Article 12.1 of the Regulation on the declaration of new substances and the classification, packaging and labelling of dangerous substances, adopted by Royal Decree 2216/1985 of 23 October, based on the Council Directives on European Communities 67 /548/EEC, and subsequent amending, provides that the tests and analyses of the substances required for the notification provided for in Article 5 shall be carried out in accredited laboratories, following the good laboratory practices.

For its part, Council Directive 87 /18/EEC states in Article 1.1 that the Member States shall take the necessary measures to ensure that laboratories carrying out tests on chemical products, in accordance with Directive 67 /548/EEC referred to above, complies with the principles of good laboratory practice as specified in Annex 2 to the Decision of the OECD Council of 12 May 1981 on the mutual acceptance of data for the assessment of the chemicals. Taking into account that these tests are aimed at assessing the potential risks of chemical products for man and for the environment, this Royal Decree is issued in accordance with Article 149.1.16. and 23. of the Spanish Constitution.

As a consequence of the provisions of Directive 87 /18/EEC, and without prejudice to the fact that the principles of good laboratory practice as referred to may be more general in application, it is necessary to provide for effective and normatively implement the guarantee of compliance.

Moreover, in the same field, and in respect of industrial products specifically, the Law of Industry 21/1992 of 16 July, Article 9 of which includes the objectives of security, is applicable. industrial prevention and protection of damage to people and the environment.

In its virtue, on the proposal of the Ministers of Industry, Commerce and Tourism, of Agriculture, Fisheries and Food and of Health and Consumption, in agreement with the Council of State and after deliberation of the Council of Ministers in its meeting on 28 May 1993,

D I S P O N G O:

Article 1.

Laboratories carrying out tests on chemical products, in accordance with Directive 67 /548/EEC, shall observe in the conduct of non-clinical studies on chemicals and substances in order to determine their effects on man, animals and the environment, the principles of good laboratory practice set out in the Annex.

Article 2.

At the delivery of the test results referred to in Article 1, the laboratories shall report, by means of the test reports, that these tests have been carried out in accordance with the principles of good practice. Laboratory referred to in the Annex.

Article 3.

Non-clinical studies that are carried out as a requirement for a marketing authorisation for chemicals and substances shall be carried out in accordance with the provisions of Article 1.

Article 4.

The competent Public Administration may, by reason of the matter, authorise the laboratories which have previously obtained the corresponding technical accreditation for the performance of each type of test. This Administration shall be responsible for the conduct of the tests by observing the principles of good laboratory practice and shall have the necessary inspection and verification to ensure compliance with the principles of good laboratory practice. obligations set out in this Royal Decree.

Article 5.

1. In the field of the General Administration of the State, in order to monitor compliance with the principles of good laboratory practice, the Ministries of Industry, Commerce and Tourism, Agriculture, Fisheries and Food, and Health and Consumer Affairs, within the scope of their respective competences.

2. In the field of their powers, the Autonomous Communities shall communicate to the Ministries referred to in paragraph 1 the authorities responsible for monitoring the application of the principles of good laboratory practice for the purposes of their communication to the Commission of the European Communities.

3. In the field of their powers, the Autonomous Communities shall communicate to the Ministries concerned the authorizations which they have granted to accredited testing laboratories, as well as the effects on the application of the principles of good practice. laboratory practices affect the results of the tests.

Single additional disposition.

This Royal Decree is dictated by the provisions of Article 149.1.16. and 23. of the Spanish Constitution.

Single end disposition.

In the field of its competences, the Ministers of Industry, Commerce and Tourism are authorized; Agriculture, Fisheries and Food, and Health and Consumer Affairs to dictate the necessary provisions for implementation and development. of the provisions of this Royal Decree.

Given in Madrid to May 28, 1993.

JOHN CARLOS R.

The Minister of Relations with the Courts and the Government Secretariat,

VIRGILIO ZAPATERO GOMEZ

ANNEX

Principles of good laboratory practice

Section 1. Introduction

A. Objective.

The principles of "good laboratory practice" will apply to the studies to be carried out, in order to obtain data on the properties of chemicals and their safety with regard to human health and the environment. Good laboratory practice will also apply to field studies.

B. Definitions.

1. Good laboratory practice (B.P.L.): Good laboratory practice refers to the organizational systems and conditions under which studies are planned, performed, controlled, recorded and presented.

2. Terms relating to the organisation of the laboratory:

a) Laboratory: It is the set of persons, premises, facilities, apparatus and materials necessary for the performance of the studies.

b) Study Director: This is the person responsible for the total realization of the study.

c) Quality Assurance Program: It is the internal control system that allows to verify that the study is carried out in accordance with the principles of good laboratory practice.

d) Procedures, standard of work: These are written procedures that describe how certain routine laboratory tests are performed, or any other activity that is not normally specified in a way detailed in the protocols, or in the guidelines of the study.

e) Promoter: It is the natural or legal person who sponsors or commissions the study.

Section 2. Principles of Good Laboratory Practice

A. Laboratory organization and personnel.

1. Responsibilities of the Laboratory Management.

(a) The direction of the laboratory shall ensure compliance with the principles of good laboratory practice.

b) The direction of the laboratory shall take care of at least:

1. Suitable staff, facilities, equipment, equipment and materials are available.

2. Keep the documentation related to the certification, training and experience and the description of the job, of all the people of scientific, technical and labor level.

3. Ensure that staff clearly understand the roles they need to perform and, where necessary, form them for them.

4. Ensure compliance with safety and hygiene standards in accordance with current legislation.

5. Ensure the establishment and enforcement of standard working procedures.

6. Ensure that a quality assurance program exists and assign the appropriate personnel to you.

7. Approve the protocol where appropriate with the study promoter.

8. Ensure that any modification to the protocol is approved and registered.

9. Keep copies of all protocols.

10. Maintain a chronological file of all standard job procedures.

11. Ensure that sufficient staff are available for the timely and correct implementation of each study.

12. To designate as the Director of the study and before the commencement of the study, a person who has the appropriate qualifications, training and experience. If it is necessary to change the Director throughout the study, it should be justified and recorded.

13. Ensure that a person is designated as responsible for file management.

2. Responsibility of the Director of the study.

a) The Director of the study has responsibility for the direction of the study and the drafting of the final report.

b) This responsibility shall include at least the following functions:

1. Approve the protocol.

2. Ensure that the standard working procedures specified in the protocol are complied with and that any modification of the protocol is justified, approved and registered.

3. Ensure that all data obtained are recorded in full.

4. Date and sign the final report, accepting responsibility for the validity of the data and confirming compliance with the principles of good laboratory practice.

5. Ensure that at the end of the study, the protocol, the final report, the primary data and all material related thereto are duly archived.

3. Staff responsibility

(a) Staff must observe safe working methods. The chemical products must be handled with the necessary precautions as long as their degree of danger has not been determined.

(b) Personnel must take the necessary hygiene precautions to minimize the risk to which they are exposed and to ensure the quality of the study.

(c) Persons whose health status may adversely alter the quality of the study shall be excluded from the conduct of operations which may affect the study.

B. Quality assurance program

1. Generalities.

(a) The laboratory shall have a quality assurance programme supported by documents, which ensures that the studies are carried out in accordance with the principles of good laboratory practice.

(b) The quality assurance programme shall be carried out by one or more persons appointed by the management of the laboratory and directly responsible to it and who are familiar with the procedures experimental.

c) These people should not participate in the conduct of the study that they guarantee.

d) These persons shall communicate all their observations, in writing, directly to the management of the laboratory and to the director of the study.

2. Responsibilities of the staff in charge of the Quality Assurance Unit.

The staff in charge of the quality assurance shall be responsible for at least the following functions:

(a) Ensure that the protocol and standard working procedures are available to the staff performing the study.

(b) Ensure that the protocol and standard procedures for work are complied with, through regular laboratory inspections and study verifications during their performance. Reports of these inspections should be kept.

(c) promptly inform the laboratory management and the director of the study of any unauthorised deviations from the protocol or standard working procedures.

d) Review final reports to confirm that the methods, procedures and observations are properly described and that the results obtained accurately reflect the primary data of the study.

e) Draft and sign a declaration, to be included in the final report, indicating the dates of the inspections carried out and the reports submitted to the laboratory management and the study director.

3. Terms relating to the study

a) Study: It is the test or set of trials aimed at obtaining data relating to the properties and safety of the substance to be tested on human health and the environment.

b) Protocol: This is the document that defines the scope of the study in any extension.

c) Guideline for testing: This is the coded description of the method defined by the competent authority, on which the study is based.

d) Experimental system: It is any animal, plant, microbial, cellular, subcellular, chemical, physical or any combination of the same, used in the study.

e) Primary data: These are laboratory annotations, orginal documents, or verified copies thereof, resulting from direct observations or from the work done throughout the study.

f) Species: It is any material extracted from the experimental system for examination, analysis, or storage.

4. Terms relating to the substance (product) to be tested

a) Substance to be tested: It is the chemical or prepared test substance.

(b) Reference substance: It is any other chemical substance or well-determined mixture used to establish a basis for comparison with the substance to be tested.

(c) Lot: It is a given quantity of the substance to be tested or of the reference substance which has been produced in a defined cycle of manufacture, in such a way as to present a uniform character.

(d) Vehicle (carrier): It is any agent used to mix, disperse or solubilise the substance to be tested or referred to, in order to facilitate its incorporation into the experimental system.

e) Shows: It is a certain amount of the substance to be tested or the reference substance.

C. Laboratory

1. Generalities

(a) The size, construction and location of the laboratory shall meet the requirements of the study and minimise any disturbance that may alter its validity.

(b) The design of the laboratory shall be such as to permit adequate improvement between the different activities, in order to ensure the correct execution of each study.

2. Facilities related to the experimental system

(a) The laboratory must have a sufficient number of rooms and premises to ensure the separation between the different experimental systems and the isolation in those studies where products are potentially used dangerous or suspected to be.

(b) The laboratory shall have appropriate facilities for the diagnosis, treatment and control of diseases of the experimental systems in order to ensure that an unacceptable degree of deterioration does not occur. of the same.

c) The laboratory must have sufficient space for the storage of supplies and equipment. The storage premises must be separated from the premises which host the experimental systems and must be sufficiently protected against any kind of infestation and contamination. The cooling of perishable products must be ensured.

3. Installations for the handling of substances to be tested and for reference substances

(a) In order to avoid any type of contamination or involuntary mixing of substances, different premises must be available for reception, storage of substances to be tested and reference substances; also for operations relating to mixtures of substances to be tested with vehicles.

(b) The storage premises of the substances to be tested shall:

1. Be separated from the premises where the experimental systems are housed.

2. Ensure that the identity, concentration, purity and stability of these substances are maintained.

3. Ensure adequate storage of hazardous substances.

4. File Rooms

File rooms must be available for storage and consultation of primary data, reports, samples, and specimens.

5. Waste disposal

(a) The handling and disposal of waste must be carried out in such a way as not to endanger the integrity of the studies being carried out.

(b) The handling and disposal of waste resulting from the conduct of a study shall be carried out in accordance with current legislation. Appropriate collection, storage and disposal facilities, as well as decontamination and transport facilities, should be available. Records of the above activities shall be maintained.

D. Apparatus, materials and reagents

1. Appliances

(a) The apparatus used in obtaining the data and in the regulation or control of the environmental factors involved in the studies must be correctly located, have an appropriate design and be adequately dimensions.

(b) The apparatus used in the studies shall be periodically and conveniently reviewed, cleaned, maintained and calibrated, in accordance with the standard working procedures. A record of these operations must be maintained.

2. Materials

The devices and materials used in the studies should not interfere with the experimental systems.

3. Reagents

Reagents should be labelled indicating the origin, identity, concentration and data on their stability, date of preparation, expiry and specific instructions for storage.

E. Experimental Systems

1. Physical and chemical

(a) The apparatus used to obtain physical and chemical data must be correctly located, be of appropriate design, and be adequately sized.

(b) Reference substances may be used to assist in verifying the integrity of the physical and chemical experimental systems.

2. Biologics

(a) The appropriate conditions for accommodation, handling, care and maintenance of animals, plants, microbial systems and other cellular and subcellular systems shall be created and maintained in order to ensure the quality of the data.

(b) These conditions shall also comply with current legislation on the import, transport, care, maintenance and use of animals, plants, microbial systems and other cellular and subcellular systems.

(c) The experimental, animal and plant systems shall, immediately after their receipt, be isolated until their health status and health conditions are assessed. If a mortality or abnormal morbidity is observed, the lot considered should not be used and should be destroyed if necessary, following humanitarian methods.

(d) Records shall be kept in which the origin, date of arrival and status of the receipt are recorded.

e) Before the start of the study, the experimental, animal, plant, microbial and cellular systems shall be acclimatised to the environmental conditions laid down therein for a sufficient period of time.

(f) The experimental systems must be correctly identified by signs or annotations which must appear on their corresponding container or housing.

g) The diagnosis and treatment of any disease that is declared in the experimental system before or during the conduct of the study must be recorded.

F. Substances to be tested and referred to

1. Receiving, handling, sampling, and storage

(a) Records shall be kept in which the characterisation of the substance, the date of receipt and the quantities received and used in the studies shall be maintained.

(b) The methods of handling, sampling and storage shall be described which ensure at all times, and as far as possible, homogeneity and stability, and prevent contamination or mixing.

c) The labeling of storage containers must include the identity, expiration date, and specific instructions for storage.

2. Characterization

(a) Any substance to be tested or referred to must be correctly identified (e.g. by a code, by its Chemical Abstracts Service number, CAS, or by name).

(b) For each study the identity of the substances to be tested or of reference, including the batch number, purity, composition, concentration and other characteristics to be defined in such a way, shall be known. appropriate each batch.

c) For each study, the stability of the substances to be tested and of reference in the storage conditions shall be known.

d) For each study, the stability of the substances to be tested and of reference under the conditions of the study should be known.

e) When the test substance is to be administered in a vehicle, the standard working procedures necessary to check the homogeneity and stability of the substance in that vehicle shall be established.

f) For studies of more than four weeks duration, a sample of each batch must be kept for analytical purposes.

G. Standard procedures for work

1. Generalities.

Each laboratory must have in writing standard working procedures, approved by management, that ensure the quality and integrity of the data obtained throughout the study.

In each separate unit of the laboratory, standard working procedures must be available, corresponding to the activities carried out in the laboratory. Text books, articles, manuals, etc., may be used as a supplement to them.

2. Application.

Standard working procedures shall be available for at least the following laboratory activities:

a) Substance to be tested and reference:

Receiving, identifying, labeling, handling, sampling, and storage.

b) Appliances and reagents:

Use, maintenance, cleaning and calibration of measuring devices and equipment for regulating environmental conditions; preparation of reagents.

c) Maintenance of records, reports, files, and query:

Coding of studies, data collection, preparation of reports, classification systems, data management, including computer systems.

d) Experimental systems (where applicable):

1. Local preparation and environmental conditions for the experimental system.

2. Procedure for reception, transfer, location, characterization, identification, care and maintenance of the experimental system.

3. Preparation of the experimental system, observations and examinations before, during and at the end of the study.

4. Manipulation of individuals from the experimental system that are found to be dying or dying during the study.

5. Collection, identification and manipulation of specimens, including necropsy and histopathology.

e) Quality Assurance Procedures:

Activities of the staff responsible for the Quality Assurance Unit for the performance and reporting of reviews and inspections of studies, as well as for reviews of the final report.

f) Safety and hygiene measures:

According to current legislation.

H. Conduct of the study

1. Protocol.

a) Before starting any study, a written protocol must be established.

b) The protocol should be retained as the primary data.

(c) All changes, modifications or revisions to the protocol, as approved by the Director of the study, including their justifications, shall be the subject of documents signed and dated by the Director of the study; preserved along with the protocol.

2. Protocol content.

The protocol must contain at least the following information:

(a) Identification of the study and the substances to be tested and reference:

1. Descriptive title.

2. Explanatory statement, specifying the nature and purpose of the study.

3. Identification of the substance to be tested by a code or by name (IUPAC, CAS number, etc.).

4. Reference substance, which is to be used.

b) Information about the promoter and the laboratory:

1. Name and address of the sponsor.

2. Name and address of the laboratory.

3. Name and address of the Director of the study.

c) Dates:

1. Date of approval of the protocol by the signature of the protocol by the Director of the study, and where necessary by the sponsor and by the management of the laboratory.

2. Proposed dates for commencement and completion of the study.

d) Test methods:

Indication of the guidelines of the OECD, EEC or other guidelines to be used.

e) Particular aspects (where applicable):

1. Justification for the choice of the experimental system.

2. Characterization of the experimental system, i.e. the species, strain, breed, variety, origin, number of individuals, weight range, gender, age and other relevant information.

3. Method of administration and the reasons for your choice.

4. Dose and/or concentration levels, as well as the frequency and duration of administration.

5. Detailed information of the experimental design where the chronological development of the study, materials, methods and conditions, the nature and frequency of the analyses, measurements, observations and examinations to be carried out will be included.

f) Records:

List of records to be retained.

3. Conduct of the study.

a) Each study will be awarded an identification of its own. All items related to it must bear this identification.

b) The study shall be carried out in accordance with the approved protocol.

(c) All data obtained during the conduct of a study must be recorded immediately, accurately and legibly by the person responsible for recording them, who must also date and sign them (heading or ).

(d) Any modification of the primary data shall be carried out in such a way as to ensure that it does not hide previous data. If necessary, the reason for the change shall be indicated, which shall be dated and signed by the person performing it.

(e) Data which is entered directly in computerised form shall be identified at the time of their introduction by the person responsible for this. Corrections shall be made separately, specifying the reason for the corrections, the date and the identity of the person making them.

I. Realization of the report based on the results of the study

1. Generalities.

a) A final report on the study will be drafted.

b) The use of the international system of units (SI) is recommended.

c) The final report shall be dated and signed by the Director of the study.

(d) When the final report includes those issued by other principal investigators who have collaborated in the conduct of the study, these reports must be dated and signed by these investigators.

(e) The corrections and additions to a final report shall be submitted in the form of amendments. Those amendments shall clearly specify the reason for such corrections or additions and shall be dated and signed by the Director of the study and by the principal investigator of each discipline involved.

2. Content of the final report.

The final report must include at least the following information:

(a) Identification of the study and the substances to be tested and reference:

1. Descriptive title.

2. Identification of the substance to be tested by a code or by its chemical name (IUPAC, CAS number, etc.).

3. Identification of the reference substance by its chemical name.

4. Characterization of the substance to be tested with particular reference to its purity, stability and homogeneity.

b) Information about the lab:

1. Name and address.

2. Name of the Director of the study.

3. Name of people who contributed their reports to the final report.

c) Dates:

Start and completion dates of the study.

d) Statements:

Statements by quality assurance officers certifying the dates of the inspections and the dates on which the observations were communicated to the management and the study director.

e) Description of the materials and test methods:

1. Description of the methods and materials used.

2. Indication of the guidelines of the OECD, EEC or other guidelines which have been used for testing.

f) Results:

1. Summary of the results.

2. All information and data required in the protocol.

3. Exposure of results, including calculations and statistical methods.

4. Assessment and discussion of the results and, if appropriate, conclusions.

g) Files:

Place where the set of samples, specimens, primary data, and final report is preserved.

J. Files: Storage and preservation of records and materials

1. Storage and query.

a) Files must be designed and equipped for the appropriate reception and storage of:

1. Protocol.

2. Primary data.

3. Final reports.

4. Reports on reviews of studies and on laboratory inspections carried out in accordance with the quality assurance programme.

5. Samples and specimens.

(b) The classification of the materials retained in the archives shall be such as to facilitate orderly storage and rapid localization.

c) Only the personnel authorized by the address may have access to the files. The document entries and outputs of the files must be duly registered.

2. Conservation.

(a) The following documents shall be kept for the period specified by the competent authority:

1. The protocol, primary data, samples, specimens and final report of each study.

2. The reports of all inspections and checks carried out, according to the quality assurance programme.

3. A summary of the qualifications, training, experience and job description of the staff.

4. Reports on equipment maintenance and calibration.

5. The chronological file of the standard working procedures.

(b) Samples and specimens shall not be kept beyond the time during which preparations are suitable for an assessment.

(c) When a laboratory or a tenant company of file premises ceases in its activities without having a legal successor, the files must be transferred to the sponsor of the study.