completed when such exposure could arise under the proposed conditions of use.

Estimation conditions U.K.

An estimation of worker exposure shall be made for crops and tasks to be carried out. Specific information including description of post-applications activities, exposure duration, application rate, number of applications, minimum spray interval and growth stage, shall be provided. If data on the amount of dislodgeable residues under the proposed conditions of use are not available, default assumptions shall be used.

At first, the estimation shall be made using available data on the exposure to be expected with the assumption that the worker is not using any personal protective equipment. Where appropriate, a second estimation shall be made with the assumption that the worker is using effective and readily obtainable protective equipment which is feasible to be used and will be worn habitually by workers, for example because it was necessitated by other aspects of task being undertaken.

7.2.3.2. Measurement of worker exposure U.K.

The study shall provide data to permit an evaluation of the worker exposure likely to arise under the proposed conditions of use. The study shall be ethically sound.

Circumstances in which required U.K.

Exposure data for the relevant exposure routes shall be reported where the model based risk assessment indicates that the relevant reference value is exceeded or where there are no representative data in available calculation models.

This will be the case, where the results of the estimation of worker exposure in accordance with point 7.2.3.1 indicate that one or both of the following conditions are fulfilled:

(a)

the AOEL established in the context of approval of the active substance may be exceeded;

(b)

the Limit Values established for the active substance and toxicologically relevant compounds of the plant protection product in accordance with Directive 98/24/EC and Directive 2004/37/EC may be exceeded.

The study shall be done under realistic exposure conditions taking into account the proposed conditions of use.

7.3. Dermal absorption U.K.

The studies shall provide a measurement of the absorption through the skin of the active substances and toxicologically relevant compounds in the plant protection product to be authorised.

Circumstances in which required U.K.

The study shall be conducted when dermal exposure is a significant exposure route, and no acceptable risk is estimated using default absorption value.

Test conditions U.K.

Data from absorption studies, preferably using human skin in vitro, shall be reported.

Studies shall be performed on representative plant protection products at both in use dilution (when applicable) as well as the concentrated form.

In case studies do not correspond with the anticipated exposure situation (for example with regard to the type of co-formulant or the concentration), scientific argument shall be provided before such data can be used with confidence.

7.4. Available toxicological data relating to co-formulants U.K.

Where relevant, the applicant shall submit and assess the following information:

(a)

the registration number in accordance with Article 20(3) of Regulation (EC) No 1907/2006);

(b)

the study summaries included in the technical dossier submitted in accordance with Article 10(a)(vi) of Regulation (EC) No 1907/2006; and

(c)

the safety data sheet referred to in Article 31 of Regulation (EC) No 1907/2006.

The safety data sheet under point (c) shall also be submitted and assessed for the plant protection product.

Any other available information shall be submitted.