Annexes to COM(1976)433 -

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dossier COM(1976)433 - .
document COM(1976)433 EN
date September 18, 1979
ANNEX V

A. METHODS FOR THE DETERMINATION OF PHYSICO-CHEMICAL PROPERTIES : for the record

B. METHODS FOR THE DETERMINATION OF TOXICITY : for the record

C. METHODS FOR THE DETERMINATION OF ECOTOXICITY : for the record


ANNEX VI GENERAL CLASSIFICATION AND LABELLING REQUIREMENTS FOR DANGEROUS SUBSTANCES

Part I

A. Save where otherwise provided in the separate Directives on dangerous preparations, the substances and preparations shall be classified as very toxic, toxic or harmful according to the following criteria: (a) classification as very toxic, toxic or harmful shall be effected by determining the acute toxicity of the commercial substance or preparation in animals, expressed in LD50 or LC50 values with the following parameters being taken as reference values: >PIC FILE= "T0015279">

(b) if facts show that for the purposes of classification it is inadvisable to use the LD50 or LC50 values as a principal basis because the substances or preparations produce other effects, the substances or preparations shall be classified according to the magnitude of these effects.


Part II

B - Corrosion criteria : for the record

- Irritation criteria : for the record


C. If the facts show the existence of effects other than the acute effects indicated by experiments with animals, e.g. carcinogenic, mutagenic, allergenic, sub-acute or chronic effects, the substances or preparations shall be classified according to the magnitude of these effects.

D. Guide for the labelling of dangerous substances and criteria for the choice of phrases allocated to dangerous substances indicating the special risks (R phrases) and the safety advice (S phrases) : for the record.


ANNEX VII INFORMATION REQUIRED FOR THE TECHNICAL DOSSIER ("BASE SET") REFERRED TO IN ARTICLE 6 (1)

When giving notification the manufacturer or any other person placing a substance on the market shall provide the information set out below.

If it is not technically possible or if it does not appear necessary to give information, the reasons shall be stated.

Tests must be conducted according to methods recognized and recommended by the competent international bodies where such recommendations exist.

The bodies carrying out the tests shall comply with the principles of good current laboratory practice.

When complete studies and the results obtained are submitted, it shall be stated that the tests were conducted using the substance to be marketed. The composition of the sample shall be indicated.

In addition, the description of the methods used or the reference to standardized or internationally recognized methods shall also be mentioned in the technical dossier, together with the name of the body or bodies responsible for carrying out the studies. 1. IDENTITY OF THE SUBSTANCE 1.1 Name 1.1.1. Names in the IUPAC nomenclature

1.1.2. Other names (usual name, trade name, abbreviation)

1.1.3. CAS number (if available)


1.2. Empirical and structural formula

1.3 Composition of the substance 1.3.1. Degree of purity (%)

1.3.2. Nature of impurities, including isomers and by-products

1.3.3. Percentage of (significant) main impurities

1.3.4. If the substance contains a stabilizing agent or an inhibitor or other additives, specify : nature, order of magnitude : ... ppm ; ... %

1.3.5. Spectral data (UV, IR, NMR)


1.4. Methods of detection and determination

A full description of the methods used or the appropriate bibliographical references


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ANNEX VIII ADDITIONAL INFORMATION AND TESTS REQUIRED UNDER ARTICLE 6 (5)

Any person who has notified a substance to a competent authority in accordance with the requirements of Article 6 of this Directive shall provide at the request of the authority further information and carry out additional tests as provided for in this Annex.

If it is not technically possible or if it does not appear necessary to give information, the reasons shall be stated.

Tests shall be conducted according to methods recognized and recommended by the competent international bodies where such recommendations exist.

The bodies carrying out the tests shall comply with the principles of good current laboratory practice.

When complete studies and the results obtained are submitted, it shall be stated that the tests were conducted using the substance marketed. The composition of the sample shall be indicated.

In addition the description of the methods used or the reference to standardized or internationally recognized methods shall also be mentioned in the technical dossier, together with the name of the body or bodies responsible for carrying out the studies.

LEVEL 1

Taking into account: - current knowledge of the substance,

- known and planned uses,

- the results of the tests carried out in the context of the base set,


the competent authority may require the following additional studies where the quantity of a substance placed on the market by a notifier reaches a level of 10 tonnes per year or a total of 50 tonnes and if the conditions specified after each of the tests are fulfilled in the case of that substance.

Toxicological studies

- Fertility study (one species, one generation, male and female, most appropriate route of administration)

If there are equivocal findings in the first generation, study of a second generation is required.

It is also possible in this study to obtain evidence on teratogenicity.

If there are indications of teratogenicity, full evaluation of teratogenic potential may require a study in a second species.

- Teratology study (one species, most appropriate route of administration)

This study is required if teratogenicity has not been examined or evaluated in the preceding fertility study.

- Sub-chronic and/or chronic toxicity study, including special studies (one species, male and female, most appropriate route of administration)

If the results of the sub-acute study in Annex VII or other relevant information demonstrate the need for further investigation, this may take the form of a more detailed examination of certain effects, or more prolonged exposure, e.g. 90 days or longer (even up to two years).

The effects which would indicate the need for such a study could include for example: (a) serious or irreversible lesions;

(b) a very low or absence of a "no effect" level;

(c) a clear relationship in chemical structure between the substance being studied and other substances which have been proved dangerous.


- Additional mutagenesis studies (including screening for carcinogenesis) A. If results of the mutagenesis tests are negative, a test to verify mutagenesis and a test to verify carcinogenesis screening are obligatory.

If the results of the mutagenesis verification test are also negative, further mutagenesis tests are not necessary at this level ; if the results are positive, further mutagenesis tests are to be carried out (see B).

If the results of the carcinogenesis screening verification test are also negative, further carcinogenesis screening verification tests are not necessary at this level ; if the results are positive further carcinogenesis screening verification tests are to be carried out (see B).

B. If the results of the mutagenesis tests are positive (a single positive test means positive), at least two verification tests are necessary at this level. Both mutagenesis tests and carcinogenesis screening tests should be considered here. A positive result of a carcinogenesis screening test should lead to a carcinogenesis study at this level.


Ecotoxicology studies

- An algal test : one species, growth inhibition test.

- Prolonged toxicity study with Daphina magna (21 days, thus study should also include determination of the "no-effect level" for reproduction and the "no-effect level" for lethality).

The conditions under which this test is carried out shall be determined in accordance with the procedure described in Article 21 in the light of the methods laid down in Annex V (C) for acute toxicity tests with Daphnia.

- Test on a higher plant.

- Test on an earthworm.

- Prolonged toxicity study with fish (e.g. Oryzias, Jordanella, etc. ; at least a period of 14 days ; thus study should also include determination of the "threshold level").

The conditions under which this test is carried out shall be determined in accordance with the procedure described in Article 21 in the light of the methods adopted under Annex V (C) for acute toxicity tests with fish.

- Tests for species accumulation ; one species, preferably fish (e.g. Poecilla reticulata).

- Prolonged biodegradation study, if sufficient (bio)degradation has not been proved by the studies laid down in Annex VII, another test (dynamic) shall be chosen with lower concentrations and with a different inoculum (e.g. flow-through system).


In any case, the notifier shall inform the competent authority if the quantity of a substance placed on the market reaches a level of 100 tonnes per year or a total of 500 tonnes.

On receipt of such notification and if the requisite conditions are fulfilled, the competent authority, within a time limit it will determine, shall require the above tests to be carried out unless in any particular case an alternative scientific study would be preferable.


LEVEL 2

If the quantity of a substance placed on the market by a notifier reaches 1 000 tonnes per year or a total of 5 000 tonnes, the notifier shall inform the competent authority. The latter shall then draw up a programme of tests to be carried out by the notifier in order to enable the competent authority to evaluate the risks of the substance for man and the environment.

The test programme shall cover the following aspects unless there are strong reasons to the contrary, supported by evidence, that it should not be followed: - chronic toxicity study,

- carcinogenicity study,

- fertility study (e.g. three-generation study) ; only if an effect on fertility has been established at level 1,

- teratology study (non-rodent species) study to verify teratology study at level 1 and experiment additional to the level 1 study, if effects on embryos/foetuses have been established,

- acute and sub-acute toxicity study on second species : only if results of level 1 studies indicate a need for this. Also results of biotransformation studies and studies on pharmacokinetics may lead to such studies,

- additional toxicokinetic studies.


Ecotoxicology

- Additional tests for accumulation, degradation and mobility.

The purpose of this study should be to determine any accumulation in the food chain.

For further bioaccumulation studies special attention should be paid to the solubility of the substance in water and to its n-octanol/water partition coefficient.

The results of the level 1 accumulation study and the physiocochemical properties may lead to a large-scale flow-through test.

- Prolonged toxicity study with fish (including reproduction).

- Additional toxicity study (acute and sub-acute) with birds (e.g. quails) : if accumulation factor is greater than 100.

- Additional toxicity study with other organisms (if this proves necessary).

- Absorption - desorption study where the substance is not particularly degradable.


ANNEX IX

A. PROVISIONS RELATING TO CHILD-RESISTANT FASTENINGS : for the record

B. PROVISIONS RELATING TO TACTILE WARNINGS OF DANGER : for the record