CANADA – CONTINUED SUSPENSION OF OBLIGATIONS IN THE EC – HORMONES DISPUTE
Document: Report of the Panel Addendum
Date: 31 March 2008
Document codes: WT/DS321/R/Add.5; WT/DS321/R.
Complainant: EU
Respondent: Canada
Third parties: Australia, Brazil, China, Taiwan, India, Mexico, New Zealand, Norway, U.S.
Dispute stage: Appellate Body
Agreements cited: Art. I, II  GATT 1994Art. 3.7, 22, 23.1, 23.2, 21.5  Dispute Settlement Understanding (DSU)

CANADA – CONTINUED SUSPENSION OF
OBLIGATIONS IN THE EC – HORMONES DISPUTE

Report of the Panel

Addendum

 This addendum contains Annex E to the Re port of the Panel to be found in document
 The other annexes can be found in the following addenda:

 – Annex A: Add.1
 – Annex B: Add.2
 – Annex C: Add.3
 – Annex D: Add.4
 – Annex F: Add.6
 – Annex G: Add.7

ANNEX E

REPLIES OF THE CODEX ALIMENTARIUS COMMISSION,
THE JOINT FAO/WHO JECFA SECRETARIAT AND
THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER
TO CERTAIN QUESTIONS POSED BY THE PANEL
TO INTERNATIONAL ORGANIZATIONS

Contents Page
Annex E-1 Replies of the Codex Alimentarius Commission to certain
questions posed by the Panel to international organizations
E-2
Annex E-2 Replies of the joint FAO/ WHO JECFA Secretariat to certain
questions posed by the Panel to international organizations
E-104
Annex E-3 Replies of the Internationa l Agency for Research on Cancer to
certain questions posed by the Panel to international organizations
E-127

ANNEX E-1

REPLIES OF THE CODEX ALIMENTARIUS COMMISSION
TO CERTAIN QUESTIONS POSED BY THE PANEL
TO INTERNATIONAL ORGANIZATIONS

1. Please briefly describe the procedure fo r the elaboration and adoption of an
international standard by Codex. What is th e decision-making process for the adoption of an
international standard?

The procedure for the elaboration and adoption of C odex standards and related texts are published in
the Procedural Manual of the Codex Alimentarius Commission (see Annex 1) . The Procedure for the
Elaboration of Codex Standards was comprehe nsively revised in 1993 to provide a uniform
elaboration procedure for all Codex standards and related texts, including maximum residue limits
(consisting of 8 Steps under the normal procedure a nd 5 Steps under the accelerated procedure). The
revised uniform elaboration procedure superseded the separate procedure for the elaboration of Codex
Maximum Residue Limits (MRLs) for Veterinary Drugs.
1 The Procedure was further revised in 2004
to introduce the strategic planning process and the critical review of new work proposals at Step 8.

In essence the 8-step procedure followed in the development and approval of the standard involves:

Prior to Step 1
: The submission of a proposal for a new standard or re lated text by a national
government or a subsidiary body of the Commission. This is usually accompanied by a project
document that indicates the purpose, scope and pr oposed timeline time frame for the new work. The
project document is reviewed by the Executive Committee, which forward its opinion to the
Commission (this process is called "critical review").

In the case of MRLs for veterinary drugs, submissi on of project documents is not required; instead,
the Codex Committee on Residues of Veterinary Drugs in Foods (CCRVDF) prepares a priority list of
veterinary drugs requiring evaluation or re-eva luation by JECFA, which is submitted to the
Commission for approval.

Step 1
 a decision by the Commission that a standard be developed as proposed. "Criteria for
the Establishment of Work Priorities" exis t to assist the Commission in its decision-
making and in selecting the subsidiary bod y to be responsible for steering the
standard through its development. If necessar y, a new subsidiary body – usually a
specialized task force - may be created. In the case of matters related to the residues
of veterinary drugs, CCRVDF always unde rtakes the standards development work
assigned by the Commission in accordance with its terms of reference (Annex 2);

Step 2
 the preparation of a proposed draft standard;

1 Elaborated by the CCRVDF and adopted by the 18 th Session of the Codex Alimentarius Commission
(1989) (ALINORM 89/40 para. 215). The 8-step procedure, involved: Steps 1, 2 and 3 : the distribution of the
draft recommendations for MRLs for veterinary drugs, based on JECFA evaluations and request comments from
Government and interested organisation; Step 4: examination by the CCRVDF in the light of the comments. The
CCRVDF, when formulating its recommendations for proposed draft MRLs, takes all appropriate matters into
consideration including the need for urgency, the government commen ts at Step 3 and the likelihood of new
evidence becoming available in the immedi ate future and, on the basis of su ch considerations, indicates to the
Commission those proposed draft MRLs which, in its view, need to be passed through the full Procedure and
those for which there might be an omission of Step 6 and 7; Steps 5-8
: as for the Procedure for the Elaboration
of world-wide standards.

Step 3 the circulation of the proposed draft standard for governments' and interested
organizations' comments; in the case of MRLs for veterinary drugs, the
recommendations of JECFA are circulated for comments at this Step;

Step 4
 the discussion at Committee level;

Step 5
 the submission of the proposed draft standard to the Commission for adoption as draft
standard ("preliminary adoption");

Step 6 the circulation of the draft standard for governments' and interested organizations'
comments;

Step 7
 the discussion at Committee level;

Step 8 the submission of the draft standard to the Commission for adoption as Codex
standard.

More details of the Elaboration Procedure are given in Annex 1.

A Committee may decide to submit a text to the Commission for adoption at Step 5 and 8, with the
omission of Steps 6 and 7. The Commission may also approve the use of an accelerated procedure for
the elaboration of these standards, using a 5-step elaboration process.

The Commission may also decide to return a proposed draft or a draft standard from Step 5 or 8 to a
previous step when it considers that more discussion is necessary at the Committee level.

The procedure for revision of Codex standards and re lated texts follows that used for the elaboration
of standards. The Commission and its subsidiary bodies are committed to the revision of Codex
standards and related texts as necessary to ensure they are consistent with and reflect current scientific
knowledge. Each member of the Commission is r esponsible for identifying and presenting to the
appropriate committee any new scientific and other relevant info rmation that may warrant revision of
existing Codex standards or related texts.

The Procedure for the Elaboration of Codex Standards and Related Texts allows for full discussion
and exchange of views on the issue under considerati on, in order to ensure the transparency of the
process and, if necessary, arrive at compromises that would facilitate consensus. Written comments
from governments and observers are solicited at Step s 3, 5, 6 and 8; furthermore, governments and
observers can present their positions directly in a committee meeting and exchange views with other
delegations at Steps 4 and 7.

The Commission attaches a great importance of achieving consensus at all stages of the elaboration of
standards and that draft standards should, as a matter of principle, be submitted to the Commission for
adoption only where consensus has been achieved at the technical level. For this purpose, the
Commission at its 26
th Session (2003) adopted "Measures to Facilitate Consensus" for inclusion in the
Procedural Manual (see Annex 3).

2. Please briefly explain the differences betw een Codex standards, codes of practice,
guidelines, principles and other recommendations.

The texts developed by the Codex Alimentarius Commission may be divided in two main groups: i)
texts intended for use by Governments and are publi shed in the Codex Alimentarius (these include
Codex standards, codes of practice, guidelines, pr inciples and other recommendations); and ii) texts

intended to guide the work of the Commission a nd its subsidiary bodies and are included in the
Procedural Manual (these include the Statutes an d Rules of Procedure of the Commission, other
procedures, guidelines, principles and other recommendations.)

Codex standards usually relate to product characteristics and may deal with all government-regulated
characteristics appropriate to the commodity, or only one characteristic. Maximum residue limits
(MRLs) for residues of veterinary drugs in foods are examples of standards dealing with only one
characteristic (i.e. numerically expressed limits of a chemical substance in a given food (animal tissue
or milk)). There are Codex general standards for food additives and contaminants and toxins in foods
that contain both general and commodity-specific provisions. The Codex General Standard for the
Labelling of Prepackaged Foods covers all foods in this category. Codex commodity standards, on the
other hand, include provisions on the product definition, essential quality factors, labelling and health-
related aspects for a given produc t or a group of products. Because standards relate to product
characteristics, they can be applie d wherever the products are traded. Codex methods of analysis and
sampling, including those for contaminants and residues of pesticides and veterinary drugs in foods,
are also considered Codex standards.

Codex codes of practice (including codes of hygienic practice) define the production, processing,
manufacturing, transport and storage practices for individual foods or groups of foods that are
considered essential to ensure the safety and suita bility of food for consumption. For food hygiene,
the basic text is the Codex General Principles of Food Hygiene, which recommends the use of the
Hazard Analysis and Critical Control Point ( HACCP) food safety management system. The Codex
Code of Practice on the Control of the Use of Vete rinary Drugs provides general guidance in relation
to the use of veterinary drugs in food production.

Codex guidelines fall into two categories: i) principles that set out policy in certain key areas; and ii)
guidelines for the interpretation of these principles or for the interpretation and/or application of the
provisions of the Codex general standards.

Codex guidelines include those for food labelling, especially the regulation of claims made on the
label. This group includes guidelines for nutrition and health claims; conditions for production,
marketing and labelling of organi c foods; and foods claimed to be "halal". There are several
guidelines that interpret the provisions of the C odex Principles for Food Import and Export Inspection
and Certification, and guidelines on the conduct of safety assessments of foods from DNA-modified
plants and micro-organisms.

The status of Codex standards and related texts within the Codex system and in the international
framework has changed several times since the Commission was established in 1962.

These changes can be identified in four periods : until 1981; from 1981 to 1995; from 1995 to 2006;
and since 2006 when Codex Acceptance Procedures were formally abolished.

Until 1981
 – The elaboration of a worldwide standard consisted of 11 Steps until the Steps beyond
Step 8 were eliminated in the 5th Edition of the Procedural Manual. The eliminated Steps were: Step 9
(the "recommended standard" is sent to FAO/W HO members for acceptance, and the latter notify
their acceptance); Step 10 (the Secretariat peri odically publishes notifications received on the
recommended standard); Step 11 (the "recommende d standard" is published as a "Codex standard"
when the Commission determines that it is appropriate to do so in the light of notifications received).

From 1981 to 1995 – Codex Standards and Related Texts had habitually been classified on the basis
of whether or not texts are intended to be s ubject to the Acceptance Procedures laid down in
paragraphs 4, 5 and 6 of the General Principles of the Codex Alimentarius (see Procedural Manuals
prior to the 15 th Edition; e.g. Annex 4). Those adopted te xts subjected to the Acceptance Procedures

were termed "mandatory" and the other texts "advisory". The term "mandatory" did not mean that
members were under obligations to accept Codex standards as were. Members could choose among
three different forms of acceptance: "Full Acceptan ce"; "Acceptance with specified deviations"; and
"Free distribution2", in accordance with their own legal and administrative procedures. The situation
was different regarding the acceptance of Codex Maximum Limits for Residues of Pesticides and
Veterinary Drugs in Food. In this case, the Ge neral Principles of the Codex Alimentarius only
provided the possibility of Full Acceptance or Free Distribution (see section 6, Annex 4).

Prior to the establishment of the WTO in 1995 and the entry in force of the WTO Agreements on the
Application of Sanitary and Phytosanitary (SPS) Measures and on Technical Barrier to Trade (TBT),
the status of Codex standards was defined only with in the Codex system; in particular they had no
direct binding effect on member countries per se. Countries were undertaking specific obligations only
when they declared acceptance according to one of the modalities indicated in section 4A, 5A and 6A of
the General Principles of the Codex Alimentarius (Annex 4). In particular, a country had the obligation
to accept a product for distribution on its territory only when it has declared acceptance.

The notifications of acceptance received in the Code x Secretariat became increasingly rare by the end
of 1980s, because many countries ceased to implemen t a national procedure for the acceptance of
standards. The Progress Report on Acceptances was a standing item in the agenda of the Commission
since its early years but was discontinued after 1993, and was replaced by a discussion on the
usefulness of acceptances in the light of the WTO Agreements. Acceptances were published in 1989
for standards and in 1983 for pesticide residues for the last time. Notifications became very rare in the
1990s.

From 1995 to 2006
 - Codex standards and related texts starte d to enjoy a new status in the framework
of WTO Agreements. In regard to the diffe rences between standards, guidelines and other
recommendations, It is worth noting the clarification provided by the WTO SPS Committee in March
1998 in response to the query sent from Codex: th e SPS Committee responded that the provisions of
the SPS Agreement did not differentiate between the three terms "standards", "guidelines" or
"recommendations" (see Annex 5).

Meanwhile, the 22
nd Session of the Codex Alimentarius Commission (1997) agreed that the use of the
terms "mandatory" and "advisory" was confusing a nd not consistent with the provisions of the SPS
and TBT Agreements, and stated that they should no longer be used.3 Once standards and related texts
have been adopted by the Codex Alimentarius Commission, they are recognized as a reference under the
SPS Agreement in matters of food safety and under TB T for other technical matters relevant to food
regulation.

After 2006 (abolition of Codex Acceptance Procedures)

The 28
th Session of the Codex Alimentarius Commissi on (2005) agreed to abolish the acceptance
procedures and amend relevant section of the Procedural Manual accordingly. 4 As stated above, the
Codex acceptance procedure covered only Codex Sta ndards (Commodity or General) and Maximum
Residue Limits, and did not cover other texts adopt ed by the Commission, such as codes of practice
and other recommendations. As a consequence of abolishing acceptance procedure, the dichotomy
between "standards and MRLs" and "other texts" within the Code x Alimentarius was removed,
resulting in a uniform status of all Codex standards and related texts.

2 "Free Distribution" was introduced as a new category of acceptance in 1989 by the 18th Session of the
Commission.
3 ALINORM 97/37, para. 171.
4 ALINORM 05/28/41, para. 36.

3. Please identify any international guidance documents relevant to the conduct of a risk
assessment with respect to veterinary drug residu es. Since when have they been available?
Please also indicate if there is any relevant ongoing work at Codex.

The Codex Alimentarius Commission initiated work to incorporate risk asse ssment principles into
Codex decision-making and procedures on the basis of the Joint FAO/WHO Conference on Food
Standards, Chemicals in Food and Food Trade, held in Rome in 1991. The Commission, at its 19
th and
20th Session agreed on the incorporation of risk asses sment principles in its procedure. To assist the
Commission, FAO and WHO convened a joint FAO/WHO expert consultation on the application of
risk analysis to food standards issues in 1995.

The Statements of principles relating to th e role of food safety risk assessment
5, adopted by the 22 nd
Session of the Codex Alimentarius Commission (1997), state that:

1. Health and safety aspects of Cod ex decisions and recommendations should
be based on a risk assessment, as appropriate to the circumstances.
2. Food safety risk assessment should be soundly based on science, should
incorporate the four steps of the risk assessment process, and should be documented
in a transparent manner.
3. There should be a functional separation of risk assessment and risk
management, while recognizing that some int eractions are essential for a pragmatic
approach.
4. Risk assessment should use available q uantitative information to the greatest
extent possible and risk characterizations should be presented in a readily
understandable and useful form.
The 22
nd Session of the Commission also adopted an Action Plan for Codex-wide Development and
Application of Risk Analysis Principles and Guide lines. In accordance with the Plan and on the basis
of the preparatory work by the Codex Committee on General Principles, the 26th Session of the Codex
Alimentarius Commission (2003) adopted the Working Principles for Risk Analysis for Application in
the Framework of the Codex Alimentarius for inclusion in the Procedural Manual6 (see Annex 6). The
objective of the Principles is to provide guidan ce to Codex subsidiary bodies and FAO/WHO expert
bodies and consultations, so that food safety and h ealth aspects of Codex standards and related texts
are based on risk analysis. The Principles clearly de fine the responsibilities of the Commission and its
subsidiary bodies for risk management decisi on and of the joint FAO/WHO expert bodies and
consultation for risk assessment.

Following the adoption of the Working Principles, the Commission requested that relevant Codex
Committees develop or complete specific guidelines on risk analysis in their respective areas for
inclusion in the Procedural Manual. The Commission noted that these texts would be submitted to the
Committee on General Principles in order to ensure coordination of work and consistency with the
overarching Working Principles.
7 At the same time, the Committee on General Principles pursued
elaboration of risk analysis guidance for use by governments (this work is still ongoing).

Within the framework of the above request by the Commission, the 16 th Session of the CCRVDF
(2006) completed work on: "Risk Analysis Prin ciples applied by the Codex Committee on Residues

5 Procedural Manual of the Codex Alimentarius Commission (15th Edition).
7 ALINORM 03/41, para. 147.

of Veterinary Drugs in Foods" and "Risk Assessme nt Policy for the Setting of MRLs in Food" and
forwarded these to the Codex Alimentarius Commission. 8 The two documents will be considered by
the 30 th Session of the Codex Alimentarius Commiss ion in 2007 (after review by the Codex
Committee on General Principles) for adoption and inclusion in the Procedural Manual.

The Principles define the responsibilities of the various parties involved: the responsibility for
providing advice on risk management concerning resi dues of veterinary drugs lies with the Codex
Alimentarius Commission (CAC) and its subsidia ry body, the Codex Co mmittee on Residues of
Veterinary Drugs in Foods (CCRDVF), while the responsibility for risk assessment lies primarily with
the Joint FAO/WHO Expert Committee on Food Additives (JECFA).

The Risk Assessment Policy applies to the work of JECFA in the context of Codex and in particular
as it relates to advice requests from CCRVDF.

4. The European Communities states that there is "no Codex standard specifically on the
risk assessment of effects of residues of veterina ry drugs" but a general one on microbiological
assessment. Is this correct? Which guidelines or principles have been used by JECFA in the
conduct of its risk assessments with respect to the hormones at issue? [see para. 192 of
EC Rebuttal Submission (US case)]

There is no adopted Codex standard or related text on the risk assessment of residues on veterinary
drugs that provides guidance to governments. However, at the request of 23
rd session of the
Commission, the CCRVDF in 2000 started develop texts on risk analysis principles in the work of the
Committee. The 16th Session of the Committee completed work on two texts: Risk Analysis Principles
applied by the Codex Committee on Residues of Ve terinary Drugs in Foods and Risk Assessment
Policy for the Setting of MRLs in Food, for inclus ion in the Procedural Manual (see the answer to
Question 3, above). The documents may be adopted by the Commission in 2007. Annex 7 describes
relevant discussion in CCRVDF to strengthen science -based approach to risk analysis into its work.

As other internal documents on risk analysis, C odex has already adopted Risk Analysis Principles
Applied by the Codex Committee on Food Additi ves and Contaminants and CCFAC Policy for
Exposure Assessment of Contaminants and Toxins in Foods and Food Groups; the Commission will
possibly adopt Risk Analysis Principles Applie d by the Codex Committee on Pesticides Residues,
finalized by the 38th Session of the CCPR (2006) in 2007.

As the adopted texts on risk analysis providing guidance to governments, Codex has: Principles and
Guidelines for the Conduct of Microbiological Ri sk Assessment (CAC/GL 30-1999); and Principles
for the Risk Analysis of Foods Derived from Modern Biotechnology (CAC/GL 44-2003) and two
accompanying guidelines for food safety assessment of foods derived from recombinant-DNA plants
and microorganisms (CAC/GL 45-2003; CAC/GL 46-2003).

In addition, the Codex Committee on Food Hygiene ( CCFH) is currently developing Principles and
Guidelines for the Conduct of Microbiological Risk Management (at Step 6) and the ad hoc Codex
Intergovernmental Task Force on Biotechnology is working on Guideline for the Conduct of Food
Safety Assessment of Foods Derived from Recombinant-DNA Animals.

5. Please briefly describe the three components of a risk analysis exercise (risk assessment,
risk management and risk communication) as defined by Codex and explain how they differ.

8 ALINORM 06/29/31 para. 111 and Appendices VIII and IX.

Definitions of Risk Analysis Terms relate d to Food Safety were adopted by the 22
nd Session of the
Codex Alimentarius Commission9 (1997) and were included in the Procedural Manual (see Annex 8).
The definitions of "Risk Management" and "Risk Communication" were revised by the 23 rd Session
of the Codex Alimentarius Commission (1999) 10 in the light of the reports of the Joint FAO/WHO
Experts Consultations on Risk Management and F ood Safety and on Risk Communication in Relation
to Food Standards and Safety Matters. The Working Principles for Risk Analysis for Application in
the Framework of the Codex Alimentarius describe the three components of risk analysis in more
detail (see Annex 6).

The Procedural Manual of the Codex Alimentarius Commission provides the following definitions ( in
italics):

Risk Assessment : A scientifically based process consisting of the following steps: (i) hazard
identification, (ii) hazard characterization, (iii) exposure assessment, and (iv) risk characterization
 11

Risk Management : The process, distinct from risk assessmen t, of weighing policy alternatives, in
consultation with all interested parties, considering risk assessment and other factors relevant for the
health protection of consumers and for the promoti on of fair trade practices, and, if needed, selecting
appropriate prevention and control options.11

Risk Communication : The interactive exchange of informa tion and opinions throughout the risk
analysis process concerning risk, risk-related facto rs and risk perceptions, among risk assessors, risk
managers, consumers, industry, the academic commun ity and other interested parties, including the
explanation of risk assessment findings and the basis of risk management decisions.11

6. Please briefly describe the four steps of a risk assessment (hazard identification, hazard
characterization, exposure assessment and risk characterization) as identified by Codex,
indicating any relevant sources.

The Procedural Manual of the Codex Alimentarius Commission provides the following definitions ( in
italics):

Hazard identification. The identification of biological, chemical and physical agents capable of
causing adverse health effects and which may be present in food.11

Hazard characterization. The qualitative and/or quantitative evaluation of the nature of the adverse
health effects associated with biological, chemical and physical agents which may be present in food.
For chemical agents, a dose-response assessment s hould be performed. For biological or physical
agents, a dose-response assessment should be performed if the data are obtainable.11

Exposure assessment . The qualitative and/or quantitative eval uation of the likely intake of
biological, chemical, and physical agents via food as well as exposures from other sources if
relevant.11

Risk characterization. The qualitative and/or quantitative estimation, including attendant
uncertainties, of the probability of occurrence and severity of known or potential adverse health
effects in a given population based on hazard iden tification, hazard charac terization and exposure
assessment.
11

11 Procedural Manual of the Codex Alimentarius Commission (15th Edition).

9. Please provide definitions for the followin g terms: Acceptable Daily Intake (ADI) and
Maximum Residue Limit (MRL).

A definition for Codex Maximum Limits of Residues of Veterinary Drugs (MRLVD) is contained in
the Procedural Manual of the Codex Alimentari us Commission (see below). A definition for
Acceptable Daily Intake (ADI) is included in the "Glossary of Terms and Definition" (CAC/MISC
5 1993) (see below), which has been elaborated by the Codex Committee on Residues of Veterinary
Drugs in Foods (CCRVDF) with a view of providing information and guidance to the Committee, and
it is intended for internal Codex use only.12

Codex Maximum Residue Limit for Veterinary Drugs (MRLVD) is the maximum
concentration of residue resulting from th e use of a veterinary drug (expressed in
mg/kg or μg/kg on a fresh weight basis) that is recommended by the Codex
Alimentarius Commission to be legally p ermitted or recognized as acceptable in or
on a food.
It is based on the type and amount of residue considered to be without any
toxicological hazard for human health as expressed by the A cceptable Daily Intake
(ADI), or on the basis of a temporary ADI that utilizes an additional safety factor. It
also takes into account other relevant public health risks as well as food
technological aspects.
When establishing an MRL, consideration is al so given to residues that occur in food
of plant origin and/or the environment. Furthermore, the MRL may be reduced to be
consistent with good practices in the use of veterinary drugs and to the extent that
practical analytical methods are available.
11
Acceptable Daily Intake (ADI): An estimate by JECFA of the amount of a veterinary
drug, expressed on a body weight basis, t hat can be ingested daily over a lifetime
without appreciable health risk (standard man = 60 kg) (Note - definition previously
established and adopted by the JECFA, which has been modified by the Codex
Committee on Veterinary Drugs in Foods).13
12. In para. 129 and 168 of its Replies to th e Panel's questions, the European Communities
states that "JECFA's traditional mandate does no t allow it to examine all risk management
options but restricts it to either propose MRLs or not." Does Codex have risk management
options other than (1) the establishment of an MRL, (2) the establishment that an MRL is not
necessary, or (3) no recommendation?

The Terms of Reference of the CCRVDF also in clude the development of codes of practice
(Annex 2). The development of a Code of Practice might therefore be considered by the Committee as
a possible option to manage risks related to residues of veterinary drugs.

The CCRVDF, at its 16
th Session, agreed to the preparation of a discussion paper to identify risk
management issues to be addressed by the Commi ttee and re-established the Working Group on
Substance with no ADI/MRL in order to, inter alia, consider management option for compound to be
evaluated by JECFA where a management decision is pending.14

12 Please note that Codex does not adopt ADI. JECFA MRLs and ADI are separate outputs of the risk
assessment process and only JECFA recommendations for MRLs are considered by the Codex process.
13 Glossary of Terms and Definition" (CAC/MISC 5-1993).
14 ALINORM 06/29/31 paras 113 and 134.

15. Please provide the definition of the term Good Veterinary Practice (GVP). Are there
any relevant Codex standards, guidelines, or recommendations relating to GVP?

There is no a Codex definition of the term Good Ve terinary Practice (GVP). Codex has developed a
definition of the term Good Practice in the Use of Veterinary Drug (GPVD) , which is contained in
the Procedural Manual of the Codex Alimentarius Commission (see below).

Good Practice in the Use of Veterinary Drugs (GPVD) is the official recommended
or authorized usage includi ng withdrawal periods, appro ved by national authorities,
of veterinary drugs under practical conditions.
12
Relevant texts related to GPVD include:

– The recommended international " Code of Practice for the Control of the Use of Veterinary
Drugs" (CAC/RCP 38-1993) sets out guidelines on the prescription, application, distribution
and control of drugs used for treating animals, preserving animal health or improving animal
production (see Annex 9);

– Codex Guidelines for the Establishment of a Regulatory Programme for Control of
Veterinary Drug Residues in Foods (CAC/GL 16-1993) (see Annex 10). Please Note that
CCRVDF is currently working on a re vision of the Guidelines (the 16
th Session of CCRVDF
has forwarded a proposed draft of the Guidelines to the 29 th Session of the Codex
Alimentarius Commission for preliminary adoption at Step 5).15

16. Please provide an update on the status of international standards with respect to the six
hormones at issue. What are the remaining pro cedures before the adoption of a standard on
melengestrol acetate (MGA)? What is the timeframe for their completion?

Oestradiol-17β – MRL adopted by the 21 st Session of the Codex Alimentarius Commission (1995);
no more considered since the 12th CCRVDF (2000);

Progesterone – MRL adopted by the 21 st Session of the Codex Alimentarius Commission (1995); no
more considered since the 12th CCRVDF (2000);

Testosterone – MRL adopted by the 21 st Session of the Codex Alimentarius Commission (1995); no
more considered since the 12th CCRVDF (2000);

Trenbolone acetate - MRL adopted by the 21 st Session of the Codex Alimentarius Commission
(1995); no more considered since 7th CCRVDF (1992);

Zeranol - MRL adopted by the 21 st Session of the Codex Alimentarius Commission (1995); no more
considered since 7th CCRVDF (1992);

Melengestrol acetate – Currently under consideration by CCRVDF. Annex 11 provides a
chronological history of the CCRVDF consideration of MGA.

18. What happens if new evidence or studies throw into doubt a Codex standard? What are
the procedures for incorporating more recent developments into Codex work? Has the
European Communities approached Codex for th is purpose with respect to the hormones at
issue in this case?

According to the Procedure of the Elaboration of Codex Standard and Related Texts, it will be for the
Commission itself to keep under review the revision of "Codex standards" (see Annex 1, para. 8) and
instruct Codex subsidiary bodies to undertake th is work. Proposals for new work, including the
revision of Codex Standards, are also submitted to the Commission by a Codex subsidiary body or a
Codex Member.

In the case of estradiol-17 beta, progesterone and te stosterone, they were re-evaluated by the 52 nd
JECFA (1999) at the initiative of the JECFA Secretariat. The 12 th CCRVDF (2000), in recognising
that it had not requested the re-evaluation of the three substances and that the new MRLs
recommended by the 52 nd JECFA did not differ significantly from the current MRLs, decided to not
consider the new recommendation of the 52nd JECFA.16

In the case of MGA, the 58
th JECFA has re-evaluated MGA at the request of the 14 th CCRVDF on the
basis of new information and a dditional data to be submitted.17 During the discussion on MGA at the
16th CCRVDF, there was no request for a further re-evaluation of MGA.18

16 ALINORM 01/31, para. 84.
18 ALINORM 06/29/31, para. 69.

List of Annexes

 Page
Annex 1 Procedures for the Elaboration of Codex Standards and Related Texts
(Procedural Manual of the Codex Alimentarius Commission, 15 th
Edition)
E-14
Annex 2 Terms of reference and meeti ngs records of the Codex Committee on
Residues of Veterinary Drugs in Foods (CCRVDF)
E-23
Annex 3 Measures to Facilitate Consensus (Procedural Manual of the Codex
Alimentarius Commission, 15th Edition)
E-24
Annex 4 General Principles of the Codex A limentarius and Guidelines for the
Acceptance Procedure for Codex Standards (Procedural Manual of the
Codex Alimentarius Commission, 14th Edition)
E-25
Annex 5 SPS Committee's clarification "how the Committee would differentiate
standards, guidelines or recommendations in relation to the
implementation of the SPS Agreement"
E-34
Annex 6 Codex Working Principles for Risk Analysis Application in the
Framework of the Codex Alimentarius (Procedural Manual of the
Codex Alimentarius Commission, 15th Edition)
E-36
Annex 7 Consideration of risk analysis in CCRVDF (history) E-41
Annex 8 Definitions of Risk Analys is Terms Related to Food Safety
(Procedural Manual of the Codex Alimentarius Commission, 15 th
Edition)
E-56
Annex 9 Recommended International Code of Practice for the Control of the
Use of Veterinary Drugs (CAC/RCP 38-1993)
E-58
Annex 10 Codex Guidelines for the Establishmen t of a Regulatory Programme
for Control of Veterinary Drug Residues in Foods (CAC/GL 16-1993)
E-62
Annex 11 Melengestrol acetate – CCRVDF chronology E-103

Other References

Reports of the past sessions (1 st to 16th) of the Codex Committee on Residues of Veterinary Drugs in
Foods

WHO 1995. Application of Risk Analysis to Food Standards Issues . Report of the Joint FAO/WHO
Expert Consultation. Geneva, Switzerland, 13-17 March 1995. WHO/FNU/FOS/95.3

FAO. 1997. Risk management and food safety. Report of a Joint FAO/WHO Consultation. Food and
Nutrition Paper 65. Rome.

FAO. 1999. The application of risk communication to food standards and safety matters . Report of a
Joint FAO/WHO Consultation. Food and Nutrition Paper 70. Rome.

WHO. 2000. The interaction between assessors and manag ers of microbiological hazards in foods .
Report of a WHO expert consultation in collaboration with FAO, Kiel, Germany, 21-23 March 2000.

FAO/WHO. 2002. Principles and guidelines for incorporating microbiological risk assessment in the
development of food safety standards, guidelines and related texts . Report of a joint FAO/WHO
consultation, Kiel , Germany, 18-22 March 2002.

FAO/WHO. 2006 (in preparation). The use of microbiological risk assessment outputs to develop
practical risk management strategies . Report of a joint FAO/WHO meeting, Kiel, Germany,
3-7 April, 2006.

ANNEX 1

PROCEDURES FOR THE ELABORATION OF
CODEX STANDARDS AND RELATED TEXTS1

Note: These procedures apply to the elaboration of Codex standards and relate d texts (e.g, codes of
practice, guidelines) adopted by the Codex A limentarius Commission as recommendations for
governments.

INTRODUCTION

The full procedure for the elaboration of Codex standards is as follows.

1. The Commission shall implement a unified appr oach in the area of standards development by
taking its decisions, based on a strategic planning pr ocess ("standards management") (See Part 1 of
this document).

2. An on-going critical review shall ensure th at proposals for new work and draft standards
submitted to the Commission for adoption continue to meet the strategic priorities of the Commission
and can be developed within a reasonable period of time, taking into account the requirements and
availability of scientific expert advice (See Part 2 of this document).

3. The Commission decides, taking into account the outcome of the on-going critical review
conducted by the Executive Committee, that a sta ndard should be elaborated and also which
subsidiary body or other body should undertake th e work. Decisions to elaborate standards may also
be taken by subsidiary bodies of the Commissi on in accordance with the above-mentioned outcome
subject to subsequent approval by the Commission at the earliest possible opportunity. The Secretariat
arranges for the preparation of a "proposed draft standard" which is circulated to governments for
comments and is then considered in the light of these by the subsidiary body concerned which may
present the text to the Commission as a "draft st andard". If the Commission adopts the "draft
standard" it is sent to governments for further co mments and in the light of these and after further
consideration by the subsidiary body concerned, the Commission reconsiders the draft and may adopt
it as a "Codex standard". The procedure is described in Part 3 of this document.

4. The Commission or any subsidiary body, subject to the confirmation of the Commission may
decide that the urgency of elaborating a Codex st andard is such that an accelerated elaboration
procedure should be followed. While taking this deci sion, all appropriate matt ers shall be taken into
consideration, including the likelihood of new sc ientific information becoming available in the
immediate future. The accelerated elaboration procedure is described in Part 4 of this document.

5. The Commission or the subsidiary body or other body concerned may decide that the draft be
returned for further work at an y appropriate previous Step in the Procedure. The Commission may
also decide that the draft be held at Step 8.

6. The Commission may authorise, on the basis of two-thirds majority of votes cast, the
omission of Steps 6 and 7, where such an omission is recommended by the Codex Committee
entrusted with the elaboration of the draft. R ecommendations to omit steps shall be notified to
Members and interested international organizati ons as soon as possible after the session of the Codex
Committee concerned. When formulating recommendations to omit Steps 6 and 7, Codex Committees
shall take all appropriate matters into consideration, including the need for urgency, and the likelihood
of new scientific information becoming available in the immediate future.

1 Procedural Manual of the Codex Alimentarius Commission (15th Edition).

7. The Commission may at any stage in the el aboration of a standard entrust any of the
remaining Steps to a Codex Committe e or other body different from that to which it was previously
entrusted.

8. It will be for the Commission itself to keep under review the revision of "Codex standards".
The procedure for revision should, mutatis mutandis, be that laid down for the elaboration of Codex
standards, except that the Commission may decide to omit any other step or steps of that Procedure
where, in its opinion, an amendment proposed by a Codex Committee is either of an editorial nature
or of a substantive nature but consequential to provisions in similar standards adopted by the
Commission at Step 8.

9. Codex standards and related texts are publis hed and are sent to governments as well as to
international organizations to which competence in the matter has been transferred by their Member
States (see Part 5 of this document).

PART 1. STRATEGIC PLANNING PROCESS

1. Taking into account the " Criteria for the Establishment of Work Priorities ", the strategic plan
shall state broad priorities against which individual proposals for standards (and revision of standards)
can be evaluated during the critical review process.
2. The strategic plan shall cover a six-year period and shall be renewed every two years on a
rolling basis.

PART 2. CRITICAL REVIEW

Proposals to Undertake New Work or to Revise a Standard

1. Prior to approval for development, each propo sal for new work or revision of a standard, shall
be accompanied by a project document, prepared by the Committee or Member proposing new work
or revision of a standard, detailing:

• the purposes and the scope of the standard;
• its relevance and timeliness;
• the main aspects to be covered;
• an assessment against the Criteria for the establishment of work priorities;
• relevance to the Codex strategic objectives;
• information on the relation between th e proposal and other existing Codex
documents;
• identification of any requirement for and availability of expert scientific advice;
• identification of any need for technical input to the standard from external bodies so
that this can be planned for;
• the proposed time-line for completion the new work, including the start date, the

proposed date for adoption at Step 5, and the proposed date for adoption by the
Commission; the time frame for developing a standard should not normally exceed
five years.
2. The decision to undertake new work or to revi se standards shall be taken by the Commission
taking into account a critical review conducted by the Executive Committee.

3. The critical review includes:

• examination of proposals for development/rev ision of standards, taking into account
the " Criteria for the Establishment of Work Priorities ", the strategic plan of the
Commission and the required supporting work of independent risk assessment;
• identifying the standard setting needs of developing countries;
• advice on establishment and dissolution of committees and task forces, including
ad hoc cross-committee task forces (in area s where work falls within several
committee mandates); and
• preliminary assessment of the need for expert scientific advice and the availability of
such advice from FAO, WHO or other relevant expert bodies, and the prioritisation of
that advice.
4. The decision to undertake new work or re vision of individual maximum residue limits for
pesticides or veterinary drugs, or the mainte nance of the General Standard on Food Additives
2, the
General Standard on Contaminants and Toxins in Foods 3, the Food Categorisation System and the
International Numbering System, shall follow the procedures established by the Committees
concerned and endorsed by the Commission.

Monitoring Progress of Standards Development

5. The Executive Committee shall review the stat us of development of draft standards against
the time frame agreed by the Commission and shall report its findings to the Commission.

6. The Executive Committee may pr opose an extension of the time frame; cancellation of work;
or propose that the work be undertaken by a Commit tee other than the one to which it was originally
entrusted, including the establishment of a limited number of ad hoc subsidiary bodies, if appropriate.

7. The critical review process shall ensure that progress in the development of standards is
consistent with the envisaged time frame, that draft standards submitted to the Commission for
adoption have been fully considered at Committee level.

8. Monitoring shall take place against the ti me line deemed necessary and revisions in the
coverage of the standard shall need to be specifically endorsed by the Commission.

This shall therefore include:

• monitoring of progress in developing standa rds and advising what corrective action
should be taken;

2 including related methods of analysis and sampling plans
3 including related methods of analysis and sampling plans

• examining proposed standards from Codex committees, before they are submitted to
the Commission for adoption:
– for consistency with the mandate of Codex, the decisions of the Commission,
and existing Codex texts,

– to ensure that the requirements of the endorsement procedure have been
fulfilled, where appropriate,

– for format and presentation, and

– for linguistic consistency.

PART 3. UNIFORM PROCEDURE FOR THE ELABORATION OF CODEX STANDARDS
AND RELATED TEXTS

Steps 1, 2 and 3

(1) The Commission decides, taking into account the outcome of the critical review conducted by
the Executive Committee, to ela borate a World-wide Codex Standard and also decides which
subsidiary body or other body should undert ake the work. A decision to elaborate a World-
wide Codex Standard may also be taken by subsidiary bodies of the Commission in
accordance with the above mentioned outcome, subject to subsequent approval by the
Commission at the earliest possible opportunity. In the case of Codex Regional Standards, the
Commission shall base its decision on the proposal of the majority of Members belonging to a
given region or group of countries submitted at a session of the Codex Alimentarius
Commission.

(2) The Secretariat arranges for the preparation of a proposed draft standard. In the case of
Maximum Limits for Residues of Pesticides or Veterinary Drugs, the Secretariat distributes
the recommendations for maximum limits, when available from the Joint Meetings of the
FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO
Core Assessment Group on Pesticide Residu es (JMPR), or the Joint FAO/WHO Expert
Committee on Food Additives (JECFA). Any othe r relevant information regarding risk
assessment work conducted by FAO and WHO shou ld also be made available. In the cases of
milk and milk products or individual standa rds for cheeses, the Secr etariat distributes the
recommendations of the International Dairy Federation (IDF).

(3) The proposed draft standard is sent to Members of the Commission and interested
international organizations for comment on all aspects including possible implications of the
proposed draft standard for their economic interests.

Step 4

The comments received are sent by the Secretariat to the subsidiary body or other body concerned
which has the power to consider such comments and to amend the proposed draft standard.

Step 5

The proposed draft standard is submitted through the Secretariat to the Executive Committee for

critical review and to the Commission with a view to its adoption as a draft standard
4. In taking any
decision at this step, the Commission will give due c onsideration to the outcome of the critical review
and to any comments that may be submitted by any of its Members regarding the implications which
the proposed draft standard or any provisions ther eof may have for their economic interests. In the
case of Regional Standards, all Members of the Co mmission may present their comments, take part in
the debate and propose amendments, but only the ma jority of the Members of the region or group of
countries concerned attending the session can decide to amend or adopt the draft. In taking any
decisions at this step, the Me mbers of the region or group of countries concerned will give due
consideration to any comments that may be subm itted by any of the Members of the Commission
regarding the implications which the proposed draft standard or any provisions thereof may have for
their economic interests.

Step 6

The draft standard is sent by the Secretariat to a ll Members and interested international organizations
for comment on all aspects, including possible implica tions of the draft standard for their economic
interests.

Step 7

The comments received are sent by the Secretariat to the subsidiary body or other body concerned,
which has the power to consider such comments and amend the draft standard.

Step 8

The draft standard is submitted through the Secretar iat to the Executive Committee for critical review
and to the Commission, together with any written proposals r eceived from Members and interested
international organizations for amendments at Step 8, with a view to its adoption as a Codex standard.
In the case of Regional standards, all Members and interested international organizations may present
their comments, take part in the debate and propose amendments but only the majority of Members of
the region or group of countries concerned attending the session can decide to amend and adopt the
draft.

PART 4. UNIFORM ACCELERATED PROCEDURE FOR THE ELABORATION
OF CODEX STANDARDS AND RELATED TEXTS

Steps 1, 2 and 3

(1) The Commission, on the basis of a two-thirds majority of votes cast, taking into account the
outcome of the critical review conducted by the Executive Committee, shall identify those
standards which shall be the subject of an accelerated elaboration process.
5 The identification
of such standards may also be made by subsidiary bodies of the Commission, on the basis of a
two-thirds majority of votes cast, subject to confirmation at the earliest opportunity by the
Commission.

4 Without prejudice to the outcome of the critical review conducted by the Executive Committee and/or
any decision that may be taken by the Commission at Step 5, the proposed draft standard may be sent by the
Secretariat for government comments prior to its consideration at Step 5, when, in the opinion of the subsidiary
body or other body concerned, the time between the relevant session of the Commission and the subsequent
session of the subsidiary body or other body concerned requires such action in order to advance the work
5 Relevant considerations could include, but need not be limited to, matters concerning new scientific
information; new technology(ies); urgent problems related to trade or public health; or the revision or up-dating
of existing standards.

(2) The Secretariat arranges for the preparation of a proposed draft standard. In the case of
Maximum Limits for Residues of Pesticides or Veterinary Drugs, the Secretariat distributes
the recommendations for maximum limits, when available from the Joint Meetings of the
FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO
Core Assessment Group on Pesticide Residu es (JMPR), or the Joint FAO/WHO Expert
Committee on Food Additives (JECFA). Any othe r relevant information regarding risk
assessment work conducted by FAO and WHO should also be made available. In the cases of
milk and milk products or individual standa rds for cheeses, the Secr etariat distributes the
recommendations of the International Dairy Federation (IDF).

(3) The proposed draft standard is sent to Members of the Commission and interested
international organizations for comment on all aspects including possible implications of the
proposed draft standard for their economic inte rests. When standards are subject to an
accelerated procedure, this fact shall be notif ied to the Members of the Commission and the
interested international organizations.

Step 4

The comments received are sent by the Secretariat to the subsidiary body or other body concerned
which has the power to consider such comments and to amend the proposed draft standard.

Step 5

In the case of standards identified as being subject to an accelerated elaboration procedure, the draft
standard is submitted through the Secretariat to the Executive Committee for critical review and to the
Commission, together with any written proposals received from Members and interested international
organizations for amendments, with a view to its adoption as a Codex standard. In taking any decision
at this step, the Commission will give due consid eration to any comments that may be submitted by
any of its Members regarding the implications wh ich the proposed draft standard or any provisions
thereof may have for their economic interests.

PART 5. SUBSEQUENT PROCEDURE CONCERNING PUBLICATION
OF CODEX STANDARDS

The Codex standard is published and issued to all Member States and Associate Members of FAO
and/or WHO and to the international organizations concerned.

The above mentioned publications will constitute the Codex Alimentarius.

SUBSEQUENT PROCEDURE CONCERNING PUBLICATION AND
POSSIBLE EXTENSION OF TERRITORIAL APPLICATION OF THE STANDARD

The Codex Regional Standard is pub lished and issued to all Member States and Associate Members
of FAO and/or WHO and to the international organizations concerned.

It is open to the Commission to consider at a ny time the possible extension of the territorial
application of a Codex Regional Standard or its conversion into a World-wide Codex Standard.

GUIDE TO THE CONSIDERATION OF STANDARDS AT STEP 8 OF THE PROCEDURE
FOR THE ELABORATION OF CODEX STANDARDS INCLUDING CONSIDERATION
OF ANY STATEMENTS RELATING TO ECONOMIC IMPACT

1. In order:

 (a) to ensure that the work of the Codex committee concerned is not made less valuable
by the passage of an insufficiently considered amendment in the Commission;

 (b) at the same time to provide scope for significant amendments to be raised and
considered in the Commission;

 (c) to prevent, as far as practicable, lengthy discussion in the Commission on points that
have been thoroughly argued in the Codex committee concerned;

 (d) to ensure, as far as practicable, that delegations are given sufficient warning of
amendments so that they may brief themselves adequately,

amendments to Codex standards at Step 8 shoul d, as far as practicable, be submitted in writing,
although amendments proposed in the Commission woul d not be excluded entirely, and the following
procedure should be employed:

2. When Codex standards are distributed to Member Countries prior to their consideration by the
Commission at Step 8, the Secretariat will indicate the date by which proposed amendments must be
received; this date will be fixed so as to allow su fficient time for such amendments to be in the hands
of governments not less than one month before the session of the Commission.

3. Governments should submit amendments in writi ng by the date indicated and should state that
they had been previously submitted to the ap propriate Codex committee with details of the
submission of the amendment or should give the reason why the amendment had not been proposed
earlier, as the case may be.

4. When amendments are proposed during a session of the Commission, without prior notice, to
a standard which is at Step 8, the Chairperson of the Commission, after consultation with the
chairperson of the appropriate committee, or, if the ch airperson is not present, with the delegate of the
chairing country, or, in the case of subsidiary bodi es which do not have a chairing country, with other
appropriate persons, shall rule whether such amendments are substantive.

5. If an amendment ruled as substantive is agreed to by the Commission, it shall be referred to
the appropriate Codex committee for its comments a nd, until such comments have been received and
considered by the Commission, the standard shall not be advanced beyond Step 8 of the Procedure.

6. It will be open to any Member of the Commissi on to draw to the attention of the Commission
any matter concerning the possible implications of a draft standard for its economic interests,
including any such matter which has not, in that Me mber's opinion, been satisfactorily resolved at an
earlier step in the Procedure for the Elaboration of Codex Standards. All the information pertaining to
the matter, including the outcome of any previous consideration by the Commission or a subsidiary
body thereof should be presented in writing to the Co mmission, together with any draft amendments
to the standard which would in the opinion of the country concerned, take into account the economic
implications. In considering statements concerning economic im plications the Commission should
have due regard to the purposes of the Codex Alimen tarius concerning the protection of the health of
consumers and the ensuring of fair practices in the food trade, as set forth in the General Principles of
the Codex Alimentarius, as well as the economic interests of the Memb er concerned. It will be open

to the Commission to take any appropriate action including referring the matter to the appropriate
Codex committee for its comments.

GUIDE TO THE PROCEDURE FOR THE REVISION AND AMENDMENT
OF CODEX STANDARDS

1. Proposals for the amendment or revision of Codex standards should be submitted to the
Commission's Secretariat in good time (not less than three months) before the session of the
Commission at which they are to be considered. The proposer of an amendment should indicate the
reasons for the proposed amendment and should also state whether the proposed amendment had been
previously submitted to and considered by the Codex committee concerned and/or the Commission. If
the proposed amendment has already been consider ed by the Codex committee and/or Commission,
the outcome of the consideration of the proposed amendment should be stated.

2. Taking into account such information regard ing the proposed amendment, as may be supplied
in accordance with paragraph 1 above, and the outcome of the on-going critical review conducted by
the Executive Committee, the Commission will decide whether the amendment or revision of a
standard is necessary. If the Commission decid es in the affirmative, and the proposer of the
amendment is other than a Codex committee, the proposed amendment will be referred for
consideration to the appropriate Codex committee, if such committee is still in existence. If such
committee is not in existence, the Commission will determine how best to deal with the proposed
amendment. If the proposer of the amendment is a Codex committee, it would be open to the
Commission to decide that the proposed amendment be circulated to governments for comments prior
to further consideration by the sponsoring Code x Committee. In the case of an amendment proposed
by a Codex Committee, it will also be open to the Commission to adopt the amendment at Step 5 or
Step 8 as appropriate, where in its opinion the amendm ent is either of an editorial nature or of a
substantive nature but consequential to provisions in similar standards adopted by it at Step 8.

3. The procedure for amending or revising a Codex standard would be as laid down in
paragraphs 5 and 6 of the Introduction to the Procedure for the Elaboration of Codex Standards.

4. When the Commission has decided to amend or revise a standard, the unrevised standard will
remain the applicable Codex standard until the revised standard has been adopted by the Commission.

ARRANGEMENTS FOR THE AMENDMENT OF CODEX STANDARDS
ELABORATED BY CODEX COMMITTEES WHICH HAVE ADJOURNED SINE DIE

1. The need to consider amending or revising a dopted Codex standards arises from time to time
for a variety of reasons amongst which can be:

 (a) changes in the evaluation of food additives, pesticides and contaminants;

 (b) finalization of methods of analysis;

 (c) editorial amendments of guidelines or other texts adopted by the Commission and
related to all or a group of Codex sta ndards e.g. "Guidelines on Date Marking",
"Guidelines on Labelling of Non-retail Containers", "Carry-over Principle";

 (d) consequential amendments to earlie r Codex standards arising from Commission
decisions on currently adopted standards of the same type of products;

 (e) consequential and other amendments aris ing from either revised or newly elaborated
Codex standards and other texts of general applicability which have been referenced

in other Codex standards (Revision of General Principles of Food Hygiene, Codex
Standard for the Labelling of Prepackaged Foods);

 (f) technological developments or economic c onsiderations e.g. pr ovisions concerning
styles, packaging media or other factors related to composition and essential quality
criteria and consequential changes in labelling provisions;

2. The "Guide to the Procedure for the Revisi on and Amendment of Codex Standards" covers
sufficiently amendments to Codex standards whic h have been elaborated by still active Codex
Committees. In the case of am endments proposed to Codex standards elaborated by Codex
Committees which have adjourned sine die, the procedure places an obligation on the Commission to
"determine how best to deal with the proposed amendment". In orde r to facilitate consideration of
such amendments, the Commission has establishe d more detailed guidance within the existing
procedure for the amendment and revision of Codex standards.

3. In the case where Codex committees have adjourned sine die:

 (a) the Secretariat keeps under review all Codex standards originating from Codex
Committees adjourned sine die and to determine the need for any amendments arising
from decisions of the Commission, in particular amendments of the type mentioned in
para. 1(a), (b), (c), (d) and those of (e) if of an editorial nature. If a need to amend the
standard appears appropriate then the Secretariat should prepare a text for adoption in
the Commission;

 (b) amendments of the type in para (f) an d those of (e) of a substantive nature, the
Secretariat in cooperation with the national secretariat of the adjourned Committee
and, if possible, the Chairperson of that Committee, should agree on the need for such
an amendment and prepare a working paper containing the wording of a proposed
amendment and the reasons for proposing such amendment, and request comments
from Member Governments: (a) on the need to proceed with such an amendment and
(b) on the proposed amendment itself. If the majority of the replies received from
Member Governments is affirmative on both the need to amend the standard and the
suitability of the proposed wording for the amendment or an alternative proposed
wording, the proposal should be submitted to the Commission with a request to
approve the amendment of the standard concerned. In cases where replies do not
appear to offer an uncontroversial soluti on then the Commission should be informed
accordingly and it would be for the Commission to determine how best to proceed.

ANNEX 2

CODEX COMMITTEE ON RESIDUES OF VETERINARY DRUGS IN FOODS
(CX-730)

Host Government: United States of America

Sessions:

1st Washington, D.C. 27-31 October, 1986

2nd Washington, D.C. 30 November - 4 December 1987

3rd Washington, D.C. 31 October - 4 November 1988

4th Washington, D.C. 24-27 October 1989

5th Washington, D.C. 16-19 October 1990

6th Washington, D.C. 22-25 October 1991

7th Washington, D.C., 20-23 October 1992

8th Washington, D.C., 7-10 June 1994

9th Washington, D.C., 5-8 December 1995

10th San José (Costa Rica), 29 October - 1 November 1996

11th Washington D.C., 15-18 September 1998

12th Washington, D.C., 28-31 March 2000

13th Charleston, South Carolina, 4 - 7 December 2001

14th Arlington, Virginia, 4-7 March 2003

15th Alexandria, Virginia, 26-29 October 2004

Terms of reference:

(a) to determine priorities for the considerati on of residues of veterinary drugs in foods;

(b) to recommend maximum levels of such substances;

(c) to develop codes of practice as may be required;

(d) to consider methods of sampling and analys is for the determination of veterinary drug
residues in foods.

(Extract from the Procedural Manual, 15
th Edition)

ANNEX 3

MEASURES TO FACILITATE CONSENSUS6

The Codex Alimentarius Commission desiring that every effort should be made to reach agreement on
the adoption or amendment of standards by c onsensus, recommends the following measures to
facilitate consensus:

• Refraining from submitting proposals in the step process where the scientific basis is
not well established on current data and, wh ere necessary, carry out further studies in
order to clarify controversial issues;
• Providing for thorough discussions and docum entation of the issues at meetings of
the committees concerned;
• Organizing informal meetings of the parties concerned where disagreements arise,
provided that the objectives of any such meetings are clearly defined by the
Committee concerned and that participation is open to all interest delegations and
observers in order to preserve transparency;
• Redefining, where possible, the scope of the subject matter being considered for the
elaboration of standards in order to cut out issues on which consensus could not be
reached;
• Providing that matters are not progressed from step to step until all relevant concerns
are taken into account and adequate compromises worked out;
• Emphasizing to Committees and their Chairper sons that matters should not be passed
on to the Commission until such time as con sensus has been achieved at the technical
level;
• Facilitating the increased involvement and participation of developing countries.

6 Decision of the 26th Session of the Commission, 2003.

ANNEX 4

GENERAL PRINCIPLES OF THE CODEX ALIMENTARIUS7

PURPOSE OF THE CODEX ALIMENTARIUS

1. The Codex Alimentarius is a collection of in ternationally adopted food standards presented in
a uniform manner. These food standards aim at protecting consumers' h ealth and ensuring fair
practices in the food trade. The Codex Alimentarius also includes provisions of an advisory nature in
the form of codes of practice, guidelines and ot her recommended measures intended to assist in
achieving the purposes of the Codex Alimentarius. The publication of the Codex Alimentarius is
intended to guide and promote the elaboration and establishment of definitions and requirements for
foods to assist in their harmonization and in doing so to facilitate international trade.

SCOPE OF THE CODEX ALIMENTARIUS

2. The Codex Alimentarius includes standards for all the principle foods, whether processed,
semi-processed or raw, for dist ribution to the consumer. Material s for further processing into foods
should be included to the extent necessary to ach ieve the purposes of the Codex Alimentarius as
defined. The Codex Alimentarius includes provisi ons in respect of food hygiene, food additives,
pesticide residues, contaminants, labelling and presentation, methods of analysis and sampling. It also
includes provisions of an advisory nature in th e form of codes of practice, guidelines and other
recommended measures.

NATURE OF CODEX STANDARDS

3. Codex standards contain requirements for food aimed at ensuring for the consumer a sound,
wholesome food product free from adulteration, corr ectly labelled and presented. A Codex standard
for any food or foods should be drawn up in accordance with the Format for Codex Commodity
Standards and contain, as appropriate, the criteria listed therein.

ACCEPTANCE OF CODEX COMMODITY STANDARDS

4.A. A Codex standard may be accepted by a count ry in accordance with its established legal and
administrative procedures in respect of distributio n of the product concerned, whether imported or
home produced, within its territorial jurisdiction in the following ways:

(i) Full acceptance

(a) Full acceptance means that the country concer ned will ensure that a product to which the
standard applies will be permitted to be distri buted freely, in accordance with (c) below,
within its territorial jurisdiction under the na me and description laid down in the standard,
provided that it complies with all the relevant requirements of the standard.

(b) The country will also ensure that products not complying with the standard will not be
permitted to be distributed under the name and description laid down in the standard.

(c) The distribution of any sound products conforming with the st andard will not be hindered by
any legal or administrative provisions in the co untry concerned relating to the health of the

7 Procedural Manual of the Codex Alimentarius Commission (14th Edition).

consumer or to other food sta ndard matters except for consid erations of human, plant or
animal health which are not specifically dealt with in the standard.

(ii) Acceptance with specified deviations

Acceptance with specified deviations means that the country concerned gives acceptance, as defined
in paragraph 4.A(i), to the standard with the excepti on of such deviations as are specified in detail in
its declaration of acceptance; it being understood that a product complying with the standard as
qualified by these deviations will be permitted to be distributed freely within the territorial jurisdiction
of the country concerned. The country concerned will further include in its declaration of acceptance
a statement of the reasons for these deviations, and also indicate:

(a) whether products fully conforming to the st andard may be distributed freely within its
territorial jurisdiction in accordance with paragraph 4.A(i);

(b) whether it expects to be able to give full acceptance to the standard and, if so, when.

(iii) Free distribution

A declaration of free distribution means that the country concerned undertakes that products
conforming with a Codex commodity standard may be distributed freely within its territorial
jurisdiction insofar as matters covered by the Codex commodity standard are concerned.

B. A country which considers that it cannot accept the standard in any of the ways mentioned
above should indicate:

 (i) whether products conforming to the standard may be distributed freely within its
territorial jurisdiction;

 (ii) in what ways its present or proposed requirements differ from the standard, and, if
possible the reasons for these differences.

C. (i) A country which accepts a Codex standard according to one of the provisions of 4.A
is responsible for the uniform and impartial applica tion of the provisions of the standard as accepted,
in respect of all home-produced and imported products distributed within its territorial jurisdiction. In
addition, the country should be prepared to offe r advice and guidance to exporters and processors of
products for export to promote unde rstanding of and compliance with the requirements of importing
countries which have accepted a Codex standard according to one of the provisions of 4.A.

 (ii) Where, in an importing country, a product claimed to be in compliance with a Codex
standard is found not to be in compliance with that standard, whether in respect of the label
accompanying the product or otherwise, the im porting country should inform the competent
authorities in the exporting country of all the relevant facts and in particular the details of the origin of
the product in question (name and address of the e xporter), if it is thought that a person in the
exporting country is responsible for such non-compliance.

ACCEPTANCE OF CODEX GENERAL STANDARDS

5.A. A Codex general standard may be accepted by a country in accordance with its established
legal and administrative procedures in respect of the distribution of products to which the general
standard applies, whether imported or home-produ ced, within its territorial jurisdiction in the
following ways:

(i) Full acceptance

Full acceptance of a general standard means that the country concerned will ensure, within its
territorial jurisdiction, that a product to which th e general standard applies will comply with all the
relevant requirements of the general standard except as otherwise provided in a Codex commodity
standard. It also means that the distribution of any sound products conforming with the standard will
not be hindered by any legal or administrative provisions in the country concerned, which relate to the
health of the consumer or to other food standard matters and which are covered by the requirements of
the general standard.

(ii) Acceptance with specified deviations

Acceptance with specified deviations means that the country concerned gives acceptance, as defined
in paragraph 5.A(i), to the general standard with the exception of such deviations as are specified in
detail in its declaration of acceptance. The country concerned will further include in its declaration of
acceptance a statement of the reasons for these deviations, and also indicate whether it expects to be
able to give full acceptance to the general standard and, if so, when.

(iii) Free distribution

A declaration of free distribution means that the country concerned undertakes that products
conforming with the relevant requirements of a C odex general standard may be distributed freely
within its territorial jurisdiction insofar as matte rs covered by the Code x general standard are
concerned.

B. A country which considers that it cannot accep t the general standard in any of the ways
mentioned above should indicate in what ways its present or proposed requirements differ from the
general standard, and if possible, the reasons for these differences.

C. (i) A country which accepts a general sta ndard according to one of the provisions of
paragraph 5.A is responsible for the uniform and impartial application of the provisions of the
standard as accepted, in respect of all home produ ced and imported products distributed within its
territorial jurisdiction. In addition, the country should be prepared to offer advice and guidance to
exporters and processors of products for export to promote understanding of and compliance with the
requirements of importing countries which have accepted a general st andard according to one of the
provisions of paragraph 5.A.

 (ii) Where, in an importing country, a produc t claimed to be in compliance with a general
standard is found not to be in compliance with that standard, whether in respect of the label
accompanying the product or otherwise, the im porting country should inform the competent
authorities in the exporting country of all the relevant facts and in particular the details of the origin of
the product in question (name and address of the e xporter), if it is thought that a person in the
exporting country is responsible for such non-compliance.

ACCEPTANCE OF CODEX MAXIMUM LIMITS FOR RESIDUES OF PESTICIDES
AND VETERINARY DRUGS IN FOOD

6.A. A Codex maximum limit for residues of p esticides or veterinary drugs in food may be
accepted by a country in accordance with its estab lished legal and administrative procedures in
respect of the distribution within its territorial jurisdiction of (a) home-produced and imported food or
(b) imported food only, to which the Codex maximum li mit applies in the ways set forth below. In
addition, where a Codex maximum limit applies to a group of foods not individually named, a country

accepting such Codex maximum limit in respect of ot her than the group of foods, shall specify the
foods in respect of which the Codex maximum limit is accepted.

(i) Full acceptance

Full acceptance of a Codex maximum limit for residu es of pesticides or veterinary drugs in food
means that the country concerned will ensure, within its territorial jurisdiction, that a food, whether
home-produced or imported, to which the Codex maximu m limit applies, will comply with that limit.
It also means that the distribution of a food co nforming with the Codex maximum limit will not be
hindered by any legal or administrative provisions in the country concerned wh ich relate to matters
covered by the Codex maximum limit.

(ii) Free distribution

A declaration of free distribution means that the country concerned undertakes that products
conforming with the Codex maximum limit for residues of pesticides or veterinary drugs in food may
be distributed freely within its territorial juri sdiction insofar as matters covered by the Codex
maximum limit are concerned.

B. A country which considers that it cannot accept the Codex maximum limit for residues of
pesticides or veterinary drugs in foods in any of the ways mentioned above should indicate in what
ways its present or proposed requirements differ fro m the Codex maximum limit and, if possible, the
reasons for these differences.

C. A country which accepts a Codex maximum limi t for residues of pesticides or veterinary
drugs in food according to one of the provisions of paragraph 6.A should be prepared to offer advice
and guidance to exporters and processors of fo od for export to promote understanding of and
compliance with the requirements of importing countries which have accepted a Codex maximum
limit according to one of the provisions of paragraph 6.A.

D. Where, in an importing country, a food claime d to be in compliance with a Codex maximum
limit is found not to be in compliance with the Codex maximum limit, the importing country should
inform the competent authorities in the exporting country of all the relevant facts and, in particular,
the details of the origin of the food in question (n ame and address of the exporter), if it is thought that
a person in the exporting country is responsible for such non-compliance.

WITHDRAWAL OR AMENDMENT OF ACCEPTANCE

7. The withdrawal or amendment of acceptance of a Codex standard or a Codex maximum limit
for residues of pesticides or veterinary drugs in fo od by a country shall be notified in writing to the
Codex Alimentarius Commission's Secretariat who will inform all Member States and Associate
Members of FAO and WHO of the notification and its date of receipt. The country concerned should
provide the information required under paragraphs 4.A(iii), 5.A(iii), 4.B, 5.B or 6.B above, whichever
is appropriate. It should also give as long a notice of the withdrawal or amendment as is practicable.

REVISION OF CODEX STANDARDS

8. The Codex Alimentarius Commission and its s ubsidiary bodies are committed to revision as
necessary of Codex standards and related texts to en sure that they are consistent with and reflect
current scientific knowledge and other relevant information. When required, a standard or related text
shall be revised or removed using the same proc edures as followed for the elaboration of a new
standard. Each member of the Codex Alimentari us Commission is responsible for identifying, and

presenting to the appropriate committee, any new scien tific and other relevant information which may
warrant revision of any existing Codex standards or related texts.

GUIDELINES FOR THE ACCEPTANCE PROCEDURE FOR CODEX STANDARDS

THE IMPORTANCE OF A RESPONSE TO EVERY NOTIFICATION

1. The Codex Alimentarius is the record of Codex Standards and of acceptances or other
notifications by Member Countries or internationa l organizations to which competence in the matter
has been transferred by their Member States. It is revised regularly to take account of the issue of
new or amended standards and the receipt of notificat ions. It is important that governments respond
to every issue of new or amended standards. G overnments should aim at giving formal acceptance to
the standards. If acceptance or free circulation ca nnot be given unconditiona lly, the deviations or
conditions, and the reasons, can be included in the response. Early and regular responses will ensure
that the Codex Alimentarius can be kept up to da te so as to serve as an i ndispensable reference for
governments and international traders.

2. Governments should ensure that the informati on in the Codex Alimentarius reflects the up to
date position. When changing nati onal laws or practices the need for a notification to the Codex
Secretariat should always be kept in mind.

3. The Codex procedure for elaboration of sta ndards enables governments to participate at all
stages. Governments should be able to make an ear ly response to the issue of a Codex standard and
should do their utmost to be ready to do so.

THE CODEX ALIMENTARIUS: NOT A SUBSTITUTE FOR,
OR ALTERNATIVE TO, REFERRING TO NATIONAL LEGISLATION

4. Every country's laws and administrative proce dures contain provisions which it is essential to
understand and comply with. It is usually the prac tice to take steps to obtain copies of relevant
legislation and/or to obtain professional advice a bout compliance. The Codex Alimentarius is a
comparative record of the substantive similar ities and differences between Codex Standards and
corresponding national legislation. The Codex Sta ndard will not normally deal with general matters
of human, plant or animal health or with trade ma rks. The language which is required on labels will
be a matter for national legislation and so will import licences and other administrative procedures.

5. The responses by governments should show cl early which provisions of the Codex Standard
are identical to, similar to or different from, the related national requirements. General statements that
national laws must be complied with should be avoided or accompanied by details of national
provisions which require attention. Judgement w ill sometimes be required where the national law is
in a different form or where it has different provisions.

OBLIGATIONS UNDER THE ACCEPTANCE PROCEDURE

6. The obligations which a country undertak es under the acceptance procedure are included in
paragraph 4 of the General Principles. Paragr aph 4.A(i)(a) provides for free distribution of
conforming products, 4.A(i)(b) with the need to en sure that products which do not conform may not
be distributed "under the name and description la id down". Paragraph 4.A(i)(c) is a general
requirement not to hinder the distribution of sound products, except for matters relating to human,
plant or animal health, not specifically dealt with in the standard. Similar provisions are included in
Acceptance with Specified Deviations.

7. The essential difference between acceptances a nd notifications of free distribution is that a
country which accepts, undertakes to enforce the Code x standard and to accept all the obligations set
out in the General Principles subject to any specified deviations.

8. The Codex Committee on General Principl es (CCGP) and the Commission (CAC) have
reviewed the acceptance procedure and notificatio ns by governments on a number of occasions.
While recognizing that difficulties can arise from time to time in reconciling the obligations of the
acceptance procedure with the laws and administ rative procedures of a Member Country, the CCGP
and the CAC have determined that the obligations ar e essential to the work and status of the CAC and
that they should not be weakened in any way. The purpose of these guidelines therefore is to assist
governments when they are considering how, in the light of the objectives of the acceptance
procedure, to respond to Codex Standards.

THE RETURN OF THE RESPONSE

9. The principal decision which is required is whether to notify an acceptance according to one
of the methods prescribed, or non acceptance as provide d for in 4.B. Free distribution (4.A(iii)) does
not carry with it the obligation to prevent non c onforming products from being circulated, and it may
be useful in cases where there is no corresponding national standard and no intention to introduce one.

THE NEED FOR AN INFORMED, RESPONSIBLE JUDGEMENT WHEN
COMPARING THE CODEX STANDARD WITH NATIONAL LAWS

10. There will be some occasions when the detail in the Codex Standard is identical with national
laws. Difficulties will arise however when national laws are in a different form, contain different
figures or no figures at all, or in cases where there may be no standard in the country which
corresponds in substance to the Codex Standard. Th e authority responsible for notifying the response
to the CAC is urged to do its best to overcome any such difficulties by the exercise of its best
endeavours and to respond, after such consulta tions as may be appropria te with the national
organizations. The grounds on which the judgement has been based can be made clear in the
notification. It may well be that they will not be such as to justify an acceptance, because of the
obligations to stop the distribution of non conforming products, but a statement of free circulation
should be possible on the basis of the facts and practices of each case. If there was a court decision or
change in the law or practice subsequently, an amending response should be made.

PRESUMPTIVE STANDARDS

11. A presumptive standard is one which is assume d to be the standard in the absence of any
other. (A presumption in law is the assumption of the truth of anything until the contrary is proved.)
Some countries have said that a Codex MRL is the presumptive limit for a pesticide residue.
Countries may be able and willing to regard a C odex Standard as the presumptive standard in cases
where there is no corresponding standard, code of practice or other accepted expression of the "nature,
substance or quality" of the food. A country need not apply the presumption to all the provisions of
the standard if the details of its additives, cont aminants, hygiene or labelling rules are different from
those in the standard. In such a case the provisions in the Codex Standard defining the description,
essential composition and quality factor s relating to the specified name and description could still be
the presumptive standard for those matters.

12. The justification for regarding the Codex Standa rd as a presumptive standard is the fact that it
is the minimum standard for a food elaborated in the CAC "so as to ensure a sound, wholesome
product free from adulteration, correctly labelled and presented". (General Principles, Paragraph 3.)
The word minimum does not have any pejorative c onnotations: it simply means the level of quality

and soundness of a product judged by consensus to be appropriate for trade internationally and
nationally.

13. Whether a presumptive standard would mer it an acceptance would depend on whether the
country concerned could say that non conforming pr oducts could not be distributed under the same
name and description laid down in the standard. However it would enable a declaration of free
circulation to be made and countries are asked to give the idea serious consideration.

FORMAT AND CONTENT OF CODEX STANDARDS

Scope

14. This section, together with the name of the standard and the name and description laid down
in the labelling section, should be examined in order to assess whether the obligations of the
acceptance procedure can properly be accepted.

Description, essential composition and quality factors

15. These sections will define the minimum standard for the food. They will be the most difficult
to address unless by chance the details are virtually identical (i.e. ignoring significant matters of
editorial expression or format). However, a country which has taken part in the elaboration of the
standard either by attending the meetings or by sending comments under the Step Procedure has, no
doubt, consulted national orga nizations on the extent to which the draft provisions in the standard
would be acceptable nationally. This factual inform ation needs to be turned into a formal response
when the standard is sent out fo r acceptance. Countries are asked to do their best to exercise an
informal judgement on lines discussed in Paragraph 7 above. Some of the quality criteria e.g.
allowances for defects may represent good manufacturing pr actice or be left to trade contracts. This
will have to be taken into account. A free distribution response ought to be possible in most cases.

Food Additives

16. The food additives included in the standard ha ve been assessed and cleared by JECFA. The
Commodity Committee and the CCFAC have assessed technological need and safety in use. If
national laws are different, all the detailed differences should be reported. It should be borne in mind,
however, that the aim of international food standardization work is to harmonize policies and attitudes
as much as possible. Therefore every effort should be made to keep deviations to the minimum.

Contaminants

17. If national limits apply they should be quoted if not the same as those laid down in the Codex
Standard. Where general laws about safety, health or nature of the food apply, the limits quoted in the
standard could properly be regarded as repres enting those which are unavoidable in practice and
within safety limits.

Hygiene and Weights and Measures

18. If national requirements are diffe rent they should be reported.

Labelling

19. The General Standard for the Labelling of Prepackaged Foods represen ts the international
consensus on information to be included on the labels of all foods.

20. Governments are exhorted to use the General St andard as a basis for their national legislation
and to keep differences to an absolute minimum esp ecially those of detail or minutiae. Governments
should observe the footnote to the Scope section an d should ensure that all compulsory provisions
relating to presentation of information which are additional to, and different from, those in the
standard should be notified. Any other compulsory provisions in national legislation should also be
notified if they are not provided for in the C odex standard. The labelling provisions in Codex
standards include sections of the revised General Standard by reference. When accepting a Codex
commodity standard, a country which has alread y accepted and responded to the General Standard
can then refer to the terms of that acceptance in any subsequent responses. As much specific
information as is relevant and helpful should be given. In particular, this should include the name and
description relating to the food, the interpretation of any special requirements relating to the law or
custom of the country, any additional details a bout presentation of the mandatory information and
detailed differences if any in the la belling requirements e.g. in relati on to class names, declaration of
added water, declaration of origin. It will be assumed that the language(s) in which the particulars
should be given will be as indicated by national legislation or custom.

Methods of Analysis and Sampling

21. The obligations which a country assumes in accepting the following Codex Defining Methods
of Analysis included in Codex standards are as follows
8:

 (a) Codex Defining Methods of Analysis (Type I) are subject to acceptance by
governments just as are the provisions which they define and which form part of
Codex standards.

 "Full acceptance" of a Codex Defining Me thod means the acceptance that the value
provided for in a Codex standard is defi ned by means of the Codex method. In
determining compliance with the value in the Codex standard, governments undertake
to use the Codex Defining Method, especi ally in cases of disputes involving the
results of analysis.

 "Non acceptance" of Codex Defining Met hod or acceptance of Codex standards with
substantive deviations in the Codex Defining Methods means acceptance of the
Codex standard with specified deviation.

 (b) The "acceptance" of Codex standards containing Codex Reference Methods of
Analysis (Type II) means the recognition th at Codex Reference Methods are methods
the reliability of which has been demons trated on the basis of internationally
acceptable criteria. They are, therefore, ob ligatory for use, i.e. subject to acceptance
by governments, in disputes involving the results of analysis. "Non acceptance" of
the Codex Reference Method or acceptance of Codex standards with substantive
deviations in the Codex Refe rence Methods for use in disputes involving methods of
analysis, should be taken to mean accepta nce of the Codex standard with specified
deviation.

 (c) The "acceptance" of Codex standard s containing Codex Alternative Approved
Methods of Analysis (Type III) means th e recognition that Codex Alternative
Approved Methods are methods the reliabilit y of which has been demonstrated in

8 The Committee on General Principles, when el aborating these Guidelines, noted that the
Classification of Methods was under review by the Codex Committee on Methods of Analysis and Sampling
and that the application of Part (b) particularly could be unnecessarily restrictive.

terms of internationally acceptable criteria. They are recommended for use in food
control, inspection or for regulatory purposes.

 "Non acceptance" of a Codex Alterna tive Approved Method does not constitute a
deviation from the Codex standard.

 (d) Since the reliability of the Tentative Methods (Type IV) has not yet been endorsed by
the Codex Committee on Methods of Analysis and Sampling on the basis of the
internationally accepted criteria, it follows that they cannot be regarded as final
Codex methods. Type IV methods may, eventually become Type I, II or III methods
with the resultant implications regarding the acceptance of Codex methods. Type IV
methods are, therefore, not recommended as Codex methods until their reliability has
been recognized by the CCMAS. They may be included in draft Codex standards or
in Codex standards provided their non approved status is clearly indicated.

SUMMARY

22. Governments are urged to respond to every i ssue of Codex standards. The inclusion of
responses in the Codex Alimentarius will enable the CAC and Member Governments to address the
question of closer approximation of international and national requirements. Governments are urged
to take the Codex standard fully into considera tion when changing their national laws. The Codex
Alimentarius will always be an invaluable refe rence for governments and for international traders
although national legislation must always be consulted and complied with.

ANNEX 5

SPS Committee's clarification "how the Committee would differentiate standards, guidelines or
recommendations in relation to the implementation of the SPS Agreement"

Geneva, 19 March 1998
Dear Mr. Orriss,

Your letter of 29 September 1997 was discussed by the Committee on Sanitary and Phytosanitary
Measures ("the Committee") at its meetings of October 1997 and Marc h 1998. The Committee
instructed me to forward to you the following response.

By way of background, it must be clearly understood that the Committee cannot formally interpret the
provisions of the SPS Agreement. This can be done only by the WTO Ministerial Conference or
General Council, or indirectly through the dispute set tlement process with regard to particular cases.
Nonetheless, the Committee is required to carry out the functions necessary to implement the
Agreement and the furtherance of its objectives a nd thus may express views, where appropriate, on
the meaning of particular terms and provisions of the Agreement.

With respect to your first question on "how the Committee would differentiate standards, guidelines
or recommendations in relation to the implemen tation of the SPS Agreement", Annex A of the
SPS Agreement defines international standards, guidelines and recommendations as follows:

"(a) for food safety, the standards, guidelin es and recommendations established by the Codex
Alimentarius Commission relating to food addi tives, veterinary drug and pesticide residues,
contaminants, methods of analysis and sampling, and codes and guidelines of hygienic practice; ..."

This definition makes no distinction between st andards, guidelines and recommendations. The SPS
Agreement does not provide specific definitions for the terms "standards", "guidelines" or
"recommendations".

Throughout the text of the SPS Agreement, the terms "international standards, guidelines or
recommendations" always appear together. Article 3.1 of the SPS Agreement states that "[t]o
harmonize sanitary and phytosanitary measures on as wide a basis as possible, Members shall base
their sanitary or phytosanitary measures on international standards, guidelines or
recommendations ...". Article 3.2 indicates that san itary measures which "... conform to international
standards, guidelines or recommendations shall be deemed to be necessary to protect human, animal
or plant life or health, and presumed to be consistent with the relevant provisions of this Agreement ...
". Article 3.3 provides that "Mem bers may introduce or maintain sa nitary or phytosanitary measures
which result in a higher level of sanitary or phytosanitary protection than would be achieved by
measures based on the relevant inte rnational standards, guidelines or recommendations, if there is a
scientific justification ...". In no case do these provisions differentiate between the three terms
"standards", "guidelines" or "recommendations".

The Committee noted that there is no legal oblig ation on Members to apply Codex standards,
guidelines and recommendations and, in accordance with the terms of Article 3 of the SPS
Agreement, Members may choose to apply them or not. The Committee observed that how a Codex
text was applied depended on its s ubstantive content rather than the category of that text (e.g.,
commodity standards, MRLs, codes of practice, guidelines). This might have some bearing on how a
Member could show that its measure is based on an international standard, guideline or
recommendation in the context of Article 3 of the SPS Agreement. For example, a Codex standard,
such as an MRL which represented a specific numeric value, may provide a higher degree of precision

than much of the content of a guideline or other Codex text. On the other hand, the Committee
considered that guidelines and recommendations are intended to allow greater discretion as to the
choice of measures which can be regarded as be ing based on the guideline or recommendation.
However, the Committee was of the view that Codex wo rk should not be constrained by this question.
The Committee considers it to be an internal decision of the Codex Alimentarius Commission
regarding the type and content of the texts it develops to address issues before it.

With respect to your second question on "the stat us the Committee would assign to Codex regional
standards and related texts", in its discussions Members noted that regional standards are not included
in the definition of international standards provide d by Annex A of the SPS Agreement, cited above.
The Committee recognized that, even if they were based on scientific evidence, regional standards
were meant to apply only within a particular geographic region. Howe ver, Members do recognize
that such scientifically-sound regional standards could become the foundation for the creation and
adoption of international standards.

 Yours sincerely,

 Alex Thiermann
 Chairman
 Committee on Sanitary and Phytosanitary Measures

ANNEX 6

WORKING PRINCIPLES FOR RISK ANALYSIS FOR APPLICATION
IN THE FRAMEWORK OF THE CODEX ALIMENTARIUS

SCOPE

1) These principles for risk analysis are intended for application in the framework of the Codex
Alimentarius.

2) The objective of these Working Principles is to provide guidance to the Codex Alimentarius
Commission and the joint FAO/WHO expert bodies and consultations, so that food safety and health
aspects of Codex standards and related texts are based on risk analysis.

3) Within the framework of the Codex Alim entarius Commission and its procedures, the
responsibility for providing advice on risk manageme nt lies with the Commission and its subsidiary
bodies (risk managers), while the responsibility fo r risk assessment lies primarily with the joint
FAO/WHO expert bodies and consultations (risk assessors).

RISK ANALYSIS - GENERAL ASPECTS

4) The risk analysis used in Codex should be:

 – applied consistently;

 – open, transparent and documented;

 – conducted in accordance with both the Statements of Principle Concerning the Role
of Science in the Codex Decision-Making Process and the Extent to Which Other
Factors are Taken into Account and the Statem ents of Principle Relating to the Role
of Food Safety Risk Assessment; and

 – evaluated and reviewed as appropriate in the light of newly generated scientific data.

5) The risk analysis should follo w a structured approach comprising the three distinct but closely
linked components of risk analysis (risk assessmen t, risk management and risk communication) as
defined by the Codex Alimentarius Commission
9, each component being integral to the overall risk
analysis.

6) The three components of risk analysis should be documented fully and systematically in a
transparent manner. While respecting legitimate c oncerns to preserve confidentiality, documentation
should be accessible to all interested parties
10.

7) Effective communication and consultation with all interested parties should be ensured
throughout the risk analysis.

9 See Definitions of Risk Analysis Terms Related to Food Safety, Codex Alimentarius Commission
Procedural Manual.
10 For the purpose of the present document, the term "i nterested parties" refers to "risk assessors, risk
managers, consumers, industry, the academic community and, as appropriate, other relevant parties and their
representative organizations" (see definition of "Risk Communication")

8) The three components of risk analysis should be applied within an overarching framework for
management of food related risks to human health.

9) There should be a functional separation of risk assessment and risk ma nagement, in order to
ensure the scientific integrity of the risk assessment, to avoid c onfusion over the functions to be
performed by risk assessors and risk managers and to reduce any conflict of interest. However, it is
recognized that risk analysis is an iterative pro cess, and interaction between risk managers and risk
assessors is essential for practical application.

10) When there is evidence that a risk to human health exists but scientific data are insufficient or
incomplete, the Codex Alimentarius Commission s hould not proceed to elaborate a standard but
should consider elaborating a related text, such as a code of practice, provided that such a text would
be supported by the available scientific evidence.
11

11) Precaution is an inherent element of risk an alysis. Many sources of uncertainty exist in the
process of risk assessment and risk management of food related hazards to human health. The degree
of uncertainty and variability in the available scien tific information should be explicitly considered in
the risk analysis. Where there is sufficient scientific evidence to allow Codex to proceed to elaborate a
standard or related text, the assumptions used for the risk assessment and the risk management options
selected should reflect the degree of uncertainty and the characteristics of the hazard.

12) The needs and situations of developing count ries should be specifically identified and taken
into account by the responsible bodies in the different stages of the risk analysis.

RISK ASSESSMENT POLICY

13) Determination of risk assessment policy shou ld be included as a specific component of risk
management.

14) Risk assessment policy should be established by risk managers in advance of risk assessment,
in consultation with risk assessors a nd all other interested parties. This procedure aims at ensuring
that the risk assessment is systematic, complete, unbiased and transparent.

15) The mandate given by risk managers to risk assessors should be as clear as possible.

16) Where necessary, risk managers should ask risk assessors to evaluate the potential changes in
risk resulting from different risk management options.

RISK ASSESSMENT
12

17) The scope and purpose of the particular risk assessment being carried out should be clearly
stated and in accordance with risk assessment policy. The output form and possible alternative outputs
of the risk assessment should be defined

18) Experts responsible for risk assessment shoul d be selected in a transparent manner on the
basis of their expertise, experience, and their inde pendence with regard to the interests involved. The
procedures used to select these experts should be documented including a public declaration of any
potential conflict of interest. This declaration should also identify and detail their individual expertise,
experience and independence. Expert bodies and consultations should ensure effective participation of
experts from different parts of the world, including experts from developing countries.

11 Statement adopted by the 24th Session of the Commission (ALINORM 01/41, paras. 81-83)
12 Reference is made to the Statements of Principle Relating to the Role of Food Safety Risk Assessment

19) Risk assessment should be conducted in accordance with the Statements of Principle Relating
to the Role of Food Safety Risk Assessment and should incorporate the four steps of the risk
assessment, i.e. hazard identification, hazard characterization, exposure assessment and risk
characterization.

20) Risk assessment should be based on all ava ilable scientific data. It should use available
quantitative information to the greatest extent possi ble. Risk assessment may also take into account
qualitative information.

21) Risk assessment should take into account rele vant production, storage and handling practices
used throughout the food chain including traditio nal practices, methods of analysis, sampling and
inspection and the prevalence of specific adverse health effects.

22) Risk assessment should seek and incorporate rele vant data from different parts of the world,
including that from developing countries. These da ta should particularly include epidemiological
surveillance data, analytical and exposure data. Where relevant data are not available from developing
countries, the Commission should request that FAO/WHO initiate time-bound studies for this
purpose. The conduct of the risk assessment should not be inappropriately delayed pending receipt of
these data; however, the risk assessment should be reconsidered when such data are available.

23) Constraints, uncertainties and assumptions havi ng an impact on the risk assessment should be
explicitly considered at each step in the risk assessment and documented in a transparent manner.
Expression of uncertainty or variability in risk estimates may be qualitative or quantitative, but should
be quantified to the extent that is scientifically achievable.

24) Risk assessments should be based on realistic exposure scenarios, with consideration of
different situations being define d by risk assessment policy. They should include consideration of
susceptible and high-risk population groups. Acute, ch ronic (including long-term), cumulative and/or
combined adverse health effects should be taken into account in carrying out risk assessment, where
relevant.

25) The report of the risk assessment should indi cate any constraints, uncertainties, assumptions
and their impact on the risk assessment. Minority opinions should also be recorded. The
responsibility for resolving the impact of uncertain ty on the risk management decision lies with the
risk manager, not the risk assessors.

26) The conclusion of the risk assessment including a risk estimate, if available, should be
presented in a readily understandable and useful form to risk managers and made available to other
risk assessors and interested parties so that they can review the assessment.

RISK MANAGEMENT

27) While recognizing the dual pur poses of the Codex Alimentarius are protecting the health of
consumers and ensuring fair practices in the fo od trade, Codex decisions and recommendations on
risk management should have as their primary objec tive the protection of the health of consumers.
Unjustified differences in the leve l of consumer health protection to address similar risks in different
situations should be avoided.

28) Risk management should follow a structured approach including preliminary risk
management activities 13, evaluation of risk management op tions, monitoring and review of the
decision taken. The decisions should be based on risk assessment, and taking into account, where
appropriate, other legitimate factors relevant for the health protection of consumers and for the
promotion of fair practices in food trade, in accordance with the Criteria for the Consideration of the
Other Factors Referred to in the Second Statement of Principles 14.

29) The Codex Alimentarius Commi ssion and its subsidiary bodies, acting as risk managers in the
context of these Working Principles, should ensure that the conclusion of the risk assessment is
presented before making final proposals or decision s on the available risk management options, in
particular in the setting of standards or maximu m levels, bearing in mind the guidance given in
paragraph 10.

30) In achieving agreed outcomes, risk manageme nt should take into account relevant production,
storage and handling practices used throughout the food chain including traditional practices, methods
of analysis, sampling and inspection, feasibility of enforcement and compliance, and the prevalence of
specific adverse health effects.

31) The risk management process should be transp arent, consistent and fully documented. Codex
decisions and recommendations on risk management should be documented, and where appropriate
clearly identified in individual Codex standard s and related texts so as to facilitate a wider
understanding of the risk management process by all interested parties.

32) The outcome of the preliminary risk management activities and the risk assessment should be
combined with the evaluation of available risk management options in order to reach a decision on
management of the risk.

33) Risk management options should be assessed in terms of the scope and purpose of risk
analysis and the level of consumer health protec tion they achieve. The option of not taking any action
should also be considered.

34) In order to avoid unjustified trade barriers, risk management should ensure transparency and
consistency in the decision-making process in a ll cases. Examination of the full range of risk
management options should, as far as possible, ta ke into account an assessment of their potential
advantages and disadvantages. When making a ch oice among different risk management options,
which are equally effective in protecting the h ealth of the consumer, the Commission and its
subsidiary bodies should seek and take into consid eration the potential impact of such measures on
trade among its Member countries and select measu res that are no more trade-restrictive than
necessary.

35) Risk management should take into account the economic consequences and the feasibility of
risk management options. Risk management should al so recognize the need for alternative options in
the establishment of standards, guidelines and othe r recommendations, consistent with the protection
of consumers' health. In taking these elements into consideration, the Commission and its subsidiary
bodies should give particular attention to the circumstances of developing countries.

13 For the purpose of these Principles, preliminary risk management activities are taken to include:
identification of a food safety problem; establishment of a risk profile; ranking of the hazard for risk assessment
and risk management priority; establishment of risk assessment policy for the conduct of the risk assessment;
commissioning of the risk assessment; and consideration of the result of the risk assessment.
14 These criteria have been adopted by the 24 th Session of the Commission (see Procedural Manual 12th
Edition - Appendix, page 165)

36) Risk management should be a continuing pro cess that takes into account all newly generated
data in the evaluation and review of risk mana gement decisions. Food standards and related texts
should be reviewed regularly and updated as neces sary to reflect new scientific knowledge and other
information relevant to risk analysis.

RISK COMMUNICATION

37) Risk communication should:

 (i) promote awareness and understanding of the specific issues under consideration
during the risk analysis;

 (ii) promote consistency and transparency in formulating risk management
options/recommendations;

 (iii) provide a sound basis for understandi ng the risk management decisions proposed;

 (iv) improve the overall effectiveness and efficiency of the risk analysis;

 (v) strengthen the working re lationships among participants;

 (vi) foster public understanding of the pro cess, so as to enhance trust and confidence in
the safety of the food supply;

 (vii) promote the appropriate involveme nt of all interested parties; and

 (viii) exchange information in relation to the concerns of interested parties about the risks
associated with food.

38) Risk analysis should include clear, interactive and documented communication, amongst risk
assessors (Joint FAO/WHO expert bodies and consulta tions) and risk managers (Codex Alimentarius
Commission and its subsidiary bodies), and recipro cal communication with member countries and all
interested parties in all aspects of the process.

39) Risk communication should be more than th e dissemination of information. Its major function
should be to ensure that all information and opi nion required for effective risk management is
incorporated into the decision making process.

40) Risk communication involving interested parties should include a transparent explanation of
the risk assessment policy and of the assessment of risk, including the uncertainty. The need for
specific standards or related texts and the proce dures followed to determine them, including how the
uncertainty was dealt with, should also be clearly explained. It should indicate any constraints,
uncertainties, assumptions and their impact on the risk analysis, and minority opinions that had been
expressed in the course of the risk assessment (see para.25).

41) The guidance on risk communication in this document is addressed to all those involved in
carrying out risk analysis within the framework of Codex Alimentarius. However, it is also of
importance for this work to be made as transpar ent and accessible as possible to those not directly
engaged in the process and other interested partie s while respecting legitimate concerns to preserve
confidentiality (See para. 6).

ANNEX 7

Consideration of Risk Analysis in CCRVDF
(relevant extracts from the report of the CCRVDF)

8
th Session of CCRVDF (June 1994) (ALINORM 95/31, paras 39-41)

At the request of the 20
th Session of the Commission (1993) a paper entitled Risk Assessment
Procedures Used by the Codex Alimentarius Commission and its Subsidiary an Advisory Bodies
(ALINORM 93/37), prepared by a consultant Dr. S. Hathaway (New Zealand) was reviewed and
discussed by the Committee.

39. The Committee supported the principles of the Hathaway paper and the view that the
establishment of MRLs for residues of veterinary drugs should continued to be linked to the risk-
based ADI (Acceptable Daily Intake). In this re gard the Committee noted that its procedures and
those of JECFA were in general consistent with the principles enunciated in the paper.

40. The Committee also agreed in principles that the use of risk analysis procedures should be
extended further in the Codex Procedures for the ela boration of standards. So me delegations were of
the opinion that the roles of the expert committ ees and the Codex committees in regard to risk
assessment and risk management respectively should be clarified. However, it was noted that the
overall Codex procedures had to ta ke into account those Committees such as Food Hygiene and Meat
Hygiene which did not receive independent external advise on a regular basis.

41. The Committee expressed concern at the fact th at the use of the various expression used by
Codex in relation to risk analysis had not been ha rmonised. It considered that further progress would
be greatly assisted by having agreed Definitions for Codex purposes. It recommended the Executive
Committee that such definitions be elaborated as a matter of priority in accordance with the new
Accelerated ("Fast Track") Procedure with a view to their adoption by the CAC at its 21
st Session.
The Committee proposed that the definitions contained in Appendix IX to the present report should be
sent to governments for comments and also consid ered by other relevant Codex Committees. It
emphasized that any definitions adopted by the Commission should be harmonised to the extent
possible with those of other relevant international organizations, for example, the OIE.

9
th Session of CCRVDF (December 1995) (ALINORM 97/31, para. 14)

At its 9th Session, at the request of the 21 st Session of the Commission (1995) examined the report of
the Joint FAO/WHO Expert Consultation on the Application of Risk Analysis to Food Standards
Issues (Geneva, Switzerland, 13-17 March 1995).

14. The Committee supported the incorporation of a science-based approach to risk analysis into
its work, and agreed that a discussion paper would be developed under the direction of France, with
assistance provided by Australia, Canada, the Neth erlands, New Zealand, Norway and the United
States, for consideration at its 10
th Session. The paper should address the possible implementation of
the recommendations of the FAO/WHO Expert Consulta tion of the Application of Risk Analysis to
Food Standards Issues as they applied to the wo rk of CCRVDF, and to consider initiatives undertaken
by other Codex Committees.

10
th Session of CCRVDF (October 1996) (ALINORM 97/31A, paras 9-13)

Following the decision of its 9
th Session, the 10 th Session of the Committee considered the paper by
France to address the implementation of the Consu ltation's recommendations as they applied to the
work of the Committee.

9. The Committee expressed its appreciation of the thorough analysis presented in the discussion
paper. It noted that the development of risk analysis in Codex and in its work was an on-going process
and that the analysis presented both a report of th e current status and issues which needed to be
addressed in the future. It concurred with the main conclusions of the paper, namely that the process
of establishing MRLs for veterinary drugs incorporat ed various the stages of risk assessment very
well, and that a number of elements relating to ri sk management were integrated. It noted that the
recommendation made by the 1995 Joint FAO/WHO E xpert Consultation to separate the risk
assessment and the risk management processes was th erefore not being curren tly followed in this
process.

10. To the extent that it was possible to cont rol strictly the conditions under which veterinary
drugs were used, and food taken from treated anim als could be collected, the Committee considered
whether the results of the MRL-setting process was not so much as to evaluate a risk which would be
socially acceptable, but to minimize risks associated with the presence of drug residues in food stuffs.
However, the Committee further recognised the need to delineate more fully the risk assessment and
the risk management of the process, and noted that government regulatory agencies and other played a
major role in risk management of drug residues in foods.

11. The Committee identified several issues wh ich required further attention, specifically:

• Better delineation of the respective roles of the Committee and JECFA;
• Improvement of transparency of the process;
• Recognition that the application of safety factors and other conventions to address
uncertainty were not strictly scientifically based and therefore introduced an element
of risk management into the risk assessment process;
• Consideration of the benefits of the use of veterinary drugs as well as risks, for
animals as well as humans;
• Problems in relation to animal studies and the potential of using in vitro studies as
alternative for such studies;
• Problems related to the generation of residue data for minor species, and;
• Problems related to old substances whic h had not been evaluated under modern
criteria, but which were still in use in many countries, and substances on the so-called
"inactive list".
12. The Committee agreed to refer its main findings to the Commission, but noting the
forthcoming Expert Consultations of the Applica tion of Risk management to Food safety Matters
(Rome 28-31 January 1997) and on Food Consum ption and Risk Assessment (Geneva,
10-14 February 1997), indicated its intention to ci rculate a revised paper for comments incorporating
the issues raised at the present session and th e outcome of these Consultations and of the
Commission's deliberations. In the meantime, dele gations were encouraged to send comments on the

discussion paper directly to the Delegation of Fr ance. The Committee welcomed the offer of the
French Delegation to revise the document accordingly.

13. The Committee agreed to review developments in risk analysis at its next Session following
consideration of this matter by the Commission.

11
th Session of CCRVDF (September 1998) (ALINORM 99/31, paras 43-44)

At its 11
th Session, the Committee considered the revised "Discussion paper on Risk Analysis in the
Codex Committee on Residues of Veterinary Drugs in Foods" (CX/RVDF 98/4)

43. The revised paper was presented by Dr J. Boi sseau (France). He noted that the paper had been
expanded to take into account the recommendations of the FAO/WHO consultations, particularly
those on risk management and risk communication. He reviewed the three elements of risk analysis as
they pertain to this Committee and in particular, not ed that issues related to risk assessment would
require the development of risk assessment policie s., In the interest of transparency, these policies
should be made explicit.

44. Several delegations congratulated the French Delegation on its excellent work. Due to the late
availability of the document, an in-depth discu ssion of the paper was not possible, The Committee
agreed to append the document to its report (see Ap pendix IX) for circulation and comments, with the
understanding that France would take the lead in revision the paper on the basis of the above
discussion and comments submitted for further considera tion at its next meeting. The Delegations of
the Netherlands, New Zealand, Sweden, th e United Kingdom and the United States and
representatives if Consumers International, COMISA , WHO and WHA agreed to assist France in this
effort. In revising the paper, the Committee also requested that the document include specific risk
assessment policy issues that may need to be addressed.

12
th Session of CCRVDF (March 2000) (ALINORM 01/31, paras 15-19)

At its 12
th Session, the Committee considered risk analysis principles and methodologies of the Codex
Committee on Residues of Veterinary Drugs in Foods (CX/RVDF 00/3 "Overview and discussion on
risk analysis by the 23 rd Session of the Commission" and CX/RVDF 00/3, Add.1 "Risk Analysis
Principles and Methodologies of the Codex Committ ee on Residues of Veterinary Drugs in Foods –
Elaboration of a Risk Assessment Policy by the CCRVDF").

15. The Committee noted and welcomed the recommendation of the 23
rd Session of the
Commission in relation to principles of risk analysis addressed to the Codex Alimentarius
Commission and its subsidiary bodies, gove rnments, and FAO and WHO. Among those
recommendations relevant to the work of this Committee, the Committee agreed that it would
consider, pending the preparation of a discussion pape r: (1) the development and application of risk
analysis principles and methodologies appropriate to the specific mandate within the framework of the
Action Plan; and (2) development of quality criteria fo r data used for risk assessment. It took note, for
implementation as appropriate, of the recommendations regarding the appointment of a developing
country(ies) as co-author(s) for positions papers; b asing risk assessment on global data including that
from developing countries; taking into account the ec onomic consequences and the feasibility of risk
management options in developing countries; and c onsideration of acute aspects of dietary exposure
to chemicals in foods. It also took note of the recommendations to increase interaction and
communication between expert bodies and the Codex Committees.

16. The Delegation of France introduces the pa per CX/RVDF 00/3-Add.1. It was stated that
comments had been received on the text containe d in Appendix IX of ALINORM 99/31 only from
Consumers International and therefore the text had not been revised. The Delegation mentioned that

the Committee had not yet established risk assessment policy which was a component of risk
management and the work should be done urgently on this issue. It was proposed that since the issue
was very technical and complex, in order to facilitate discussion on the plenary, a drafting group
should be formed to prepare a discussion paper containing solid recommendations regarding risk
analysis principles and methodologies including ri sk assessment policy. For this purpose, the
Delegation drew the attention of the Committee to existing reference documen ts of JECFA relevant
to the issue.

17. A number of delegations supported the crea tion of a drafting group. Several delegation and
one observer stated that the paper prepared for the last session contained useful information that
should be used as a basis for further development.

18. A delegation stated that risk management was the function of Codex Committees and national
governments, the leadership in this work should be taken by this Co mmittee; and all efforts should be
made to encourage developing countries to take part in the draft. Another delegation proposed that
information should be requested from all concerned on subjects to be included in the paper in addition
to what has been done by JECFA.

19. The Committee agreed that a drafting group (A ustralia, Brazil, Canada, Chile, France, Japan,
Mexico, Netherlands, New Zealand, Philippines, Poland, Sweden, Switzerland, Thailand, United
States, JECFA Secretariat, European Commun ity, OIE, WHO, Consumers International and
COMISA) led by France and Poland would prepare a discussion paper for government comments well
before the next session of the Committee. In order to facilitate the drafting process, member countries
were invited to provide comments and information rele vant to the subject to France. It was mentioned
that the drafting process should be accelerated buy using modern communication technologies. It was
noted that the process of drafting the paper should be as transparent as possible.

13
th Session of CCRVDF (December 2001) (ALINORM 03/31, paras 65-70)

At its 13
th Session, the Committee considered a document on Risk Analysis Principles and
Methodologies of the Codex Committee on Residues of Veterinary Drugs in Foods (CX/RVDF 01/9)
and noted the recommendation of the 24
th Session of the Commission that relevant Codex committees
should continue to develop and document the application of risk analysis in their work.

65. The Committee was also inform ed of the Commission request to FAO and WHO to convene a
consultation to review the status and procedures of expert bodies and to develop recommendations for
consideration by the Directors-General on additi onal ways to improve the quality, quantity and
timeliness of scientific advice to the Commission. It was noted that this review would include the
examination of increased coordination between th e JECFA, JMPR and other groups devoted to
microbiological contamination and biotechnology on matters including selection and establishment of
a roster of experts for such bodies, including increased transparency in the process.

66. In presenting the Discussion Paper, the de legation of France noted that the document
contained three major sections, namely: a backgro und section describing the major elements of risk
analysis and their relation to the mandates of CCRVDF and JECFA; Annex I – Establishment by
CCRVDF of a Risk Assessment Policy for the Setti ng of Maximum Residue Limits for Veterinary
Drugs in Foods; and, Annex II - Risk Management and Codex Procedures fo r Establishing MRLs of
Veterinary Medicinal Products. The delegation of France noted th at Annex I examined various
aspects of risk assessment which need to be addressed in taking risk management decisions within the
CCRVDF and contained a list of questions to JECFA to be answered at various steps of JECFA
evaluation, including outstanding issues related to the harmonization of risk assessments between
JECFA and JMPR as well as between CCRVDF and CCPR; the extrapolation of MRLs to minor
species and the importance of criteria concerning the protection of public health and the promotion of

fair trading practices when prioritizing compounds for JECFA review. It was noted that Annex II
contained four recommendations related to the un certainty of whether or not a substance to be
considered should be marketed or not; the importa nce of prioritizing compounds for reasons of public
health protection as well as for the promotion of trad e and the availability of a dossier for evaluation;
the importance of the availability of JECFA reports in a timely manner; and, the elaboration of risk
management principles and criteria.

67. The Committee confirmed that in undertaking its responsibilities related to risk analysis it was
necessary to formulate a coherent risk assessment policy so that sound risk management decisions
could be taken in the elaboration of MRLVDs and the scientific integrity of JECFA would be
protected and for transparency. It was noted that notwithstanding the independence of JECFA, this
would allow the Committee to take a full role in th e consideration of JECFA evaluations and in this
regard, it was suggested that Annex I could be exam ined at the next JECFA Meeting. It was noted
that Annex I could provide the basis for the futu re development of a risk assessment policy which
would facilitate discussions and relations with JECFA in the establishment of MRLVDs.

68. Although the Committee did not reach any fina l conclusion on Annex 1, it was decided to
forward Annex I of the document to FAO and WHO, so that it would be taken into consideration in a
joint project to update and consolidate principl es and methodologies of risk assessment and that
JECFA would review and comment back to the CCR VDF, with the understanding that these issues
would be further considered by the CCRVDF at its next Session. It was noted that the review could
greatly contribute to increased communication and tr ansparency between risk assessors and managers
and would help the Committee in defining risk assess ment policies and risk management guidelines
related to the establishment of MRLVDs.

69. The Committee generally agreed that risk management methodologies including policies for
risk assessment and risk management, be drafted to address the needs of the Codex Alimentarius
Commission pertaining to the activities of this Committee. The Committee concluded that the
delegation of France, with the assistance of Austra lia, Brazil, Canada, Chile, China, Indonesia, Japan,
Korea, Mexico, the Netherlands, New Zealand, Ph ilippines, Poland, Sweden, Switzerland, Thailand,
United States, CI, EC, FAO, IFAH, OIE and WHO, would elaborate an internal policy document on
"Risk Management Methodologies, including Risk Assessment Policies, in the Codex Committee on
Residues of Veterinary Drugs in Foods" consid ering Annex II of CX/RVDF 01/9 and the comments
of JECFA on Annex I of CX/RVDF 01/9. It was agreed that the paper should address the written
comments submitted as well as issues raised at the curre nt meeting under agenda items 9, 11 and 13
that were relevant to risk analysis. The Committee agreed that the document should be circulated for
comment and further consideration at its next m eeting, and with the understanding that the policy
document would remain as internal guidance to the CCRVDF.

70. It was further agreed that the drafting group w ould also consider risk management options for
substances which were on the past agendas of JECFA but for which no ADI or MRLs had been
recommended due to various reasons, including insuffici ent or lack of data or where no sponsor was
identified.

14
th Session of CCRVDF (March 2003) (ALINORM 03/31A, paras 91 and 94-96)

At its 14
th Session, the Committee considered the revi sed discussion paper on risk management
methodologies, including risk assessment policies (C X/RVDF 03/8) that described the mandate, the
role of various parties with responsibilities in risk assessment and risk management and the steps of
risk management in CCRVDF. The paper also prov ided practical recommendations to the questions
raised by the CCRVDF regarding the need to accelerate the establishment of MRLVDs, the
interactions between risk assessors and risk mana gers; the establishment of criteria and methods to
propose temporary ADIs, and; the substances with no acceptable ADI and/or MRLs .

91. The Committee expressed general support for the document prepared by France as the
recommendations adequately addressed issues related to the application of risk analysis policy, the
efficiency of the work of CCRVDF and the propo sal of Thailand. It was recommended to better
specify the responsibilities of risk managers and ri sk assessors, their interac tive mechanisms and the
communication aspects in recommendations 3, 5, 6, and 7 and to highlight the primary purpose of
protecting consumers health in the establishment of MRLVDs.

94. The Committee considered the further developm ent of the discussion paper. Some delegations
suggested to follow an approach similar to the Codex Committees on Pesticide Residues and on Food
Additives and Contaminants and to consider the deve lopment of a dynamic document for internal use
of the Committee and in consideration of the furt her development of specific guidelines for risk
analysis.

95. The Committee agreed that a working group (lead by France, and with the assistance of
Australia, Canada, China, Costa Rica, Italy, Kor ea, The Netherlands, New Zealand, Poland, Spain,
Switzerland, Thailand, United Kingdom, United St ates, Consumers International, European
Commission, FAO, IFAH, OIE and WHO) would prepare a revised version of the discussion paper on
"Risk Management Methodologies, including Risk Assessment Policies in the Codex Committee on
Residues of Veterinary Drugs in Foods" for circulation, additional comments and further
consideration at its 15
th Session. The Committee accepted the ki nd offer of the European Community
to possibly host a meeting of the working group in Brussels to discuss the further development of the
document.

96. The Committee agreed that the revised doc ument should specifically address the issue of
substances with no ADI and/or MRL, should ta ke account of the above discussion, the written
comments submitted at the current meeting and the comments of the 60
th meeting of JECFA on
Annex I of CX/RVDF 01/9.

15
th Session of CCRVDF (October 2004) (ALINORM 05/28/31, paras 141-153)

At its 15
th Session, the Committee considered and review ed the internal policy document on risk
management methodologies, including risk asse ssment policies (CX/RVDF 04/15/08), which was
prepared by the drafting group on the basis of the document presented at its previous session and the
comments provided by JECFA.

141. The Committee had an extensive discussion on the need for communication strategies for risk
analysis. Several delegations stressed the need for better communication between risk assessors and
risk managers. The Observer from Consumers Inte rnational expressed the view that communication
with the public was an essential aspect of risk an alysis in order to ensure public confidence in the
process. The Delegation of the European Commun ity expressed the view that the document should
concentrate on communication between risk assessors and risk managers and that communication
with the public might be better addressed by national governments.

142. The JECFA Secretariat highlighted the im portance of adequate risk communication,
especially if new procedures were developed for risk analysis of veterinary drugs, and in the case of
substances that currently had no ADI or MRLs.

143. The Committee agreed that risk communication strategies should be further considered in the
development of the document, and noted that the section on Risk Communication in the Working
Principles for Risk Analysis in the Fr amework of the Codex Alimentarius could be taken into account
in the process.

144. In reply to a question on risk assessment procedures, the Representatives of FAO and WHO
informed the Committee that the procedures of JECF A and JMPR were in the process of review and
would be available upon completion of the Joint FAO/WHO Project to Update the Principles and
Methods for the Risk Assessment of Chemicals in Foods, scheduled fo r 2005. It was noted that what
constitute Good Veterinary Practices, as applied to milk withdrawal time, should be considered a
component of the risk management process.

Risk Management in the CCRVDF

Identification of a Food Safety Problem

145. The Committee noted that to be consistent w ith the mandate of the Codex Alimentarius, food
safety needs and public health concerns (parag raphs 11 and 13), trade issues of relevance for
governments should also be identified.

146. The Committee noted the written comments of Argentina, which was not present at the
meeting, concerning intellectual property in paragraph 12. In this resp ect, the Secretariat informed the
Committee that the Working Principles for Risk Analysis in the Framework of the Codex Alimentarius
(paragraph 6) addressed the issue of confidentiality as related to the accessibility of documentation.

147. Some delegations and the Observer from IFAH expressed the view that what constituted
"documentation" for the purpose of risk analysis s hould be more clearly defi ned and that intellectual
property issues should be further clarified.

148. The JECFA Secretariat recalled that procedures existed to ensure confidentiality of
proprietary information in JECFA but that toxicological information was published in the report of the
risk assessment.

149. The Committee agreed that a risk assessment policy should be established and the issue of
"drugs with a long history of use" should be a ddressed, and noted that this was related to the
establishment of lists of substances of interest to member governments that would be considered in
the discussion on priorities (see also Agenda Item 12).

150. Regarding the provisions on the risk profile in paragraph 16, the JECFA Secretariat clarified
that the qualitative risk profile should be provided by the delegation that initially proposed the
substance for evaluation, in reply to the questionnaire sent to request comments on priorities.

Monitoring and review of the decisions taken

151. The Committee agreed that a list of veterina ry drugs for which no ADI or MRL had been
established should be compiled and discussed whethe r a policy should be established concerning the
status of that list but did not come to a conclusion. Some delegations pointed out that the absence of a
MRL did not directly relate to a food safety issue, as in some cases MRLs had not been established,
due to insufficient data or lack of data for minor species. In reply to a question, the JECFA Secretariat
indicated that a Summary of JECFA Evaluations of Veterinary Drugs Residues from the 32
nd Meeting
to the present (62 nd Meeting) had been published in the document FAO FNP 41/16. This document
also contains a list of compounds which have been evaluated by JECFA but for which an ADI and/or
MRL was not recommended.

152. The Committee recalled the request of the Commission for Codex Co mmittees to complete
their work on guidelines on risk an alysis in their respective areas a nd agreed that the discussion paper
should be redrafted as a working document for inclusi on in the Procedural Manual, with a view to its

finalization at the next session. The Committee ag reed that the document was being developed in
response to a direct request of the Commission and did not need to go through the Step Procedure.

153. The Committee agreed that the document shoul d be redrafted by the Delegation of France
with the assistance of a working group
15 taking into account the written comments, the discussion at
the present session, and the recommendations of the Joint FAO/WHO Technical Workshop on
Residues of Veterinary Drugs without ADI/MRL, wh ere applicable. It requested the Working Group
to submit the revised version by September 2005, for comments and consideration by the next session.

16
th Session of CCRVDF (May 2006) (ALINORM 06/29/31, para. 111 and Appendices VII and IX)

At its 16 th Session, the Committee considered the revised paper on risk management methodologies
(CX/RVDF 06/16/10) which included two texts on: Risk Analysis Methodologies in the Codex
Committee on Residues of Veterinary Drugs in Food s and Risk Assessment Policy for the Setting of
MRLs in Food.

111. The Committee agreed to forw ard the renamed Risk Analysis Principles applied by the Codex
Committee on Residues of Veterinary Drugs in Foods and the Risk Assessment Policy for the Setting
of MRLs in Food to the Codex Alimentarius Commission, through the Codex Committee on General
Principles, for adoption and inclusion in the Codex Procedural Manual (see Appendices VIII and IX).

ALINORM 06/29/31, Appendix VIII

PROPOSED DRAFT
RISK ANALYSIS PRINCIPLES APPLIED BY THE CODEX COMMITTEE
ON RESIDUES OF VETERINARY DRUGS IN FOODS
(for inclusion in the Codex Procedural Manual)

1. PURPOSE – SCOPE

1. The purpose of this document is to specify Risk Analysis Principles applied by the Codex
Committee on Residues of Veterinary Drugs in Foods.

2. PARTIES INVOLVED

2. The Working Principles for Risk Analysis for application in the framework of the Codex
Alimentarius
16 has defined the responsibilities of the vari ous parties involved. The responsibility for
providing advice on risk management concerning resi dues of veterinary drugs lies with the Codex
Alimentarius Commission (CAC) and its subsidia ry body, the Codex Co mmittee on Residues of
Veterinary Drugs in Foods (CCRDVF), while the responsibility for risk assessment lies primarily with
the Joint FAO/WHO Expert Committee on Food Additives (JECFA).

3. According to its mandate, the responsibilities of CCRVDF regarding veterinary drug residues
in food are:

15 Australia, Burkina Faso, Brazil, Canada, China, Colombia, Costa Rica, European Community, Japan,
Korea, Malaysia, Netherlands, Sw itzerland, Sweden, Thailand, United States, ALA, CI, IFAH, OIE, and
OIRSA
16 Codex Procedural Manual, 15th Edition page 101 (English version).

 (a) to determine priorities for the considera tion of residues of veterinary drugs in foods;

 (b) to recommend MRLs for such veterinary drugs;

 (c) to develop codes of practice as may be required;

 (d) to consider whether available methods of sampling and analysis for the determination
of veterinary drug residues in foods.

4. CCRVDF shall base its risk management recommendations to the Codex Alimentarius
Commission (CAC) on JECFA's risk assessments of veterinary drugs in relation to proposed MRLs.

5. CCRVDF is primarily responsible for recommending risk management proposals for adoption
by the Codex Alimentarius Commission (CAC).

6. JECFA is primarily responsible for provi ding independent scientific advice, the risk
assessment, upon which CCRVDF base their risk ma nagement decisions. It assists the CCRVDF by
evaluating the available scientific data on the ve terinary drug prioritised by CCRVDF. JECFA also
provides advice directly to FAO and WHO and to Member governments.

7. Scientific experts from JECFA are selected in a transparent manner by FAO and WHO under
their rules for expert committees on the basis of the competence, expertise, experience in the
evaluation of compounds used as veterinary drugs and their independence with regard to the interests
involved, taking into account geographical representation where possible.

3. RISK MANAGEMENT IN CCRVDF

8. Risk management should follow a structured approach including:

 – preliminary risk management activities;

 – evaluation of risk management options; and

 – monitoring and review of decisions taken.

9. The decisions should be based on risk assess ment, and take into account, where appropriate,
other legitimate factors relevant for the health prot ection of consumers and for fair practices in food
trade, in accordance with the Criteria for the Consideration of the Other Factors Referred to in the
Second Statement of Principles
17.

3.1 PRELIMINARY RISK MANAGEMENT ACTIVITIES

10. This first phase of risk management covers:

 – Establishment of risk assessment policy for the conduct of the risk assessments;

 – Identification of a food safety problem;

 – Establishment of a preliminary risk profile;

 – Ranking of the hazard for risk assessment and risk management priority;

17 Codex Procedural Manual, 15th Edition page 159 (English version)

 – Commissioning of the risk assessment; and

 – Consideration of the result of the risk assessment.

3.1.1 Risk Assessment Policy for the Conduct of the Risk Assessment

11. The responsibilities of CCRVDF and JECFA and th eir interactions along with core principles
and expectations of JECFA evaluations are provided in Risk Assessment Policy for the Setting of
MRLs in Food, established by the Codex alimentarius Commission.

3.1.2 Identification of a Food Safety Problem (establishment of the priority list)

12. CCRVDF identifies, with the assistance of Me mbers, the veterinary drugs that may pose a
consumer safety problem and/or have a potential adverse impact on international trade. CCRVDF
establishes a priority list for assessment by JECFA.

13. In order to appear on the priority list of ve terinary drugs for the establishment of a maximum
residue limit (MRL), the proposed veterinary drug shall meet some or all of the following criteria:

 – A Member has proposed the compound for evaluation;

 – A Member has established good veterinary practices with regard to the compound;

 – The compound has the potential to cause pub lic health and/or international trade
problems;

 – It is available as a commercial product; and

 – There is a commitment that a dossier will be made available.

14. The CCRVDF takes into account the protecti on of confidential information in accordance
with WTO rules article 39, and makes every effort to encourage the willingness of sponsors to provide
data for JECFA assessment.

3.1.3 Establishment of a Preliminary Risk Profile

15. Member(s) request(s) the inclusion of a veteri nary drug on the priority list. The available
information for evaluating the request shall be provi ded either directly by the Member(s) or by the
sponsor. A preliminary risk profile shall be developed by the Member(s) making the request, using the
template presented in the ANNEX.

16. The CCRVDF considers the preliminary risk profile and makes a decision on whether or not
to include the veterinary drug in the priority list.

3.1.4 Ranking of the Hazard for Risk Assessment and Risk Management Priority

17. The CCRVDF establishes an ad-hoc Working Group open to all its Members and observers,
to make recommendations on the veterinary drugs to in clude into (or to remove from) the priority list
of veterinary drugs for the JECFA assessmen t. The CCRVDF considers these recommendations
before agreeing on the priority list. taking into account pending issues such as temporary Acceptable
Daily Intakes (ADIs) and/or MRLs. In its report, the CCRVDF shall specify the reasons for its choice
and the criteria used to establish the order of priority.

18. Prior to development of MRLs for new veteri nary drugs not previously evaluated by JECFA,
a proposal for this work shall be sent to the C odex Alimentarius Commission with a request for
approval as new work in accordance with the Procedures for the Elaboration of Codex Standards and
Related Texts.18

3.1.5 Commissioning of the Risk Assessment

19. After approval by the Codex Alimentarius Co mmission of the priority list of veterinary drugs
as new work, the CCRVDF forwards it to the JECFA with the qualitative preliminary risk profile as
well as specific guidance on the CCRVDF risk assessment request. JECFA, WHO and FAO experts
then proceed with the assessment of risks rela ted to these veterinary drugs, based on the dossier
provided and/or all other available scientific information.

3.1.6 Consideration of the Result of the Risk Assessment

20. When the JECFA risk assessment is comple ted, a detailed report is prepared for the
subsequent session of the CCRVDF for consideration. This report shall clearly indicate the choices
made during the risk assessment with respect to scien tific uncertainties and the level of confidence in
the studies provided.

21. When the data are insufficient, JECFA may recommend temporary MRL on the basis of a
temporary ADI using additional safety considerations
19. If JECFA cannot propose an ADI and/or
MRLs due to lack of data, its report should clearly indicate the gaps and a timeframe in which data
should be submitted, in order to allow Members to make an appropriate risk management decision.

22. The JECFA assessment reports related to th e concerned veterinary drugs should be made
available in sufficient time prior to a CCRVDF m eeting to allow for careful consideration by
Members. If this is, in exceptional cases not possible, a provisional report should be made available.

23. The JECFA should, if necessary, propose differe nt risk management options. In consequence,
JECFA should present, in its report, different risk management options for CCRVDF to consider. The
reporting format should clearly distinguish between th e risk assessment and the evaluation of the risk
management options.

24. The CCRVDF may ask JECFA any additional explanation.

25. Reasons, discussions and conc lusions (or the absence thereo f) on risk assessment should be
clearly documented, in JECFA reports, for each option reviewed. The risk management decision taken
by CCRVDF (or the absence thereof) should also be fully documented.

3.2 EVALUATION OF RISK MANAGEMENT OPTIONS

26. The CCRVDF shall proceed with a critical evaluation of the JECFA proposals on MRLs and
may consider other legitimate factors relevant fo r health protection and fair trade practices in the
framework of the risk analysis. According to the 2nd statement of principle, the criteria for the
consideration of other factors s hould be taken into account. These other legitimate factors are those
agreed during the 12
th session of the CCRVDF 20 and subsequent amendments made by this
Committee.

18 Codex Procedural Manual, 15th Edition pages 19-30 (English version).
19 Codex Procedural Manual, 15th Edition page 45 (English version).
20 See Report of the 12th session of the CCRVDF ALINORM 01/31 para 11.

27. The CCRVDF either recommends the MRLs as proposed by JECFA, modifies them in
consideration of other legitimate factors, considers other measures or asks JECFA for reconsideration
of the residue evaluation for the veterinary drug in question.

28. Particular attention should be given to ava ilability of analytical methods used for residue
detection.

3.3 MONITORING AND REVIEW OF THE DECISIONS TAKEN

29. Members may ask for the review of decisions taken by the Codex Alimentarius Commission.
To this end, veterinary drugs should be proposed for in clusion in the priority list. In particular, review
of decisions may be necessary if they po se difficulties in the application of the Guidelines for the
Establishment of a Regulatory Program for the Control of Veterinary Drug Residues in Foods.

30. CCRVDF may request JECFA to review any new scientific knowledge and other information
relevant to risk assessment and concerning decisions already taken, including the established MRLs.

31. The risk assessment policy for MRL shall be reconsidered based on new issues and
experience with the risk analysis of veterinary drugs . To this end, interaction with JECFA is essential.
A review may be undertaken of the veterinary drugs appearing on prior JECFA agendas for which no
ADI or MRL has been recommended.

4. RISK COMMUNICATION IN THE CONTEXT OF RISK MANAGEMENT

32. In accordance with the Working Principles for Risk Anal ysis for Application in the
Framework of the Codex Alimentarius
21, the CCRVDF, in cooperation with JECFA, shall ensure that
the risk analysis process is fully transparent and thoroughly documented and that results are made
available in a timely manner to Members. The CCRVDF recognises that communication between risk
assessors and risk managers is critical to the success of risk analysis activities.

33. In order to ensure the transparency of the assessment process in JECFA, the CCRVDF
provides comments on the guidelines related to assess ment procedures being drafted or published by
JECFA.

ANNEX

TEMPLATE FOR INFORMATION NECESSARY FOR PRIORITIZATION BY CCRVDF

Administrative information

1. Member(s) submitting the request for inclusion

2. Veterinary drug names

3. Trade names

4. Chemical names

5. Names and addresses of basic producers

21 Codex Procedural Manual, 15th Edition page 161 (English version).

Purpose, scope and rationale

6. Identification of the food safety issue (residue hazard)

7. Assessment against the criteria for the inclusion on the priority list

Risk profile elements

8. Justification for use

9. Veterinary use pattern

10. Commodities for which Codex MRLs are required

Risk assessment needs and questions for the risk assessors

11. Identify the feasibility that su ch an evaluation can be carried out in a reasonable framework

12. Specific request to risk assessors

Available information
22

13. Countries where the veterinary drugs is registered

14. National/Regional MRLs or a ny other applicable tolerances

15. List of data (pharmacology, toxicology, meta bolism, residue depletion, analytical methods)
available

Timetable

16. Date when data coul d be submitted to JECFA

ALINORM 06/29/31, Appendix IX

PROPOSED DRAFT
RISK ASSESSMENT POLICY FOR THE SETTING OF MRLS IN FOOD
(for inclusion in the Codex Procedural Manual)

ROLE OF JECFA

1. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) is an independent
scientific expert body convened by both Director Generals of FAO and WHO according to the rules

22 When preparing a preliminary risk profile, Memb er(s) should take into account the updated data
requirement, to enable evaluation of a veterinary drug for the establishment of an ADI and MRLs, published by
JECFA.

of both organizations, charged with the task to pr ovide scientific advice on veterinary drug residues in
food.

2. This annex applies to the work of JECFA in the context of Codex and in particular as it
relates to advice requests from CCRVDF

 (a) JECFA provides CCRVDF with scien ce-based risk assessments conducted in
accordance with the Statements of principles relating to the role of food safety risk
assessment
23 and incorporating the four steps of risk assessment. JECFA should
continue to use its risk assessment pr ocess for establishing ADIs and proposing
MRLs.

 (b) JECFA should take into account all ava ilable scientific data to establish its risk
assessment. It should use available quantita tive information to the greatest extent
possible and also qualitative information.

 (c) Constraints, uncertainties and assumptions that have an impact on the risk assessment
need be clearly communicated by JECFA.

 (d) JECFA should provide CCRVDF with info rmation on the applicability, public health
consequences and any constraints of the risk assessment to the general population and
to particular sub-populations and, as far as possible, should identify potential risks to
specific group of populations of potentially enhanced vulnerability (e.g. children).

 (e) Risk assessment should be based on realistic exposure scenarios.

 (f) When the veterinary drug is used both in veterinary medicine and as a pesticide, a
harmonised approach between JECFA and JMPR should be followed.

 (g) MRLs, that are compatible with the ADI, should be set for all species based on
appropriate consumption figures. When requested by CCRVDF, extension of MRLs
between species will be considered if appropriate data are available.

DATA PROTECTION

3. Considering the importance of intellectual pr operty in the context of data submission for
scientific evaluation, JECFA has established procedur es to cover the confidentiality of certain data
submitted. These procedures enable the sponsor to declare which data is to be considered as
confidential. The procedure includes a formal consultation with the sponsor.

EXPRESSION OF RISK ASSESSMENT RESULTS IN TERMS OF MRLS

4. MRLs have to be established for target an imal tissues (e.g. muscle, fat, or fat and skin,
kidney, liver), and specific food commodities (e.g. eggs, milk, honey) originating from the target
animals species to which a veterinary drug can be administered according to good veterinary practice.

5. However, if residue levels in various target tissues are very different, JECFA is requested to
consider MRLs for a minimum of two. In this case, the establishment of MRLs for muscle or fat is
preferred to enable the control of the safety of carcasses moving in international trade.

23 Codex Procedural Manual 15th Edition page 161 (English version).

6. When the calculation of MRLs to be compa tible with the ADI may be associated with a
lengthy withdrawal period, JECFA should clearly describe the situation in its report.

ANNEX 8

DEFINITIONS OF RISK ANALYSIS TERMS RELATED TO FOOD SAFETY24

Hazard: A biological, chemical or physical agent in, or condition of, food with the potential to cause
an adverse health effect.

Risk: A function of the probability of an adverse hea lth effect and the severity of that effect,
consequential to a hazard(s) in food.

Risk Analysis: A process consisting of three components: risk assessment, risk management and risk
communication.

Risk Assessment : A scientifically based process consisting of the following steps: (i) hazard
identification, (ii) hazard characterization, (iii) exposure assessment, and (iv) risk characterization.

Risk Management : The process, distinct from risk assessment, of weighing policy alternatives, in
consultation with all interested parties, consideri ng risk assessment and other factors relevant for the
health protection of consumers and for the promotion of fair trade practices, and, if needed, selecting
appropriate prevention and control options.

Risk Communication : The interactive exchange of information and opinions throughout the risk
analysis process concerning risk, risk-related factors and risk perceptions, among risk assessors, risk
managers, consumers, industry, the academic communi ty and other interested parties, including the
explanation of risk assessment findings and the basis of risk management decisions.

Risk Assessment Policy : Documented guidelines on the choice of options and associated judgements
for their application at appropriate decision points in the risk assessment such that the scientific
integrity of the process is maintained.

Risk Profile: The description of the food safety problem and its context.

Risk Characterization : The qualitative and/or quantitative estimation, including attendant
uncertainties, of the probability of occurrence a nd severity of known or potential adverse health
effects in a given population based on hazard iden tification, hazard characterization and exposure
assessment.

Risk Estimate: The quantitative estimation of risk resulting from risk characterization.

Hazard Identification : The identification of biological, chem ical, and physical agents capable of
causing adverse health effects and which may be present in a particular food or group of foods.

Hazard Characterization: The qualitative and/or quantitative evalua tion of the nature of the adverse
health effects associated with biol ogical, chemical and physical agents which may be present in food.
For chemical agents, a dose-response assessment s hould be performed. For biological or physical
agents, a dose-response assessment should be performed if the data are obtainable.

Dose-Response Assessment : The determination of the relationship between the magnitude of
exposure (dose) to a chemical, biological or phy sical agent and the severity and/or frequency of
associated adverse health effects (response).

24 Procedural Manual of the Codex Alimentarius Commission (15th Edition).

Exposure Assessment: The qualitative and/or quantitative evaluation of the likely intake of biological,
chemical, and physical agents via food as well as exposures from other sources if relevant.

Food Safety Objective (FSO): The maximum frequency and/or concentration of a hazard in a food at
the time of consumption that provides or contributes to the appropriate level of protection (ALOP).

Performance Criterion (PC) : The effect in frequency and/or conc entration of a hazard in a food that
must be achieved by the application of one or more control measures to provide or contribute to a PO
or an FSO.

Performance Objective (PO): The maximum frequency and/or concentration of a hazard in a food at a
specified step in the food chain before the time of consumption that provides or contributes to an FSO
or ALOP, as applicable.

ANNEX 9

RECOMMENDED INTERNATIONAL CODE OF PRACTICE FOR
CONTROL OF THE USE OF VETERINARY DRUGS

CAC/RCP 38-1993

INTRODUCTION

1. This Code sets out guidelines on the prescripti on, application, distribution and control of
drugs used for treating animals, preserving animal health or improving animal production. The Code
is intended to apply to all States which are memb ers of the organizations under whose auspices the
project is being developed and to contribute towards the protection of public health.

2. Good practice in the use of veterinary drugs (GPVD), as defined by the CCRVDF, is the
official recommended or authorized usage incl uding withdrawal periods , approved by national
authorities, of veterinary drugs under practical cond itions. The maximum residue limit for veterinary
drugs (MRLVD) may be reduced to be consistent w ith good practice in the use of veterinary drugs.
The MRLVD is based on the type and amount of r esidue considered to be without toxicological
hazard for human health while taking into account ot her relevant public health risks as well as food
technological aspects.

3. Veterinary products (including premixes for manufacture of medicated feedingstuffs) used in
food producing animals should be administered (or in corporated into feed) in compliance with the
relevant product information approved by national authorities and/or in accordance with a prescription
and/or instruction issued by a qualified veterinarian.

REGISTRATION AND DISTRIBUTION - GENERAL REQUIREMENTS

4. All medicinal products (i.e., all veterinary therapeutic products) and medicinal premixes for
inclusion in animal feeds should comply with th e OIE Code of Practice for the Registration of
Veterinary Drugs and be registered with the nationa l authority. Products should only be distributed
through veterinarians, registered wholesalers, pharm acists or other retail ou tlets permitted by national
laws and regulations. Records of products taken in to and leaving the premises should be maintained.
Storage and transport conditions must conform to the specifications on the label, in particular those
concerning temperature, humidity, light, etc.

RESPONSIBILITY OF THE VETERINARIAN AND OF OTHERS AUTHORIZED TO
HANDLE OR ADMINISTER MEDICINES - GENERAL PROVISIONS

5. Whenever veterinary drugs are handled or administered it is important to recognize that
potentially hazardous effects may occur in animals or in human operators. When the administration
of a medicine is not under direct veterinary s upervision, it is therefore essential that, after the
diagnosis, clear instructions s hould be provided on dose and methods of use, taking account of the
competence of the user performing the work and ensuring that the correct calculation of, and the
importance of adhering to, withdrawal periods is fully understood. It is similarly important to ensure
that the farm facilities and management systems em ployed enable the withdrawal periods to be
observed.

6. In determining treatments, it is necessary to en sure that an accurate diagnosis is obtained and
be guided by the principles of maximum effect iveness combined with minimum risk. Specific

treatments should be presented using as few products as possible and avoiding the use of combination
products, unless pharmacological advantages have been demonstrated.

7. Veterinarians should keep in mind that unc ontrolled and unlimited use of medicinal products
may lead to the accumulation of undesirable residues in the animals treated and in the environment,
and that the continuous use of anticoccidial, an tibacterial or anthelmintic products may favour the
development of resistance. It is the responsibility of the veterinarian or other authorized persons to
draw up programmes of preventive medicine for th e farmer and to stress the importance of sound
management and good husba ndry procedures in order to reduce the likelihood of animal diseases.
Every effort should be made to use only those dr ugs known to be effective in treating the specific
disease.

8. The veterinarian should stress the need fo r diseased animals to be segregated from healthy
animals and treated individually where possible.

9. Beyond his responsibility for advice on measur es that will reduce the incidence of disease and
for controlling it when it arises, the veterinarian is also responsible for taking the welfare of livestock
fully into account.

INFORMATION OF VETERINARY DRUGS

10. Product information considered essential by the national authority to ensure the safe and
effective use of veterinary medicinal products must be made available in the form of labelling, data
sheets or leaflets. Information on dosage schedules should be complemented by instructions on
dose-related recommended withdrawal periods, in teractions, contra-indi cations and any other
constraints on the use of the product including any precautions regarded as necessary.

AMOUNTS TO BE SUPPLIED

11. Medicines should not be supplied in excess of immediate requirements as this may lead to
incorrect use or to deterioration of the products.

PREPARATION OF MEDICINES

12. The preparation of medicines and medicated feeds should be undertaken by suitably trained
personnel, using appropriate techniques and equipment.

ADMINISTRATION OF MEDICINES

13. Special attention should be paid to the prescr iption and to using the correct dosage, site and
route of administration. Note should be take n of all warning statements, interactions and
contra-indications for use (in particular any incomp atibility with other medici nal products). It is
important not to use the product once the expiry date has passed.

14. In disease circumstances where no authorized prod uct exists or certain indications or target
species are not provided for in the product literature , the veterinarian can on his own responsibility or
with advice from the manufacturer have recourse to other licensed products or off label use.
Administration of products in this manner, however, may have unpredictable side effects and give rise
to unacceptable residue levels. Veterinarians should therefore only embark on such uses, especially in
food-producing animals, after the most careful consideration of the needs of the disease situation.
Under these circumstances, a significantly extended withdrawal time should be assigned for drug
withdrawal prior to marketing milk, meat or eggs . The veterinarian is responsible for providing
written instructions on the use and withdrawal times fo r all medicines used off label. Off label use by

persons other than veterinarians must not be permitted except when such use is conducted or
permitted under the supervision or prescription of the veterinarian.

15. To avoid the presence of unacceptable residues in meat or other by-products of animal origin,
it is essential that the livestock owner adheres to the withdrawal period la id down for each product
and dose regime or to a suitably lengthy withdrawal period, prescribed by a veterinarian, where none
is specified. Full instructions should be given as to how this period is to be observed, including the
use of on site residue detection methods where applicable and on the disposal of any animals
slaughtered during treatment or before the end of th e withdrawal period. If animals are sold before
the end of the withdrawal period, the buyer must be informed.

RECORD KEEPING REQUIREMENTS

16. The veterinarian and/or the livestock owner or other authorized persons should keep a record
of the products used, including the quantity, the da te of administration and the identity of animals on
which the medicines were used. E ach record should be kept for at least two years, and presented
when required by the competent authorities.

WITHDRAWAL OF VETERINARY DRUGS

17. Where the veterinarian or other authorized person suspects that unexpected adverse reactions
involving illness, abnormal clinical signs, or death in animals, or any harmful effects in persons
administering veterinary medicines have been associ ated with a veterinary product, they should be
reported to the appropriate national authority. Regular feed-back or information to veterinarians and
manufacturers on suspected adverse reactions should be encouraged.

STORAGE OF VETERINARY DRUGS

18. Veterinary products s hould be correctly stored in accord ance with label instructions. It
should be kept in mind that storage temperatures are critical for some medicines, while exposure to
light or to moisture can damage others. Prescription medicines should be separated from
non-prescription medicines.

19. All veterinary products shoul d be stored in secure premis es and kept under lock and key
where practicable and out of reach of children and animals.

DISPOSAL OF VETERINARY DRUGS

20. Veterinary drugs remaining after treatment h as been completed must be disposed of safely
according to labelled instructions. Partially used c ontainers should not be retained for future use.
Unused drugs beyond their expiry date may howe ver be returned to the vendor if there is an
agreement to that effect. Where administrati on of medicines is not under direct veterinary
supervision, users should be advised about corr ect disposal measures, e.g., to reduce potential
contamination of the environment.

DISPOSAL AND CLEANING OF DRUG ADMINISTRATION EQUIPMENT

21. Disposable equipment used for administration of veterinary drugs must be disposed of safely
and in accordance with correct disposal proce dures. Where drugs are not administered under
veterinary supervision, disposable syringes, needles, catheters and other drug administration
equipment should, wherever practicable, be returned to the supplying veterinary practice to ensure
correct disposal procedures.

22. Cleaning of equipment used for the administrati on of veterinary drugs must be carried out in a
manner that ensures the safety of human health a nd the environment. After cleaning, any material
containing residues of the veterinary drug should be disposed of using the same procedures that apply
to disposal of the drug itself.

ANNEX 10

CODEX GUIDELINES FOR THE ESTABLISHMENT OF A REGULATORY PROGRAMME
FOR CONTROL OF VETERINARY DRUG RESIDUES IN FOODS

CAC/GL 16-1993

 Governments need regulatory control progra mmes to ensure their citizens of a safe and
wholesome food supply. Specifications of a resi due control programme are determined by the
importance of the various health risks that could be incurred by consumers of products derived from
animal food products.

 One type of risk may occur if meat is handled and consumed from animals excessively
contaminated with microorganisms or toxins that coul d affect the health of consumers. This type of
health risk can be minimized by establishing me at inspection programmes that emphasize appropriate
and provide specific procedures on how to recognize the signs of disease in food producing animals.

 Another kind of risk can occur if food animal s have been raised using veterinary drugs or
pesticides in an inappropriate manner. The impr oper use of such chemicals can result in unsafe
residues of these substances in food derived from th e treated animals. The safety of the human food
requires a full scientific evaluation of the rela tive hazard as well as quantity of a drug residue
remaining in the tissues of treated livestock and poultry when used according to good veterinary
practices, and a systematic set of procedures that will ensure effective control of such residues in
human food.

 In addition to the health protection benefits in having an effective residue control programme,
a country with such a programme has the capability to participate in the community of food trading
nations with greater confidence. This is because an effective residue control programme can also
serve as the foundation for certifying the safety of the country's exported food products, as well as
provide assurance of safety of such products imported into the country.

 When establishing a programme for control of residues in foods, it is important to distinguish
between the notion of "unbiased statistical samp ling", where the samples are obtained from animals
that are presented for inspection, and the notion of "biased or directed sampling", where samples are
obtained from suspect food products. The purpose of unbiased statistical sampling is to determine the
frequency of occurrence of contaminated products among those presented for inspection.

 Samples are taken at random from food considered safe, and it is not necessary to retain these
food products while waiting for the results of analy tical testing. The sampling plan is determined
beforehand, using statistical rules to ensure that the results are representative of the overall quality of
the product(s) under consideration. The results may be used to certify the exported food products are
in compliance with Codex MRLVDs. Conversel y, directed sampling focuses on food products
suspected of having residue concentrations that exceed the maximum residue limits. The food
products are detained while waiting for results of la boratory testing, and are not released for human
consumption should test results be unfavourable. The number of samples to be taken during the year
for directed sampling may not, by definition, be pr edetermined. The results of directed sampling do
not have statistical representativeness.

 In establishing an effective residue contro l programme, a country should first establish a
comprehensive system for determining the safety of veterinary drugs. This may be accomplished, for
example, through an organization with suitable tec hnical expertise and administrative authority.
Veterinary drugs may be approved taking into consideration several relevant criteria, among which

will be the safety evaluation of the veterinary drug for animals and for human food consumption. The
scientific evaluation of the safety of veterinary drugs is a long and rigorous task, that, perhaps, may
not be necessary to perform in each country, especi ally in developing countries. Evaluation could be
performed by the interested country, using the techni cal expertise of international organizations such
as the Joint FAO/WHO Expert Comm ittee on Food Additives (for veterinary drugs), or the technical
evaluation results in other countries having an acceptable, technically qualified safety assessment
organizations.

 To establish an effective programme for the cont rol of residues of veterinary drugs in food, a
country should include but not necessarily be limited to the following items:

1. Establishing the regulatory authority res ponsibility for implementing inspection programmes
and laboratory analyses.

2. Elaborating an integrated inspection prog ramme, including a residue control programme for
the inspection of foods. The organization in ch arge of implementing th is inspection programme
should be granted the authority to take all the steps necessary to control products when residues
exceed the maximum residue limits established for a food commodity.

3. Compiling a register of veterinary drugs and/ or pure chemical; substances used in the country,
including the products manufactured in the countr y and those products that are imported into the
country.

4. Elaborating regulations concerning the distribu tion of veterinary drugs as a whole, providing
for procedures for the authorized sale, manufacture, distribution and use of such products.

5. Elaborating procedures for determining the safet y and efficacy of veterinary drugs in animals
and residues in food from use of such veterinary drugs. This should include describing procedures for
determining maximum residue limits fo r veterinary drugs in food and procedures for analysis of test
samples intended to verify compliance with those limits.

6. Establishing procedures for sampling food produc ts of animal origin, indicating the specific
drug residues of greatest health concern, the numbe r of samples to be taken for unbiased statistical
sampling, and the nature of the tissue and quantity of sample to be taken. Procedures for sampling for
residue control in a country may be required for certain substances for purposes other than the
enforcement of MRLVDs. These analyses, for exam ple, come within the scope of exploratory
surveys for determining residues in foods wher e unapproved substances may be used in food
producing animals or poultry. This type of data is essential to provide a residue control programme
the flexibility necessary to be adapted to national needs.

7. Selecting the methods of analysis to be used . As an initial step, a residue control programme
should include screening methods. The use of these methods should not require investment in
complex laboratory instrumentation nor in costly r eagents or personnel training, and should provide
analysis of samples in a cost effective manner. Screening methods are generally defined as qualitative
or semi-quantitative methods of analysis that detect the presence of a substance at a concentration that
is equal to or lower than the maximum residue limits. A positive result indicates the possibility that
the maximum residue limit has been exceeded. Add itional testing measures should be required, as
determined by the objectives set forth in a country's residue control programme, to verify or confirm
the results of screening methods.

8. Implementing a quality assurance programme to assure the highest quality results for methods
of analysis. Such a programme will assure regulat ory control authorities that the methods used will

give reliable results that are comp atible with the MRLVD or within the limits established by national
regulations.

9. Developing an educational programme(s ) for producers and veterinarians providing
instruction in the proper use of veterinary drugs, and encouraging the use of preventive measure to
reduce the occurrence of residues in food animals and poultry.

 For determining maximum residue limits, the Joint FAO/WHO Expert Committee on Food
Additives (for veterinary drugs) may constitute a useful resource for obtaining these data.

10. Specific details concerning the establishmen t of a regulatory programme for control of
veterinary drug residues in foods, as based on the above general principles, are attached to these
guidelines as follows:

 PART 1: Sampling for the Control of Residues of Veterinary Drugs in Foods

 Appendix A: Sampling for the Control of Veterinary Drug Residues in Meat and
Poultry Products

 Appendix B: Sampling for the Control of Veterinary Drug Residues in Fish, Milk,
and Egg Products

 Appendix C: Sampling for the Contro l of Veterinary Drug Residues in Honey

 PART 2: General Considerations on Analytical Methods for Residue Control

 PART 3: Attributes of Analytical Met hods for Residues of Veterinary Drugs in
Foods

PART I

SAMPLING FOR THE CONTROL OF RESIDUES OF VETERINARY DRUGS IN FOODS

1. INTRODUCTION

1.1 Basis for the Sampling Principle

 The Codex Alimentarius Commission has deci ded that recommended sampling procedures
for food additives, pesticide residu es and residues of veterinary drugs in food are exempted from the
general sampling procedures of food commodities de veloped by the Codex Committee on Methods of
Analysis and Sampling - Normal Practice. That co mmittee's work is concerned mainly with sampling
procedures for the visible and measurable qualities a nd attributes of various commodities and foods;
sampling to determine whether standards of identit y and composition have been met and to measure
traditional attributes of quality, such as dust and mo isture content in grain. The Codex Committees
that are responsible for establishing permitted levels of regulated added substances - food additives,
pesticides, veterinary drugs in food, have been given authority to prepare their own recommendations
for methods of analysis and sampling. In this regard, the Codex Committee on Residues of
Veterinary Drugs in Foods established an Ad Hoc Working Group on Methods of Analysis and
Sampling at its first meeting.

1.2 General Principles

 Sampling for analytical testing is only one el ement of a country's residue control programme
and, by itself, cannot accomplish the entire objective of protecting public health. Sampling is a tool
used as part of the system for developing informa tion to determine if a supply of foodstuffs meets
public health requirements, in this case, that the c oncentration of veterinary drug residues are within
specified limits.

 Sampling has varying purposes and statisti cal parameters. This guideline discusses the
various objectives which sampling may address and pr ovides technical guidance to be applied for
sampling products within the terms of reference of this Codex Committee. By using Codex standards,
including agreed upon sampling methods, member c ountries can comply with Article III of the
General Agreement on Tariffs and Trade.

 In sampling for residues of an added, regulat ed substance such as a veterinary drug, it is
important to sample as near as possible to where an imals raised for food are cared for and slaughtered
in herds or flocks. The most meaningful sampli ng for tissue residues will occur in conjunction with
slaughter. For other food products within the sc ope of this Committee, such as honey, the most
meaningful sampling for residues will occur at th e time of collection, prior to commingling of
samples from different producers.

 Sampling at an abattoir in conjunction with sla ughter of a herd or flock or with preliminary
slaughter of a small number of test animals or birds, may involve testing samples drawn from live
animals or birds. In these situations, analyses performed on tissues drawn from test animals or body
fluids from live animals may provide test results fo r an inspector before a herd or flock is presented
for slaughter or shipment. Analyses associated w ith pre-slaughter must be designed to prevent
subsequent administration of drugs. In a like ma nner, for processed foods such as might be obtained
from fish or honey, any sampling and testing must be designed to prevent subsequent administration
of drugs. When body fluids are used for residue testing, care must be taken to have established tissue-
fluid relationships between the analytic results in these fluids and results in tissues where the
MRLVDs are established.

 Shortly after slaughter or after appropriate ly harvesting the principle food products, these
products may be commingled to an extent that it d estroys the possibility of drawing a representative
sample. Samples for fresh meat or poultry or fresh chilled meat or poultry may be drawn from
different days' production, for example. Processed products such as sausage or minced fish may be
made with meat tissues from different days' or even different establishments' production. Although
under some circumstances lots for sampling have been defined as products from the same consignor
or packer, sample homogeneity can best be guaranteed when it is taken in conjunction with slaughter
or primary collection point.

2. OBJECTIVES OF SAMPLING

2.1 Primary Point of Origin Sampling

2.1.1 Non-biased sampling

 Non-biased sampling is designed to provide pr ofile information on the occurrence of residues
in specified food producing populations on an annual, national basis. For residue testing, the focus is
on gathering information on the prevalence of residue violations; therefore, only compounds with
established safe limits such as MRLVDs are usua lly considered for residue testing programmes.
Compounds selected for statistically designed non- biased sampling are usually based on risk profiles
(considering toxicity of residues and use) and th e availability of laboratory methods suitable for
regulatory control purposes. Information is obtaine d through a statistically based selection of random
samples from animals presented for inspection. Limited or geographical area sampling may be
conducted where a localized potential drug residue pr oblem appears. The information obtained from
this type of sampling should be reviewed periodi cally to assess residue control programmes and to
allocate resources according to specific needs.

 In addition to profile information, residue data provides a basis for further regulatory action.
In particular, the results can be used to iden tify producers marketing animals, or other food
commodity within the terms of reference of this Co mmittee, with violative concentrations of residues.
When these producers subsequently bring animals, fish or honey for inspection, they will be subjected
to more directed and specific sampling and testi ng until compliance with MRLVDs is demonstrated.
Other auxiliary uses of the data are to indicate prev alence and concentrations of residue violations, to
evaluate residue trends, and to identify residue problem areas within the industry where educational or
other corrective efforts may be needed. Thus, non- biased sampling gathers information and assists in
deterring practices that lead to residue violations.

 As a general practice, samples collected by inspectors are sent for residue analysis to a
laboratory designated by national authorities. No w, however, advances in analytical technology
provide inspection authorities an opportunity for performing residue screening tests on commodities
at an abattoir or similar facility. In these s ituations, inspectors may send tissue samples to a
laboratory designated by national authorities for mo re definitive analyses when results obtained from
the screening test suggest a positive residue finding.

 In some cases and situations where samples ar e sent directly to a designated laboratory for
residue testing, the laboratory results may not be available until after the product has moved into
consumer markets and become untrac eable. Because of this pragmatic limitation, some animals, fish
or honey containing violative residues may inevitably pass into consumer markets, regardless of the
regulatory control efforts to limit this occurrence as much as possible. The consequences to human
health, however, are minimal as long as the frequency of violative residues is low. This is because
MRLVDs represent the maximum residue concentrati on determined to be safe for daily consumption
within the limits of the acceptable daily intake ( ADI) over a lifetime. As a result of employing safety

factors for determining an ADI, and subsequent ly the MRLVD, the occasional consumption of
products with slightly higher residue concentrations than the MRLVD is unlikely to result in adverse
health effects.

 Non-biased sampling should have a statistically specified reliability. This may be expressed
in reference to a confidence level and a prevalence rate. For example, sampling may be designed to
detect, with 95% certainty, a prevalence occurring in 1% of healthy animals submitted for inspection.
When a confidence level and prevalence rate is established, the number of samples necessary to
achieve the desired objective can be determined from Table 1.

Table 1: Number of samples required to detect at least one violation with predefined
probabilities (i.e., 90, 95, and 99 percent) in a population having a known violation prevalence.

Violation prevalence
(% in a population)
Minimum number of samples required to detect
a violation with a confidence level of:
 90% 95% 99%
 35 6 7 11
 30 7 9 13
 25 9 11 17
 20 11 14 21
 15 15 19 29
 10 22 29 44
 5 45 59 90
 1 230 299 459
 0.5 460 598 919
 0.1 2302 2995 4603

2.1.2 Directed sampling

 Directed sampling is designed to investigate and control the movement of potentially
adulterated products. The sampling is often purposely biased and is directed at particular carcasses,
products or producers in response to information from statistically based sampling (or other regulatory
control agency data), or from inspector observati ons during ante-mortem or post-mortem inspection
indicating that violative residues may be present. In -plant or on site residue testing procedures may
be performed by the inspector, or samples may be submitted for analysis to a laboratory designated by
national authorities. Depending upon the weight of evidence for testing in support of directed
sampling, product may be retained until test result s indicate the appropriate regulatory disposition.
Laboratory analysis of directed residue test sa mples should be completed as rapidly as possible and
take precedence over routine, statistically based samp les. In directed sampling situations, herds of
animals, flocks of birds, lots of fish or honey, should be considered unacce ptable until it can be
demonstrated that they are in compliance with C odex MRLVDs or national regulations in the country
of origin for the specific commodity.

 The probability of failing to detect a residue violation and accepting the lot depends upon the
directed sampling programmes' sample size and pr evalence of the residue violation frequency.
Table 2 shows the probability of fa iling to detect a residue violation using different sample sizes from
an "infinite" population with a specified proportion of violations. For example, selecting 5 samples
from a large lot in which 10 percent of the units cont ain violative residues would, on the average, fail
to detect a residue violation in 59.0 percent of su ch lots (i.e., 59.0 percent of the lots would be

accepted). Assuming the same conditions as the prev ious example, but using a sample size of 50,
would result in only 0.5 percent of such lots being accepted.

Table 2: Probability of failing to detect a residue violation

Prevalence Number of animals in sample tested
(%) 5 10 25 50 75 100 200 250 500 1000
 1 0.951 0.904 0.779 0.605 0.471 0.366 0.134 0.081 0.007 0.000
 2 0.904 0.817 0.603 0.364 0.220 0.133 0.018 0.006 0.000
 3 0.859 0.737 0.467 0.218 0.102 0.048 0.002 0.000
 4 0.815 0.665 0.360 0.130 0.047 0.017 0.000
 5 0.774 0.599 0.277 0.077 0.021 0.006
 6 0.734 0.539 0.213 0.045 0.010 0.002
 7 0.696 0.484 0.163 0.027 0.004 0.001
 8 0.659 0.434 0.124 0.015 0.002 0.000
 9 0.624 0.389 0.095 0.009 0.001
 10 0.590 0.349 0.072 0.005 0.000
 12 0.528 0.279 0.041 0.002
 14 0.470 0.221 0.023 0.001
 16 0.418 0.175 0.013 0.000
 18 0.371 0.137 0.007
 20 0.328 0.107 0.004
 24 0.254 0.064 0.001
 28 0.193 0.037 0.000
 32 0.145 0.021
 36 0.107 0.012
 40 0.078 0.006
 50 0.031 0.001
 60 0.010 0.000

 Risk and cost factors should be considered in determining the sample sizes used in a directed
sampling programme. Also, because of possible ga ins in the probability of detecting unacceptable
herds of animals, flocks of birds, lots of fish or honey due to residue vi olations, the feasibility of
selecting separate samples from separate lots instead of from a single lot should be considered.

2.2 Secondary Point of Sampling

2.2.1 Port of entry sampling

 Port of entry testing of products derived fro m food producing animals, poultry, or fish, and
honey, imported by member countries of Codex Alimentarius is a means of verifying the effectiveness
of the exporting country's residue control programme. The purpose of port of entry sampling and
testing is not to replace an exporting country's residue control programmes.

 Results of residue testing that indicate imported product is in compliance with Codex
MRLVDs should be permitted to move into commerc e. When test results indicate that imported
product contains violative residues, subsequent shipments of the same product group from that

establishment or company should be retained at th e port of entry until laboratory results indicating
compliance with MRLVDs are known by regulatory control authorities. Consideration should be
given to placing all subsequent shipments of si milar products from the country of origin on an
increased testing schedule until a record of compliance with Codex MRLVDs is re-established.

 Compounds selected for residue testing at port of entry should take into account the
compounds approved for use in the exporting countr y, as well as those included in the domestic
residue control programme of the importing and ex porting country. Guidance for collecting samples
for port of entry testing is summarized in A ppendix A, Table A, Appendix B, Table B and
Appendix C.

Appendix A

SAMPLING FOR THE CONTROL OF VETERINARY DRUG RESIDUES
IN MEAT AND POULTRY PRODUCTS

1. OBJECTIVE

 To provide instructions for sampling a lot of meat or poultry products to determine
compliance with Codex Maximum Residue Limits for Veterinary Drugs (MRLVDs).

2. DEFINITIONS

2.1 Lot

 An identifiable quantity of food delivered for slaughter or distribution at one time, and
determined to have common characteristics, such as origin, variety, type of packing, packer or
consignor, or markings, by the sampling official. Several lots may make up a consignment.

2.2 Consignment

 A quantity of food as described on a particular contractor's shipping document. Lots in a
consignment may have different origins or may be delivered at different times.

2.3 Primary Sample

 A quantity of tissue taken from a single anim al or from one place in the lot, unless this
quantity is inadequate for the residue analysis. Wh en the quantity is inadequate, samples from more
than one animal or location can be combined for the primary sample (such as poultry organs).

2.4 Bulk Sample

 The combined total of all the primary samples taken from the same lot.

2.5 Final Sample

 The primary sample or a representative portion of the primary sample to be used for control
purposes.

2.6 Laboratory Sample

 The sample intended for laboratory analysis. A whole primary sample may be used for
analysis or the sample may be subdivided into representative portions, if required by national
legislation.

3. COMMODITIES TO WHICH THE GUIDELINE APPLIES

3.1 Selected Class B: Primary Food Commodities of Animal Origin

 Type 06 Mammalian Products

 No. 030 Mammalian Meat

 No. 031 Mammalian Fats

 No. 032 Mammalian Edible Offal

 Type 07 Poultry Products

 No. 036 Poultry Meats

 No. 037 Poultry Fats

 No. 038 Poultry Edible Offal

3.2 Selected Class E: Processed Products of Animal Origin made from only Primary Food
Nos. 030, 032, 036, and 038

 Type 16 - Secondary Products

 Type 18 - Manufactured (single ingredient) Products of a Minimum of One Kilogram
Container or Unit Size

 Type 19 - Manufactured (multiple ingredient ) Products of a Minimum of One Kilogram
Container or Unit Size

4. PRINCIPLE ADOPTED

 For purposes of control, the maximum residue limit (MRLVD) is applied to the residue
concentration found in each labor atory sample taken from a lot. Lot compliance with a Codex
MRLVD is achieved when none of the laboratory samples contains a residue greater than the
MRLVD.

5. EMPLOYMENT OF AUTHOR IZED SAMPLING OFFICIALS

 Samples must be collected by offi cials authorized for this purpose.

6. SAMPLING PROCEDURES

6.1 Product to Sample

 Each lot to be examined must be sampled separately.

6.2 Precautions to Take

 During collection and processing, contamination or other changes in the samples which would
alter the residue or affect the analytical determination must be prevented.

6.3 Collection of a Primary Sample

 Detailed instructions for collection of a prim ary sample of various products are provided in
Table A. Quantities to collect are dependent on the analytical method requirements. Minimum
quantity requirements are included in Table A. The following are general instructions.

 a. Each primary sample should be taken from a single animal or unit in a lot, and when
possible, be selected randomly.

 b. When multiple animals are required for ad equate sample size of the primary sample
(i.e., poultry organs), the samples should be collected consecutively after random
selection of the starting point.

 c. Canned or packaged product should not be opened for sampling unless the unit size is
at least twice the amount required for the primary laboratory sample. The primary
sample should contain a representative por tion of juices surrounding the product.
Each sample should then be frozen as described in paragraph 6.8.d.

 d. Frozen product should not be thawed before sampling.

 e. Large, bone-containing units of product (i.e., prime cuts) should be sampled by
collecting edible product only as the primary sample.

6.4 The Number of Primary Samples to Collect from a Lot

 The number of primary samples collected will vary depending on the status of the lot. If a
residue violation is suspected be cause of its origin from a source with a past history of residue
violations of the MRLVD, by evidence of contam ination during transport, by signs of toxicosis
observed during ante- or post-mortem inspection, or by other relevant information available to the
inspection official, the lot is designated a suspect lot. If there is no reason to suspect adulteration, the
lot is designated a non-suspect lot.

6.4.1 Sampling suspect lots

 A minimum of six to a maximum of thirty primary samples should be collected from a
suspect lot. When the su spected adulteration is expected to o ccur throughout the lot or is readily
identifiable within the lot, the smaller number of samples is sufficient.

6.4.2 Sampling non-suspect lots

 A statistically-based, non-biased sampling progra mme is recommended for non-suspect lots.
Any of the following types of sampling can be used.

 a. Stratified random sampling

 In a complex system where commodities must be sampled at many locations over extended
time periods, it is very difficult to apply simple random criteria in the design of a sampling
programme. A useful alternative sampling desi gn is stratified random sa mpling which separates
population elements into non-overlapping groups, ca lled strata. Then samp les are select ed within
each stratum by a simple random design. Homogene ity within each stratum is better than in the
whole population. Countries or geographic region s are natural strata because of uniformity in
agricultural practices. Time strata (e.g., mont h, quarter) are commonly used for convenience,
efficiency, and detection of seasonal variability. Random number tables or other objective techniques

should be used to ensure that all elements of a population have an equal and independent chance of
being included in the sample.
 b. Systematic sampling

 Systematic sampling is a method of selecting a sample from every 'K' quantity of product to
be sampled, and then sampling every 'K' unit therea fter. Systematic sampling is quicker, easier, and
less costly than non-biased sampling, when ther e is reliable information on product volumes to
determine the sampling interval that will provide the desired number of samples over time. If the
sampling system is too predictable, it may be abu sed. It is advisable to build some randomness
around the sampling point within the sampling interval.

 c. Biased or estimated worst case sampling

 In biased or estimated worst case sampling, th e investigator should use their judgement and
experience regarding the population, lot, or sampling frame to decide which sa mples to select. As a
non-random technique, no inferen ces should be made about the population sampled based on data
collected. The population group anticipated to be at greatest risk may be identified.

 Exporting countries should conduct a comprehens ive residue testing programme and provide
results to importing countries. Based on an importi ng country's data, testing may be conducted as
applied to non-suspect products. Countries that do not provide residue testing results showing
compliance with MRLVDs should be sampled as suspect lots.

6.5 Preparation of the Bulk Sample

 The bulk sample is prepared by combining and thoroughly mixing the primary samples.

6.6 Preparation of the Final Sample

 The primary sample should, if possible, constitu te the final sample. If the primary sample is
too large, the final sample may be prepared from it by a suitable method of reduction.

6.7 Preparation of the Laboratory Sample

 The final sample should be submitted to the labor atory for analysis. If the final sample is too
large to be submitted to the laboratory, a representative subsample should be prepared. Some national
legislation may require the final sample be subdivide d into two or more portions for separate analysis.
Each portion should be representative of the final sa mple. Precautions in paragraph 6.2 should be
observed.

6.8 Packaging and Transmission of Samples

 a. Each sample should be placed in a clean, chemically inert container to protect the
sample from contamination and from being damaged in shipping.

 b. The container should be sealed so that unauthorized opening is detectable.

 c. The container should be sent to the laboratory as soon as possible, after taking
precautions against leakage and spoilage.

 d. For shipping, all perishable samples should be frozen to minus 20
oC, immediately
after collection, and packed in a suitable c ontainer that retards thawing. If possible,

the shipping container should be placed in a freezer for 24 hours prior to packing and
shipping the frozen sample.

7. RECORDS

 Each primary sample should be correctly identif ied by a record with the type of sample, its
origin (e.g., country, state, or town), its locati on of collection, date of sampling, and additional
information useful to the analyst or to regulatory officials for follow-up action if necessary.

8. DEPARTURE FROM RECOMMENDED SAMPLING PROCEDURES

 If there is a departure from recommended sa mpling procedures, records accompanying the
sample should fully describe procedures actually followed.

TABLE A: MEAT AND POULTRY PRODUCTS

Commodity Instructions for coll ection Minimum quantity required
for laboratory sample
I. Group 030
 (Mammalian Meats)

A. Whole carcass or side, unit
weight normally 10 kg or more
Collect diaphragm muscle, supplement with cervical
muscle, if necessary, from one animal.
500 g
B. Small carcass
 (e.g., rabbit)
Collect hind quarter or whole carcass from one or more
animals.
500 g after removal of skin
and bone
C. Fresh/chilled parts
 1. Unit minimum weight of 0.5
kg, excluding bone (e.g.,
quarters, shoulders, roasts)
 2. Unit weighing less than 0.5 kg
(e.g., chops, fillets)

Collect muscle from one unit.

Collect the number of units from selected container to
meet laboratory sample size requirements.

500 g

500 g after removal of bone
D. Bulk frozen parts Collect a frozen cross-section from selected container, or
take muscle from one large part.
500 g
E. Retail packaged frozen/chilled
parts, or individually wrapped
units for wholesale
For large cuts, collect muscle from one unit or take
sample from number of units to meet laboratory sample
size requirements.
500 g after removal of bone
Ia. Group 030
 (Mammalian Meats where MRL
is found in carcass fat)

A. Animals sampled at slaughter See instructions under II. Group 031.
B. Other meat parts Collect 500 g of visibl e fat, or sufficient product to yield
50-100 g of fat for analysis. (Normally 1.5-2.0 kg of
product is required for cuts without trimmable fat).
Sufficient to yield 50-100 g
of fat
II. Group 031
 (Mammalian Fats)

A. Large animals sampled at
slaughter, usually weighing at
least 10 kg
Collect kidney, abdominal, or subcutaneous fat from one
animal.
500 g

Commodity Instructions for coll ection Minimum quantity required
for laboratory sample
B. Small animals sampled at
slaughter25
Collect abdominal and subcutaneous fat from one or
more animals.
500 g
C. Bulk fat tissue Collect equal size por tions from 3 locations in container. 500 g
III. Group 032
 (Mammalian Edible Offal)

A. Liver Collect whole liver(s) or portion sufficient to meet
laboratory sample size requirements.
400 - 500 g
B. Kidney Collect one or both kidneys, or kidneys from more than
one animal, sufficient to meet laboratory sample size
requirement. Do not collect from more than one animal
if size meets the low range for sample size.
250 - 500 g
C. Heart Collect whole heart or ventricle portion sufficient to meet
laboratory sample size requirement.
400 - 500 g
D. Other fresh/chilled or frozen,
edible offal product
Collect portion derived from one animal unless product
from more than one animal is required to meet laboratory
sample size requirement. A cross-section can be taken
from bulk frozen product.
500 g
IV. Group 036
 (Poultry Meats)

A. Whole carcass of large bird,
typically weighing 2-3 kg or
more (e.g., turkey, mature
chicken, goose, duck)
Collect thigh, leg, and other dark meat from one bird. 500 g after removal of skin
and bone
B. Whole carcass of bird typically
weighing between 0.5-2.0 kg
(e.g., young chicken, duckling,
guinea fowl)
Collect thigh, legs, and other dark meat from 3-6 birds,
depending on size.
500 g after removal of skin
and bone
C. Whole carcasses of very small
birds typically weighing less than
500 g (e.g., quail, pigeon)
Collect at least 6 whole carcasses. 250 - 500 g of muscle
tissue
D. Fresh/chilled or frozen parts
 1. Wholesale packaged
 a. Large parts
 b. Small parts

Collect an interior unit from a selected container.
Collect sufficient parts from a selected layer in the
container.

500 g after removal of skin
and bone
 2. Retail packaged Collect a number of units from selected container to meet
laboratory sample size requirement.
500 g after removal of skin
and bone
IVa. Group 036
 (Poultry Meats where MRLVD is
expressed in carcass fat)

A. Birds sampled at slaughter See instructions under V. Group 037
B. Other poultry meat Collect 500 g of fat or sufficient product to yield 50-100
g of fat. (Normally, 1.5-2.0 kg is required.)
500 g of fat or enough
tissue to yield 50-100 g of
fat
V. Group 037
 (Poultry Fats)

25 When adhering fat is insufficient to provide a suitable sample, the sole commodity without bone, is analyzed and
the MRL will apply to the sole commodity.

Commodity Instructions for coll ection Minimum quantity required
for laboratory sample
A. Birds sampled at slaughter Collect abdominal fat from 3-6 birds, depending on size. Sufficient to yield 50-100 g
of fat
B. Bulk fat tissue Collect equal size por tions from 3 locations in container. 500 g
VI. Group 038
 (Poultry Edible Offal)

A. Liver Collect 6 whole livers or a sufficient number to meet
laboratory sample requirement.
250 - 500 g
B. Other fresh/chilled or frozen
edible offal product
Collect appropriate parts from 6 birds. If bulk frozen, take
a cross-section from container.
250 - 500 g
VII. Class E - Type 16
 (Secondary Meat and Poultry
Products)

A. Fresh/chilled or frozen
comminuted product of single
species origin
Collect a representative fresh or frozen cross-section from
selected container or packaged unit.
500 g
B. Group 080
 (Dried Meat Products)
Collect a number of packaged units in a selected
container sufficient to meet laboratory sample size
requirements.
500 g, unless fat content is
less than 5% and MRLVD
is expressed on a fat basis.
Then 1.5-2.0 kg is required.
VIII. Class E-Type 18
 (Manufactured, single ingredient
product of animal origin)

A. Canned product (e.g., ham, beef,
chicken), unit size of 1 kg or
more
Collect one can from a lot. When unit size is large
(greater than 2 kg), a representative sample including
juices may be taken.
500 g, unless fat content is
less than 5% and MRLVD
is expressed on a fat basis.
Then 1.5-2.0 kg is required.
 B. Cured, smoked, or cooked
product (e.g., bacon slab, ham,
turkey, cooked beef), unit size of
at least 1 kg
Collect portion from a large unit (greater than 2 kg), or
take whole unit, depending on size.
500 g, unless fat content is
less than 5% and MRLVD
is expressed on a fat basis.
Then 1.5-2.0 kg is required.
IX. Class E - Type 19
 (Manufactured, multiple
ingredient, product of animal
origin)

A. Sausage and luncheon meat rolls
with a unit size of at least 1 kg
Collect cross-section portion from a large unit (greater
than 2 kg), or whole unit, depending on size.
500 g

Appendix B

SAMPLING FOR THE CONTROL OF VETERINARY DRUG RESIDUES
IN FISH, MILK AND EGG PRODUCTS

1. OBJECTIVE

 To provide instructions for sampling a lot of eggs, milk, or aquatic animal products, to
determine compliance with Codex Maximum Residue Limits for Veterinary Drugs (MRLVDs).

2. DEFINITIONS

2.1 Lot

 An identifiable quantity of food delivered for slaughter or distribution at one time, and
determined to have common characteristics, such as origin, variety, type of packing, packer or
consignor, or markings, by the sampling official. Several lots may make up a consignment.

2.2 Consignment

 A quantity of food as described on a particular contractor's shipping document. Lots in a
consignment may have different origins or be delivered at different times.

2.3 Primary Sample

 A quantity of food take n from a single animal or from one place in the lot, unless this quantity
is inadequate for the residue analysis. When the quantity is inadequate, samples from more than one
location in the lot can be combined for the primary sample.

2.4 Bulk Sample

 The combined total of all the primary samples taken from the same lot.

2.5 Final Sample

 The bulk sample or a representative portion of the bulk sample to be used for control
purposes.

2.6 Laboratory Sample

 The sample intended for laboratory analysis. A whole primary sample may be used for
analysis or the sample may be subdivided into representative portions, if required by national
legislation.

3. COMMODITIES TO WHICH THE GUIDELINE APPLIES

3.1 Selected Class B : Primary Food Commodities of Animal Origin

 Type 06 Mammalian Products

 No. 033 Milks

 Type 07 Poultry Products

 No. 039 Eggs

 Type 08 Aquatic Animal Products

 No. 040 Freshwater Fish

 No. 041 Diadromous Fish

 No. 043 Fish Roe and Edible Offal of Fish

 No. 045 Crustaceans

 Type 09 Amphibians and Reptiles

 No. 048 Frogs, Lizards, Snakes and Turtles

 Type 10 Invertebrate Animals

 No. 049 Molluscs and Other Invertebrate Animals

3.2 Selected Class E: Processed Products of Animal Origin made from only Primary Food
Nos. 033, 039, 040, 041, 043, 045, 048, and 049

 Type 16 - Secondary Products

 Type 17 - Derived Edible Produc ts of Aquatic Animal Origin

 Type 18 - Manufactured (single ingredient) Products of a Minimum of One Kilogram
Container or Unit Size

 Type 19 - Manufactured (multiple ingredient ) Products of a Minimum of One Kilogram
Container or Unit Size

4. PRINCIPLE ADOPTED

 For purposes of control, the maximum residue limit (MRLVD) is applied to the residue
concentration found in each labor atory sample taken from a lot. Lot compliance with a Codex
MRLVD is achieved when none of the laboratory samples contains a residue greater than the
MRLVD.

5. EMPLOYMENT OF AUTHOR IZED SAMPLING OFFICIALS

 Samples must be collected by offi cials authorized for this purpose.

6. SAMPLING PROCEDURES

6.1 Product to Sample

 Each lot to be examined must be sampled separately.

6.2 Precautions to Take

 During collection and processing, contamination or other changes in the samples must be
prevented which would alter the residue, affect the analytical determination, or make the laboratory
sample not representative of the bulk or final sample.

6.3 Collection of a Primary Sample

 Detailed instructions for collection of a prim ary sample of various products are provided in
Table B. Quantities to collect are dependent on the analytical method requirements. Minimum
quantity requirements are included in Table B. The following are general instructions.

 a. Each primary sample should be taken from a single unit in a lot, and when possible,
be selected randomly.

 b. Canned or packaged product should no t be opened for sampling unless the unit size is
at least twice the amount required for the primary laboratory sample. Each primary
sample should contain a representative por tion of juices surrounding the product.
Each sample should then be frozen as described in paragraph 6.8.d.

 c. Frozen product should not be thawed before sampling.

6.4 The Number of Primary Samples to Collect from a Lot

 The number of primary samples collected will vary depending on the status of the lot. If a
residue violation is suspected be cause of its origin from a source with a past history of residue
violations of the MRLVD, by evidence of contam ination during transport or by other relevant
information to the inspection official, the lot is d esignated a suspect lot. If there is no reason to
suspect adulteration, the lot is designated a non-suspect lot.

6.4.1 Sampling suspect lots

 A minimum of six to a maximum of thirty primary samples should be collected from a
suspect lot. When the su spected adulteration is expected to o ccur throughout the lot or is readily
identifiable within the lot, the smaller number of samples is sufficient.

6.4.2 Sampling non-suspect lots

 A statistically-based, random sampling programme is recommended for non-suspect lots.
Any of the following types of sampling can be used.

 a. Stratified random sampling

 In a complex system where commodities must be sampled at many locations over extended
time periods, it is very difficult to apply simple random criteria in the design of a sampling
programme. A useful alternative sampling desi gn is stratified random sa mpling which separates
population elements into non-overlapping groups, ca lled strata. Then samp les are select ed within
each stratum by a simple random design. Homogene ity within each stratum is better than in the
whole population. Countries or geographic region s are natural strata because of uniformity in
agricultural practices. Time strata (e.g., mont h, quarter) are commonly used for convenience,
efficiency, and detection of seasonal variability. Random number tables or other objective techniques
should be used to ensure that all elements of a population have an equal and independent chance of
being included in the sample.

 b. Systematic sampling

 Systematic sampling is a method of selecting a sample from every 'K' quantity of product to
be sampled, and then sampling every 'K' unit therea fter. Systematic sampling is quicker, easier, and
less costly than random sampling, when there is reliable information on product volumes to be used to
determine the sampling interval that will provide the desired number of samples over time. If the
sampling system is too predictable, it may be abu sed. It is advisable to build some randomness
around the sampling point within the sampling interval.

 c. Biased or estimated worst case sampling

 In biased or estimated worst case sampling, the investigator should use their own judgement
and experience regarding the population, lot, or sampling frame to decide which samples to select. As
a non-random technique, no inferenc es should be made about the population sampled based on data
collected. The population group anticipated to be at greatest risk may be identified.

 Exporting countries should conduct a comprehens ive residue testing programme and provide
results to importing countries. Based on an importi ng country's data, testing may be conducted as
applied to non-suspect products. Countries whic h do not provide residue testing results showing
compliance with MRLVDs should be sampled as suspect lots.

6.5 Preparation of the Bulk Sample

 The bulk sample is prepared by combining and thoroughly mixing the primary samples.

6.6 Preparation of the Final Sample

 The primary sample should, if possible, constitu te the final sample. If the primary sample is
too large, the final sample may be prepared from the primary sample by a suitable method of
reduction.

6.7 Preparation of the Laboratory Sample

 The final sample should be submitted to the labor atory for analysis. If the final sample is too
large to be submitted to the laboratory, a representative subsample should be prepared. Some national
legislation may require the final sample be subdivide d into two or more portions for separate analysis.
Each portion should be representative of the final sa mple. Precautions in paragraph 6.2 should be
observed.

6.8 Packaging and Transmission of Samples

 a. Each sample or subsample should be placed in a clean, chemically inert container to
protect the sample from contamination and from being damaged in shipping.

 b. The container should be sealed so that unauthorized opening is detectable.

 c. The container should be sent to the laboratory as soon as possible, after taking
precautions against leakage and spoilage.

 d. For shipping, all perishable samples should be frozen to minus 20
oC, immediately
after collection, and packed in a suitable c ontainer that retards thawing. If possible,

the shipping container should be placed in a freezer for 24 hours prior to packing and
shipping the frozen sample.

7. RECORDS

 Each sample must be correctly identified by a record with the type of sample, origin of the
sample (e.g., country, state, or town), location of collection of the sample, date of sampling, and
additional information useful to the analyst or to regulatory officials for follow-up action if necessary.

8. DEPARTURE FROM RECOMMENDED SAMPLING PROCEDURES

 If there is a departure from recommended sa mpling procedures, records accompanying the
sample should fully describe procedures actually followed.

TABLE B: MILK, EGGS, DAIRY PRODUCTS AND AQUATIC ANIMAL PRODUCTS

Commodity Instructions for collection Minimum quantity
required for laboratory
sample
I. Group 033
 ( Milks)

 Whole liquid milk
 raw, pasteurized, UHT &
sterilized
In bulk.
Mix thoroughly and immediately take a sample by
means of a dipper.

In retail containers.
Take sufficient units to meet laboratory sample size
requirements.
500 ml
II. Group 082
 (Secondary Milk Products)

A. Skimmed milk
 skimmed and semi-skimmed
As for whole liquid milk. 500 ml
B. Evaporated milk
 evaporated full cream &
skimmed milk
Bulk containers (barrels, drums).
Mix the contents carefully and scrape adhering material
from the sides and bottom of the container. Remove 2
to 3 litres, repeat the stirring and take a 500 ml sample.

Small retail containers.
Take sufficient units to meet laboratory sample size
requirements.
500 ml
C. Milk powders
 1. Whole

 2. Low fat

Bulk containers.
Pass a dry borer tube steadily through the powder at an
even rate of penetration. Remove sufficient bores to
make up a sample of 500 g.

Small retail containers.
Take sufficient units to meet laboratory sample size
requirements.

As for whole milk powders.

500 g

500 g

Commodity Instructions for collection Minimum quantity
required for laboratory
sample
III. Group 087
 ( Derived Milk Products)

A. Cream
 fresh, frozen & UHT;
 single, whipping, whipped,
double & clotted
Bulk containers.
Plunge to ensure thorough mixing moving the plunger
from place to place avoiding foaming, whipping and
churning. Take a 200 ml sample by means of a dipper.

Small containers.
Take sufficient units to meet laboratory sample size
requirements.
200 ml
B. Butter
 including whey butter and low
fat spreads containing butterfat
In bulk.
Take two cores or more of butter so that the minimum
total sample weight is not less than 200 g

In pats or rolls.
For units weighing over 250 g divide into four and take
opposite quarters. For units weighing less than 250 g
take one unit as sample.
200 g
C. Butteroil
 including anhydrous butteroil
and an- hydrous milkfat
Mix thoroughly and take a 200 g sample. 200 g
IV. Group 090
 (Manufactured Milk Products -
single ingredient)

A. Yoghurt
 natural, low fat through to full
cream
Select number of units sufficient to meet laboratory
requirements.
500 g
B. Cheeses
 all varieties
Make two cuts radiating from the centre of the cheese if
the cheese has a circular base, or parallel to the sides if
the base is rectangular. The piece removed should meet
the laboratory sample size requirements. For small
cheeses and wrapped portions of cheese take sufficient
units to meet laboratory sample requirements.
200 g
V. Group 092
 (Manufactured Milk Products -
multi- ingredient)

A. Dairy ice cream
 only ice cream containing 5%
or greater of milk fat
Select block or units sufficient to meet laboratory
sample size requirements.
500 ml
B. Processed cheese preparations Select units sufficient to meet laboratory sample size
requirements.
200 g
C. Flavoured yoghurt As for natural yoghurt. 500 g
D. Sweetened condensed milk As for evaporated milk. 500 ml
VI. Group 039
 (Eggs and Egg Products)

A. Liquid and frozen eggs Use sample schedul e. Subsample size will be 0.25 litre
liquid or 0.5 litre packed shavings from aseptic drillings
into containers.
 500 g

Commodity Instructions for collection Minimum quantity
required for laboratory
sample
B. Dried egg products Use sample schedule. For containers of 0.5 kg or less or
0.25 litre or less, collect a minimum of 2 units per
subsample. For containers of 0.5 to 10 kg select 1 unit
per subsample. for containers of 10 kg or more collect 1
kg from each unit sampled. Collect with aseptic
technique.
 500 g
C. Shell eggs
 1. Retail packages

 2. Commercial cases

Use sample schedule. Subsample size is 1 dozen.

For 15 cases or less collect 1 dozen from each case,
minimum of 2 dozen eggs. For 16 or more cases collect
1 dozen from 15 random cases.

500 g or 10 whole eggs

500 g or 10 whole eggs
VII. Class B - Type 08
 (Aquatic Animal Products)

A. Packaged fish
 fresh, frozen, smoked, cured, or
shellfish (except oysters)
Collect 12 subsamples randomly. Minimum subsample
size is 1 kg.
1000 g
B. Bulk fish
 0.5 - 1.5 kg
Collect 12 subsamples randomly. Each subsample
should total 0.5 kg of edible fish.
1000 g
C. Bulk shellfish
 (except oysters)
Collect 12 subsamples randomly. 1000 g
D. Other fish and shellfish products
 (including oysters)
Collect 12 - 0.25 litre subsamples. 1000 g
VIII. Class E - Type 17
 (Derived Edible Products of
Aquatic Animal Origin)

A. Canned fish and shellfish products
 (except oysters)
Collect 12 subsamples of 5 cans per subsample. 1000 g
B. Other fish and shellfish products -
fish flour and meal
Use sample schedule. Collect 1 kg per subsample. 1000 g

Appendix C

SAMPLING FOR THE CONTROL OF VETERINARY DRUG RESIDUES
IN HONEY

1. OBJECTIVE

 To provide instructions for sampling a lot of honey to determine compliance with Codex
Maximum Residue Limits for Residues of Veterinary Drugs (MRLVDs).

2. DEFINITIONS

2.1 Lot

 An identifiable quantity of food (honey) delivered for distribution at one time, and determined
to have common characteristics, such as origin, vari ety, type of packing, packer or consignor, or
markings, by the sampling official. Several lots may make up a consignment.

2.2 Consignment

 A quantity of food (honey) as described on a particular contractor's shipping document. Lots
in a consignment may have different origins or may be delivered at different times.

2.3 Primary Sample

 A quantity of honey taken from one place in the lot, unless this quantity is inadequate for the
residue analysis. When the quantity is inadequa te, samples from more than one location can be
combined for the primary sample.

2.4 Bulk Sample

 The combined total of all the primary samples taken from the same lot.

2.5 Final Sample

 The bulk sample or a representative portion of the bulk sample to be used for control
purposes.

2.6 Laboratory Sample

 The sample intended for laboratory analysis. A whole primary sample may be used for
analysis or the sample may be subdivided into representative portions, if required by national
legislation.

3. COMMODITIES TO WHICH THE GUIDELINE APPLIES

3.1 Selected According to Origin

 Blossom or nectar honey that comes mainly from nectaries of flowers.

 Honeydew honey that comes mainly from secr etions of or on living parts of plants.

3.2 Selected According to Mode of Processing

 Comb honey that is stored by bees in the cells of freshly built broodless combs, and sold in
sealed whole combs or sections of such combs.

 Extracted honey that is obtained by centrifuging decapped broodless combs.

 Pressed honey that is obtained by pressing broodless combs with or without the application of
moderate heat.

4. PRINCIPLE ADOPTED

 For purposes of control, the maximum residue limit (MRLVD) is applied to the residue
concentration found in each labor atory sample taken from a lot. Lot compliance with a Codex
MRLVD is achieved when none of the laboratory samples contain a residue greater than the MRLVD.

5. EMPLOYMENT OF AUTHOR IZED SAMPLING OFFICIALS

 Samples must be collected by offi cials authorized for this purpose.

6. SAMPLING PROCEDURES

6.1 Product to Sample

 Each lot to be examined must be sampled separately.

6.2 Precautions to Take

 During collection and processing, contamination or other changes in the samples must be
prevented which would alter the residue, affect the analytical determination, or make the laboratory
sample not representative of the bulk or final sample.

6.3 Collection of a Primary Sample

 Quantities to collect are dependent on the anal ytical method requirements. Minimum quantity
requirements and detailed instructions for collectio n of a primary sample of honey are provided in
Appendix C, paragraph 9. The following are general instructions.

 a. Each primary sample should be taken from a single unit in a lot, and when possible,
be selected randomly.

 b. Packaged product should not be opened for sampling unless the unit size is at least
twice the amount required for the primary laboratory sample. The primary sample
should contain a representative portion of the product. Each sample should be
prepared for analysis as referenced in paragraph 6.5.

6.4 The Number of Primary Samples to Collect from a Lot

 The number of primary samples collected will vary depending on the status of the lot. If
adulteration is suspected by origin from a source with a past history of residue violations of the
MRLVD, by evidence of contamination during transport or by the availability of other relevant
information to the inspection official, the lot is d esignated a suspect lot. If there is no reason to
suspect adulteration, the lot is designated a non-suspect lot.

6.5 Preparation of the Primary Sample

 The primary sample is prepared as described in paragraph 9.

6.6 Preparation of the Laboratory Sample

 The primary sample should, if possible, constitu te the final sample. If the primary sample is
too large, the final sample may be prepared from it by a suitable method of reduction.

6.7 Preparation of the Laboratory Sample

 The final sample should be submitted to the labor atory for analysis. If the final sample is too
large to be submitted to the laboratory, a representative subsample should be prepared. Some national
legislation may require that the final sample be subdivided into two or more portions for separate
analysis. Each portion should be representative of the final sample. Precautions in paragraph 6.2
should be observed.

6.8 Packaging and Transmission of Primary Samples

 a. Each primary sample should be placed in a clean, chemically inert container to
protect the sample from contamination and from being damaged in shipping.

 b. The container should be sealed so that unauthorized opening is detectable.

 c. The container should be sent to the laboratory as soon as possible, after taking
precautions against leakage and spoilage.

7. RECORDS

 Each primary sample should be correctly identif ied by a record with the type of sample, its
origin (e.g., country, state, or town), its locati on of collection, date of sampling, and additional
information useful to the analyst or to regulatory officials for follow-up action if necessary.

8. DEPARTURE FROM RECOMMENDED SAMPLING PROCEDURES

 If there is a departure from recommended sa mpling procedures, records accompanying the
sample should fully describe procedures actually followed.

9. SAMPLING INSTRUCTIONS

9.1 Liquid or Strained Honey

 If sample is free from granulation, mix thoroughly by stirring or shaking; if granulated, place
closed container in water-bath without submerging, a nd heat 30 min at 60°C; then if necessary heat at
65°C until liquefied. Occasional shaking is essentia l. Mix thoroughly and cool rapidly as soon as
sample liquefies. If foreign matter, such as wax, sticks, bees, particles of comb, etc., is present, heat
sample to 40°C in water-bath and strain through cheesecloth in hot-water-funnel before sampling.

 Collect 250 ml of liquid or strained honey.

9.2 Comb Honey

 Cut across top of comb, if sealed, and separate completely from comb by straining through a
sieve the meshes of which are made by so weaving wire as to form square opening of 0.500 mm by
0.500 mm (ISO 565-1983)
26. When portions of comb or wax pass through sieve, heat samples as in
paragraph 9.1 and strain through cheesecloth. If h oney is granulated in comb, heat until wax is
liquefied; stir, cool and remove wax.

 Collect 250 ml of liquid honey.

26 Such sieve could be replaced by US sieve with No. 40 standard screen (size of opening 0.420 mm).

PART II

GENERAL CONSIDERATIONS ON ANALYTICAL METHODS
FOR RESIDUE CONTROL

 It would be ideal to have analytical met hods available for determining compliance with
MRLVDs that are effective and practical to detect , quantify, and identify all residues of veterinary
drugs and pesticides (used as veterinary drugs) that may be present in commodities within the terms
of reference of this Codex Committee. These method s could be routinely used by regulatory control
authorities of member governments for their residue testing programmes to assure compliance with
food safety requirements.

 Methods with the capabilities mentioned above are not available for many compounds of
interest because of the extensive number of pote ntial veterinary drug residues which may find their
way into food within the terms of reference of the CCRVDF. To optimize the effectiveness of
regulatory programmes to test for veterinary dr ug residues, residue control programmes must use
available residue methodology to assure complianc e with Codex MRLVDs and, as necessary, take
appropriate regulatory action agai nst adulterated products , consistent with the reliability of the
analytical data.

 To assist regulatory authorities in determini ng their analytical needs for residue control
programmes, this document will describe the types of methods available and a set of attributes which
residue control programmes may utilize in carrying out their missions.

 The principal attributes of analytical methods for residue control programmes are specificity,
precision, accuracy (measured as systematic error a nd recovery), and sensitivity. Determining these
principal attributes in a method requires well designed multi-laboratory studies. The attributes noted
above will be presented in a subsequent section of this paper in more detail.

TYPES OF ANALYTICAL METHODS

 Several types of methods are available to food safety agencies and programmes to conduct
analyses that are consistent with the needs of resi due testing programmes. Decisions on the use of a
specific analytical method depends on the intende d objectives of the regulatory programme and the
analytical performance characteristics of methods.

 Methods that are suitable for determining co mpliance with MRLVDs are those that have
successfully completed an extensive multi-labor atory study for specific tissue and species
combinations. These methods provide analytical resu lts for either quantitation or identification that
are appropriate to take regulatory action without th e need for additional anal yses. In some cases,
these methods may be considered reference met hods, but reference methods frequently are not
routine.

 Many methods currently being used by r esidue control programmes have successfully
completed a multi-laboratory study. Multi-laborat ory method performance st udies generally satisfy
these analytical requirements. Validated met hods are those subjected to a properly designed
inter-laboratory study with three or more analysts, and preferably, in three different laboratories.
Collaborative study methods have successfully completed method evaluation in six or more
laboratories in an acceptable, statistically designed study. Some residue control methods that have
demonstrated their usefulness for determining comp liance with MRLVDs have an historical origin.
These history based methods were considered to be the best available at the time of initial regulatory

use and have continued in use over an extended pe riod of time in the absence of more effective
validated methods.

 Collaborative study and validated methods ma y be extended to additional tissues, species,
products, or combinations of these, not included in the original multi-laboratory study by completing
additional properly designed labor atory studies. On a case by case b asis, analytical results from
method extension studies may require additional analys is and/or review before reporting results or
taking regulatory action.

 Methods that have not been validated by trad itional inter-laboratory study, but provide results
that may be correlated and compared with data obtained from a collaborative study or validated
method, may serve a regulatory purpose. The validated and non-validated methods must be compared
in a statistically acceptable study design using porti ons of the same (homogeneous) samples prepared
for this comparison. The data from these studies should be reviewed by a peer group of regulatory
scientists to determine the comparability of method performance.

 There are some non-routine veterinary drug residue methods suitable for enforcement of
MRLVDs. These methods may not have been subject ed to an inter-laboratory study because they
require specialized expertise or equipment. Good quality control and quality assurance procedures
must be applied with these methods. Analytical data obtained from these methods should be reviewed
by a peer group of regulatory analysts before r ecommending any regulatory action. These analytical
methods may require analysis by another method to corroborate the initial experimental findings.

 Occasionally, a method may be suitable for Codex purposes because the toxicology of an
analyte does not allow an MRLVD to be established. Methods for analytes such as chloramphenicol
would be in this category. Some methods in th is category will include those presented above which
are not sufficiently sensitive to quantitate and/or id entify analyte(s) at or below the MRLVD. Such
methods also may not meet other performance factors stated above.

 There are some methods for which additional an alysis is required to support regulatory action.
This category may include methods that do not provide adequate information of structure or residue
concentration. Analytical methods that may have been subjected to ruggedness testing, but not
successfully to a multi-laboratory study to evaluate method performance, may have limited usefulness
in a residue control programme. However, th ese methods may be useful in non-recurring or
infrequent residue analyses, but they commonly require use of a rigorous protocol for sample analysis.
Results from such methods should be considered only as estimates of analyte concentration or
identification without additional supporting analyti cal information. Results from these methods can
be useful for gathering residue information and determining whether there is a need to develop a more
definitive method. These methods should not be used alone for residue control purposes on official
samples without additional information (e.g., such as the presence of an injection site in the sample).

 Certain methods may only be suitable for dete rmining whether or not a veterinary drug
residue problem exists in a sampling population. Me thods in this category are used for information
gathering, or exploratory residue control studies. Exploratory studies may also be undertaken using
methods which have not been subjected to inter-l aboratory study. These non-routine methods may be
complex, or require highly specialized instrumenta tion, and may have been developed and used only
in a single laboratory. Analytical results from th ese methods should not be used independently for
taking regulatory action, but may be used to determine the need for additional testing and/or
development of a method suitable for routine enforcement of MRLVDs.

 Methods designed to analyze large numbers of samples quickly may be useful for determining
the presence or absence of one or more compounds in a quantitative or semi-quantitative manner, at or
above a specified concentration. Results at or above the MRLVD commonly require additional

analysis using a method with acceptable performance characteristics before taking regulatory action.
Results from methods of this type that are below the MRLVD but above a level of reliable
measurement of a more definitive method, may have limited use in determining exposure patterns.

METHOD DEVELOPMENT CONSIDERATIONS

 Developing an analytical method requires analysts, laboratory space, equipment, and financial
support. To optimize the benefit of these resourc es, it is important to provide introductory and
background information to establish a perspective for planning an analytical method development
project, and for evaluating the performance of the analytical method.

 Residue control programmes should use methodology suitable to the analytes of interest to
assure a safe and wholesome food supply. Necess ary and appropriate regul atory action should be
taken against adulterated products, co nsistent with the reliability of the analytical data. Before
initiating method development activities, the intended use and need for a method in a residue control
programme should be established. Other consider ations include the compound or class of compounds
of interest (and potential interfering substances), pot ential measurement systems and their properties,
the pertinent physical and chemical properties that may influence method performance, the specificity
of the desired testing system and how it was determ ined, analyte and reagent stability data and purity
of reagents, the acceptable operating conditions for meeting method performance factors, sample
preparation guidelines, environmental factors that may influence method performance, safety items,
and any other specific information pertinent to programme needs.

ANALYTICAL PERFORMANCE CHARACTERISTICS

 Specificity is the ability of a method to distinguish between the analyte of interest and other
substances which may be present in the test sample . A residue control method must be able to
provide unambiguous identification of the compou nd being measured. The ability to quantitatively
differentiate the analyte from homologues, analogu es, or metabolic products under the experimental
conditions employed is an important consideration of specificity.

 Precision of a method is the closeness of agre ement between independent test results obtained
from homogeneous test material under the stipulated conditions of use. Analytical variability between
different laboratories is defined as reproducibility, and variability from repeated analyses within a
laboratory is repeatability. Precision of a method is usually expressed as standard deviation. Another
useful term is relative standard deviation, or coeffi cient of variation (the standard deviation, divided
by the absolute value of the arithmetic mean). It may be reported as a percentage by multiplying by
one hundred. Method variability achieved in the deve loping laboratory after considerable experience
with a method, is usually less than the variability achieved by other laboratories that may later also
use the method. For this reason, analytical data from a method should be statistically analyzed by
procedures described by Youden and Steiner (Ref: Statistical Manual of the AOAC, AOAC
INTERNATIONAL, Gaithersburg, MD, 1975) before prep aring a final method write up. If a method
cannot achieve a suitable level of performance in the developing laboratory, it cannot be expected to
do any better in other laboratories.

 Accuracy refers to the closeness of agreem ent between the true value of the analyte
concentration and the mean result that is obtained by applying the experimental procedure a large
number of times to a set of homogeneous samples. Accuracy is closely related to systematic error
(analytical method bias) and analyte recovery (measured as percent recovery). The accuracy
requirements of methods will va ry depending upon the planned regulatory use of the results.
Generally, the accuracy at and below the MRLVD or leve l of interest must be equal to or greater than
the accuracy above the level of interest.

 The percent recovery of analyte added to a blank test sample is a related measurement that
compares the amount found by analysis with th e amount added to the sample. In interpreting
recoveries, it is necessary to recognize that analyt e added to a sample may not behave in the same
manner as the same biologically incurred analyte (veterinary drug residue). At relatively high
concentrations, analytical recoveries are expected to approach one hundred percent. At lower
concentrations and, particularly with methods involving a number of steps including extraction,
isolation, purification, and concen tration, recoveries may be lower. Regardless of what average
recoveries are observed, recovery with low variability is desirable.

 The sensitivity of a method is a measure of its ability to detect the pres ence of an analyte and
to discriminate between small differences in analyt e concentration. Sensitivity also requires the
ability to differentiate between analyte, relate d compounds and background interferences. For
analytical instruments used in residue analysis, sens itivity is determined by two factors: instrumental
response to the analyte and background interference, or instrument noise. Response is measured by
the slope of the calibration curve with analyte sta ndards at concentrations of interest. An ideal
situation would be afforded by a linear curve. Instrument noise is the response produced by an
instrument when no analyte is present in the test sample.

 There are a number of collateral attributes suitable for analytical methods for regulatory
control programmes beyond these principle method attr ibutes. Methods should be rugged or robust,
cost effective, relatively uncomplicated, portable, and capable of simultaneously handling a set of
samples in a time effective manner. Ruggedness of a method refers to results being relatively
unaffected by small deviations from the optimal amount s of reagents used in the analytical method,
time factors for extractions or reactions, or temp erature. This does not provide latitude for
carelessness or haphazard techniques. Cost-effectiv eness is the use of relatively common reagents,
instruments, or equipment customarily available and used in a laboratory devoted to veterinary drug
residue analyses. An uncomplicated method uses si mple, straightforward mechanical or operational
procedures throughout the method.

 Portability is the analytical method characteris tic that enables it to be transferred from one
location to another without loss of established analytical performance characteristics.

 The capability of a residue control method to si multaneously analyze a set of samples aids in
method efficiency by allowing sets or batches of sa mples to be analyzed at the same time. This
attribute reduces the analytical time requirements of sample analysis. It provides, for example, the
capability of completing four or more analyses in a normal working day. This is important when
large numbers of samples must be analyzed in short or fixed time frames.

 Establishing method performance attributes is very important. These attributes provide the
necessary information for food safety agencies to develop and manage their public health
programmes. Performance attributes for analyt ical methods also provide a basis for good
management decisions in future planning, evaluation, and product disposition. For the animal health
care industry, it provides a guideline for knowing exactly what performance must be achieved in
developing analytical procedures. All will be nefit by having well defined analytical method
performance factors.

INTEGRATING ANALYTICAL METHODS FOR RESIDUE CONTROL

 Residue control and standard setting organiza tions have different terminologies to describe
application of analytical methods. Methods of anal ysis for veterinary drug residues in foods must
ultimately be able to reliably detect the presence of an analyte of interest, determine its concentration,
and correctly identify the analyte at and above an established maximum residue limit (MRLVD) for
regulatory enforcement actions to be taken. The latter methods would be classified as confirmatory

methods. These confirmatory methods may or ma y not have a quantitative or semi-quantitative
component.

 Other types of methods that may be used in residue control programmes, and which can
strengthen such a programme, may be classified into two additional categories. These categories are
quantitative methods and screening methods. Qu antitative methods provide precise information
concerning the amount of an analyte that may be pr esent, but may only provide indirect information
about the structural identity of the analyte. Screening methods may quickly determine the presence of
one or more compounds, based upon one or more common characteristic of a class of veterinary drugs
in a qualitative or semi-quantitative manner at a sp ecified concentration limit. They may also
determine that an analyte is below the limit of detection of the screening method.

 These three categories of methods, confirmatory, quantitative, and screening, often share a
common set of performance characteristics describe d above. In addition, they may have other
specific considerations. Understanding the relations hip between these three categories of methods is
important in the development a nd operation of a balanced residue control programme. Screening
methods are useful because they provide greater an alytical efficiency (i.e., a greater number of
analyses may be performed in a given time frame) th an quantitative and/or confirmatory methods. In
many circumstances screening methods can be perfo rmed in non-laboratory environments. Screening
methods suitable for use in non-laboratory environm ents may be less expensive for regulatory control
programmes than conducting all testing within a labo ratory setting. Screening methods can be to
separate test samples with no detectable residue fro m those that indicate the presence of a veterinary
drug residue at or below an MRLVD or an approp riate level of interest. This would allow a
laboratory to focus more of its efforts on quan titation of the presumptive positive test samples of
regulatory interest.

 Screening tests may also be used efficientl y in a laboratory setting because they analyze a
larger numbers of samples in a given time fram e than their corresponding quantitative methods. The
cost savings may not be as great as when screening methods are used in non-laboratory environments
because the costs associated with the handling and shipping of samples must still be incurred.
Presumptive positive results obtained from laboratory screening methods should not be used
independently in taking regulatory action. Data obtained from such methods may be used to
determine the need for additional testing and/or the development of a method suitable for routine
enforcement of MRLVDs.

METHOD DEVELOPMENT AND VALIDATION CONSIDERATIONS FOR RESIDUE
CONTROL METHODS

 The multi-laboratory method validation study is the most important factor in providing
analytical data to define method performance characteristics.

 In developing a residue control method, whenever possible, data should be collected from
three types of samples. Contro l test material from non-treated an imals provides information about
analytical background and matrix interferences. Fo rtified test material, containing known amounts of
the analyte added to the control material, yields information about the method's ability to recover the
analyte of interest under controlled conditions. Do sed or biologically incurred tissue, from food
producing animals and birds that have been treate d with the drug, provide additional analytical
performance information about biological or other interactions that may occur when analyzing residue
control samples.

 Residue methods should be designed with as much simplicity as possible. Analytical
simplicity helps minimize the variety, size, and type of glassware and equipment needed, minimizes
the potential for analytical errors, and reduces labor atory and method costs. Reagents and standards

must be available commercially or from some ot her reliable source. Instrumentation should be
selected based on its performance characteristics rather than a particular manufacturer.

 Residue methods are sometimes designed using inte rnal standards for analytical control. A
properly used internal standard will compensate for so me of the analytical variability of an analysis,
improving precision. However, an improperly used in ternal standard may obscure variables that are
an important part of the analytical measurement. If an internal standard is used, it should be added to
a sample as early as possible in the procedure, preferab ly to the test material before analysis begins.
Caution must be taken in the choice of internal sta ndards to ensure that they do not alter the percent
recovery of the analyte of interest or interfere w ith the measurement process. It is important to know
the extent and predictability of the effects of the in ternal standard on an analytical method. Internal
standards can greatly enhance method performance when used properly.

 Residue control methods that may be subjected to widely variable physical test environments
will place some additional requirements on methods . Addressing these may help improve method
ruggedness. Warmer environments may require reagen ts to be more thermally stable, while solvents
used in the analysis will have to be less volatile, and test sample requirements to be more lenient.
Cooler environments may require reagents and solvents to have different physical properties, such as
lower freezing point and greater solvating characteristi cs, to ensure effective extraction of an analyte.
Environmental temperatures may influence the time required to perform an analysis, as well as
influencing reaction rates, gravitational separations and colour development. These considerations
may strain efforts to standardize methods for use in broadly differing environments because of the
need to adapt methods to compensate for these factors.

 An analytical method developed and used in only one laboratory may have limited use in a
residue control programme. The reliability of repor ted values may be a concern even though strong
quality control procedures may have been employed. As a minimum, three laboratories expected to
use these methods should be used to develop pe rformance characteristics for residue control,
including analytical variability, and obtain sta tistically acceptable agreem ent on the same samples
divided among the testing laboratories. Methods wi th higher reliability for residue testing should be
able to successfully undergo a collaborative study involving at least six different laboratories (Ref:
Use of Statistics to Develop and Evaluate Analytical Methods (by G.T. Wernimont and W. Spendley,
AOAC INTERNATIONAL, Gaithersburg, MD), and Compound Evaluation and Analytical
Capability National Residue Programme Plan 1990 , (section 5, USDA, Food Safety and Inspection
Service, Washington, D.C.)).

 The principles for conducting either a validati on or collaborative study of a residue control
method are the same. Samples for evaluating met hod performance should be unknown to the analyst,
contain the residue near the MRLVD as well as samples with the analyte above and below the level of
interest, and test material blanks. All study sam ples should be analyzed over a limited number of
days, preferably with replicate analysis, to improve statistical evaluation of method performance. It
should be noted that these are only minimal requirements. Duplicate analyses in only six laboratories
with one or two animal species and tissues would yield limited quality estimates for repeatability and
reproducibility.

 Quality control and quality assurance principles are essential components of residue analysis.
They provide the basis for ensuring optimum me thod performance for all methods, regardless of
method attributes, whenever they are used. Quality control monitors those factors associated with the
analysis of a sample by a tester, while quality assurance provides the oversight by independent
reviewers to ensure that the analytical programme is performing in an acceptable manner. Quality
control and quality assurance programmes are inva luable to support decision-making for residue
control agencies, improving the reliability of analy tical results, and providing quality data for residue

control programmes to demonstrate food safety to consumers, producers, and law making bodies
regarding residues of veterinary drugs in food.

PART III

ATTRIBUTES OF ANALYTICAL METHODS FOR RESIDUES
OF VETERINARY DRUGS IN FOODS

 The performance characteristics of analytical methods for determining compliance with
MRLVDs must be defined and prop osed methods evaluated accordingl y. This will ensure reliable
analytical results and provide a secure basis for dete rmining residues of veterinary drugs in foods for
commodities in international trade. Part II, General Considerations of Analytical Methods for
Regulatory Control, presents a discussion of general types or categories of regulatory methods, and
provides a scheme for using these analytical me thods based upon their intended purpose in a
regulatory framework. In the discussion below, attributes common to three categories of methods for
determining compliance with Code x MRLVDs referred to as Level I, Level II and Level III methods
will be presented followed by additional attributes that are applicable to only one or two categories of
methods.

(Note: This Part contains numerous definitions. The CCRVDF has attempted to harmonize these
definitions with those provided in the "Definitions for the Purpose of the Codex Alimentarius" in
Volume 1.)

GENERAL CRITERIA FOR ATTRIBUTES

 All methods may be characterized by a set of attributes or properties that determine their
usefulness: specificity - what is being measured; precision - the variability of the measurement; and
systematic error or bias - measured as analytical recovery. Another attribute, accuracy, usually refers
to the closeness of agreement, or trueness of an an alytical result, between the true value and the mean
value obtained by analyzing a large number of samp les of the test material. For semi-quantitative
methods and screening methods, accuracy may also be defined as a measure of false negative and
false positive responses. The limit of detection , method sensitivity, practicality of use , tissue/species
applicability, limit of detection and limit of quantitation are additional attributes that have varying
relevance to some methods, depending upon the intended use of the analytical results.

 Methods may be described according to perform ance attributes as an alternative to classifying
them by intent of use or purpose. This altern ative approach defines methods by the analytical
information and detail provided concerning the amount and nature of the analyte(s) of interest. Level
I methods are the most definitive, while Level III methods usually provide ge neral information about
the presence of an analyte and semi-quantitative information about the amount of material present.

 Level I methods quantify the amount of a specific analyte or class of analytes and positively
identify the analyte, providing the greatest amount of reliability for quantitation and structure
identification of the analyte at the level of inte rest. These methods may be a single procedure that
determines both the concentration and identity of the analyte, or a combination of methods to quantify
and confirm the structure of a veterinary drug residue. A good example of the latter is a
chromatographic technique combined with a m ass spectrometry procedure. Although Level I
methods are generally instrumental procedures, observation of a pathologic or other morphologic
change that specifically identifies exposure to a cl ass of veterinary drugs, could potentially be a Level
I method, if it has sufficient sensitivity and precision.

 Level I methods may be limited to analytes with appropriate physical and chemical properties
amenable to chromatographic and other instrumental methods of analysis. For example, at the present
time, there are very few antibiotic drugs for veteri nary use that have mass spectrometric procedures
useful to determine compliance with MRLVDs beca use of the relatively low volatility and stability of

antibiotic drugs to chemical techniques common ly employed for mass spectrometry analysis.
However, new technology and instrumentation is now making development of these confirmatory
methods possible. Level I methods are sometimes referred to as reference methods.

 Level II methods commonly determine the concentrat ion of an analyte at the level of interest,
but do not provide unequivocal structure identification. These methods may use structure, functional
group, or immunological properties as the basis for th e analytical scheme. A common practice is to
use one Level II method as the determinative assay and a second Level II method as the positive
identification procedure. These methods may also be used to verify the presence of a compound or
class of compounds. Two Level II methods may provi de information suitable for a Level I method,
when they use different chemical procedures. The majority of analytical methods commonly used to
support MRLVDs are quantitative Level II laboratory methods.

 Level III methods are those that generate less de finitive but useful information. These testing
procedures generally determine the presence or the absence of a compound or class of compounds at
some designated level of interest. They are ofte n based on non-instrumental techniques. For these
reasons, Level III methods are commonly referred to as screening or semi-quantitative methods.
Results on a given sample are not as reliable as Leve l I or II methods and usually need corroborating
information for regulatory action. For exam ple, Level III methods may provide good semi-
quantitative information, but poor identification. Alternatively, they may provide strong or
unequivocal identification with very little quantitativ e information. Level III methods are not poorly
described or sloppy methods. They must ha ve a well-defined opera ting protocol, operating
characteristics and performance data.

 Many of the microbiological agar plate assay procedures, enzyme inhibition assays and
immunology based systems are in this category. They are useful for residue control programmes
because of their high sample capacity, portability, convenience and potential suitability to non-
laboratory environments. The limitation of Level III type methods is that action based on individual
positive results usually requires verification using Le vel I or II methods. Individual results may be
verified by epidemiological information.

 Level III methods may offer s ubstantial advantages to a resi due control programme. Their
advantages include analytical speed, sample effi ciency through batch analysis, portability to non-
laboratory environments, good sensitivity, or the abili ty to detect classes of compounds. Even though
a Level III method may not detect a specific compound at a regulatory limit (i.e., an MRLVD) with
every sample, it may be better than relying on Leve l I and II methods because of their ability to test
more samples.

 The decision to use Level III methods should be determined in part by performance
characteristics, as well as the need to test large numbers of samples within a given time frame. Two
key characteristics to consider for Level III methods are the percent false positives and percent false
negatives, determined by comparison with a validat ed quantitative assay in a statistically designed
protocol. The percent false negatives must be quite lo w at the levels of interest, while slightly more
flexibility may be acceptable for false positives. Re sidue detection limits can be described based on
these two parameters.

METHOD ATTRIBUTES

 Specificity is the ability of a method to dis tinguish between the analyte being measured and
other substances which may be present in the test ma terial. A proposed method also must provide the
required specificity for the compound being measured and discriminate between other structurally
similar substances. This characteristic is predom inately a function of the measuring principle or
detection system used. Certain instrumental techniques such as Fourier transform infrared

spectroscopy or mass spectrometry may be sufficiently specific by themselves to provide
unambiguous identification. These are often re ferred to as confirmatory methods. Positive
identification from a confirmatory method is usuall y considered necessary before regulatory action is
taken in those instances when an analytical result is not sufficiently specific for regulatory purposes.
Confirmatory methods may be considered Level I me thods when they provide a determinative result
to quantify and tentatively identify a given analyte, and a procedure which verifies the identity of the
analyte of interest.

 Other techniques, when they are used in combination, may be capable of achieving a
comparable degree of specificity as confirmatory techniques. For example, specificity may be
verified by combinations of methods such as thin layer chromatography, element-specific gas-liquid
chromatography and accompanying detection syst ems, formation of characteristic derivatives
followed by additional chromatography, or dete rmining compound specific relative retention times
using several chromatographic systems of differing polarity. Such procedures must be applicable at
the designated maximum residue limit (MRLVD) of the analyte.

 The specificity of a screening method normally is not as great as that of a determinative
method, because screening methods often take advantage of a structural feature common to a group or
class of compounds. These methods generally fit into the Level III methods category. Techniques
based on biological assays, immunoassays, or chro mogenic responses are not expected to be as
specific as those techniques which unequivocally id entify a compound. Specificity of a screening
method may be increased by the use of chromatographic or other separation technique.

 If a non-specific response or some ambiguity in a test result is obtained (i.e., cross-reactivity
with components of the matrix other than that for which the analysis was designed), studies that
approximate the concentration of the non-specific re sponse of the analytical method may be required
to identify the compounds that respond to the detec tion system. If the method is not sufficiently
specific, then a confirmatory or identification pro cedure will be needed to ch aracterize the analyte of
interest.

 Precision is an important performance charac teristic of residue control methods. This
attribute is common to all methods, and as noted be low, acceptable precision may not be a function of
the type of method, but of the concentration of the analyte in the original sa mple. There are several
types of precision. Inter-laboratory precision, or reproducibility, is the closeness of agreement
between test results obtained with the same method on id entical test material in different laboratories.
The variation in replicate analyses of a test mate rial within a laboratory when performed by one
analyst is repeatability. The intra-laboratory vari ability among analysts performing the same analysis
is within-laboratory bias, and is primarily due to random error. Precision is usually expressed as a
standard deviation (an absolute value determined experimentally). More useful is the relative
standard deviation, or coefficient of variation. This parameter expresses variability as a function of
concentration, and is relatively constant over a given concentration interval.

 Precision limits for analytical methods, as a f unction of concentration, are presented below.
The recommended values take into consideration the wide variety of methods, analytes, matrices, and
species within the terms of reference of the Comm ittee and that are usually applied in a broad-based
residue control programme.

Concentration Coefficient of Variability (CV)
(Repeatability)
≤ 1 µg/kg 35%
≥ 1 µg/kg ≤ 10 µg/kg 30%
≥ 10 µg/kg ≤ 100 µg/kg 20%
≥ 100 µg/kg 15%

 The variability achieved in the laboratory wher e a method was developed, and where there is
considerable experience, is usuall y smaller than that attained by laboratories that may later use the
method and have less experience with it. The fi nal version of the method should be optimized by
using procedures such as ruggedness testing to identi fy its critical control points and ensure that its
performance will not be adversely affected by small ch anges in using the analytical procedure. If a
method cannot achieve acceptable perfo rmance in the sponsor's laboratory, its performance usually
will not be any better in other laboratories.

 When developing analytical data to be used to define expected method variability and other
performance characteristics, methods should be perform ed by an analyst who has not been directly
involved in developing the method. This procedur e will verify the adequacy of the method's written
description and help identify critical parameters which affect method performance.

 The within laboratory coefficient of variation should be
≤ 15 percent when the designated
concentration of the analyte is greater than or e qual to 100 µg/kg. When the designated concentration
of the analyte is 10 - 100 µg/kg, the within laboratory coefficient of variation should be ≤ 20 percent.
When the concentration of interest is belo w 10 µg/kg, a coefficient of variation of ≤ 30 percent is
acceptable.

 A Level III method should be capable of identifying samples that contain a residue
concentration at the level of interest. When a sample contains a residue that exceeds the MRLVD
using a semi-quantitative (screening) method, regulat ory action requires additional analysis. In this
situation, the sample will require analysis usi ng a determinative method and a confirmatory method
with defined performance characteristics. A useful attribute for Level III methods is its precision at
and just below the MRLVD. Precision may be somewhat less important above the MRLVD.

 Systematic error, or method bias, is the di fference between the experimentally determined
(measured) value and the mean result that would be obtained by applying the experimental procedure
a very large number of times to the test material. Systematic errors are always of the same sign and
magnitude. Random error, however, is variable in magnitude and sign and the mean of random errors
may approach zero if sufficient samples are tested. Accuracy is generally expressed as the percent
recovery of the analyte of interest. Recovery is obtained experimentally by adding known quantities
of the analyte directly to separate portions of the test material and comparing the amount recovered
with the amount added. The percent recovery of an analyte added directly to the sample matrix is
generally a higher value than is obtained experimentally when isolating the same biologically incurred
analyte from a given sample matrix. At relativel y high analyte concentrations, recoveries are
expected to approach 100 percent. At lower concen trations or with multi-step methods that require
extractions, solvent transfers, concentration steps, and absorption chromatography, recoveries will be
lower. Variability of analyte recovery is usually as important as the percent recovery itself and should
be small.

 Average recoveries of 80 to 110 percent should be obtained when the MRLVD for the analyte
is 100 µg/kg or greater and when the analytical method can be performed with acceptable precision.

 Recommended acceptable recoveries at lower MR LVDs are 70 to 110 percent when the
MRLVD is 10 µg/kg to 100 µg/kg, and 60 to 120 percent when the MRLVD is less than 10 µg/kg.
These recovery limits are reasonable when viewed with in the context of the wide variety of residues,
methods, matrices, and species normally included in a broad-based residue testing programme.
Variability in recovery should be small regardless of the percent recovery.

 Correction factors for more or less than 100 percent recovery may be appropriate when
analytical methods use isotope dilution procedures or other appropriate intern al reference standards
for quantitation purposes.

 The accuracy requirements of different types of methods will vary with the intended use for
the results. In general, methods should have thei r greatest accuracy at the MRLVD. The accuracy
requirements of confirmatory methods may not be as great as is required for quantitative methods,
because in most residue control programmes the se methods are only performed after a residue
concentration greater than the MRLVD has been determined by a quantitative method. Most
confirmatory methods have a quantitative aspect bu ilt into them which serves as an additional check
on the previously performed quantitative method. Suggested accuracy requirements for methods are
given below, and are based upon the previously stated considerations of a broad-based residue testing
programme.

Concentration Acceptable range
≤ 1 µg/kg -50 to +20%
≥ 1 µg/kg ≤ 10 µg/kg -40 to +20%
≥ 10 µg/kg ≤ 100 µg/kg -30 to +10%
≥ 100 µg/kg -20 to +10%

 Level III methods may be useful for residue c ontrol programmes in several scenarios. For
example, they may be used in situations wher e no MRLVD can be established or where one does not
otherwise exist, and regulatory ac tion may be taken if any amount of the drug residue is found. Non-
quantitative methods may also be used when the MRLVD or the level of interest is less than the limit
of detection of the screening method. In both cases, it is necessary to evaluate proposed methods for
the specified residue test to experimentally determ ine the lowest concentration at which an analyte
can be detected and to determine method accuracy a nd limits by using data on false negatives (i.e., a
negative analytical result is obtained when the an alyte is present), and false positives, (i.e., a positive
result is obtained when the analyte is not present) at or above the MRLVD.

 If Level III methods involve a manufactured test kit, at a minimum, the accuracy, precision,
specificity and lowest detection limit data should be provided by the manufacturer. The users should
verify the validity of this data through their ow n studies and evaluate performance by quality control
checks. The lowest detectable concentration of an analyte should represent the smallest amount of an
individual analyte that can be reliably observed or found in the test sample. The method accuracy,
expressed in terms of false negatives and false positives, should be determined by a statistically valid,
scientifically correct study with appropriate controls.

 In general, non-quantitative methods should produce less than 5 percent false negatives and
less than 10 percent false positives when analysis is performed on the test sample. These values may
vary depending on the type of action that will be ta ken as a result of the analytical test. Conservative
values should be chosen appropriate to residue testing needs.

 The limit of detection is the smallest measured concentration of an analyte from which it is
possible to deduce the presence of the analyte in the test sample with acceptable certainty. This
determination should consider matrix related interferences with an instrumental signal to noise (S/N)
ratio greater than 5:1 or the concentration determined by a factor of 3 standard deviations of the signal
response for blank tissue, whichever is less.

 Sensitivity is a measure of the ability of a method to detect the presence of an analyte and to
discriminate between small differences in analyte cont ent. This may be determined by the slope of
the standard curve at concentrations of interest.

COLLATERAL PARAMETERS FOR METHODS SUITABLE FOR ROUTINE USE FOR
ENFORCEMENT OF MAXIMUM RESIDUE LIMITS

 Residue control methods should be capable of analyzing several samples simultaneously,
normally in groups of four or more during a no rmal work period. These methods should ideally
require no more than about 2 hours of analytical ti me per sample. This does not require that results
for a set of analytical samples must be complete d within 2 hours. Several hours may be necessary to
prepare a set of extracts or complete a microbiological incubation, for example, before analysis of test
sample results can be completed. Regulatory me thods should be able to be completed within
reasonable time periods consistent with regulatory objectives.

 The applicability of a method refers to the tissu e matrices and animal species that a particular
method has demonstrated acceptable method performance for compliance with an MRLVD.

 The limit of quantitation corresponds to the sma llest measured concentration of residue from
endogenously incurred test material above which a de termination of the analyte can be made with a
specified degree of certainty to its accuracy and precision.

 For determining compliance with an MRLVD, an analytical method should require only
instrumentation generally available in a laboratory devoted to trace analyses in the appropriate test
material. The methods should be capable of analyzin g analytes at or below the MRLVD. In addition,
the methods should have written protocols that include extensive quality assurance and quality control
components. These quality assurance plans should also include analyst training needs.

 Whenever applicable, methods should be evalua ted in an inter-laboratory study using some
test samples with biologically incurred analyte. Experience suggests that using biologically incurred
residues for method evaluation provides a bette r description of the expected performance
characteristics of the method as it would be used routinely by regulatory authorities.

 Residue testing methods must demonstrate that they can be performed at their described
performance characteristics by expe rienced analysts who have received adequate method training.
Acceptable methods performance can be demonstrat ed by successfully analyzing sets of samples
containing the analyte of interest in sample ma trices within the scope of the CCRVDF terms of
reference.

 Methods to determine compliance with MR LVDs should utilize commercially available
reagents and equipment. Methods may become impractical and potentially unreliable if new or
unusual reagents are not readily available. New or unusual reagents and standards must be assured by
the method sponsor upon request.

 Regulatory methods for residue control should not use large quantities of solvents, reagents,
and supplies which would render the method economi cally impractical. Methods for determining
compliance with Codex MRLVDs should be designed for safe performance by trained analysts.

 Several other indicators of satisfactory performan ce may be helpful in determining whether or
not a method is acceptable for Codex purposes. These include: (a) calibration (standard) and
analytical (recovery) curves; (b) information on th e effectiveness of extraction for removing specific
potential interferences; (c) adequate method sensitivity (slope of the standard calibration curve) with a
linear dynamic range at the concentration of interest; (d) adequate resolution from matrix components;
(e) sufficiently low and reproducibly consistent blanks; and (f) stability studies performed on the
matrix, the analyte within the matrix, and reagents u sed in the procedure. The analytical response of
the blank should be no more than 10% of the anal yte response at the MRLVD, whenever an MRLVD
is established. Critical control points within the an alytical procedure, those steps where extreme care
must be taken to insure optimum method performan ce, and stopping points within the method need to
be identified and noted in the written procedure.

SPECIFIC DATA NEEDED

 The developer of a method must provide per tinent information and supporting data necessary
to familiarize other intended users of a method so they can achieve satisfactory methods performance.
This necessary information should include the following:

 For Codex methods, the developer of a method should collect and provide data from three
types of samples: (a) control tissue samples from an imals that are known not to have been exposed to
the analyte; (b) tissue samp les that are fortified or spiked at the levels of interest by the addition of
known amounts of the analyte to uncontaminated control tissue; and (c) dosed or incurred tissue
samples at the concentration of interest (MRLVD) obtained from animals treated with the veterinary
drug according to good veterinary practices.

 Methods provided by developers, drug sponsors and commercially available test kits intended
for use with Codex MRLVDs should only be recomme nded for use after it can be demonstrated that
the method(s) will meet established performance char acteristics or provide an improvement to current
methods, regulatory decision making and regulatory consistency.

 The developer of the method must determine: (a) the analytical response obtained when the
matrix is known to be free from ch emical interferences; (b) the met hod variability, and (c) the lowest
concentration at which the amount of analyte presen t can be detected with reasonable statistical
certainty. The data should demonstrate that th e proposed method can satisfactorily recover and
identify known amounts of the analyte that have been added to the test sample. Finally, the developer
should demonstrate that the proposed method can sa tisfactorily recover the analyte from the target
tissue matrix in which it has been biologically bound or incurred. Recovery studies must demonstrate
absence of responses from substances that may interfe re or adversely affect the reliability of the
analysis.

 The method must demonstrate acceptable method performance in controlled laboratory
environments and in field trials which represent anticipated operating conditions, if that is the
intended use of the method. The results must be verified by appropriate quality assurance and quality
control procedures, including analysis of known bl ank and positive control samples. Analysis of
sufficient numbers of both positive and negative contro l samples must be performed to establish false
positive and false negative rates, with a statistically appropriate number of these samples analyzed by
a separate method to verify the results.

 A complete description of the method must be provided which includes the scientific
principle(s) upon which the method is based, prepara tion of analytical standards, appropriate tissues
the method is suitable for, shelf-life and storage cond itions for the analyte in solution and in the target
tissue matrix, reagent and standard shelf-life st ability, instrumentation as well as their performance

standards and calibration procedures, and identifica tion of critical steps and stopping places. Test
limitations as well as appropriate a nd inappropriate uses of the test must be described. Critical test
components and reagents must be identified and specifications described. The developer must
provide procedures for demonstrating evidence of satisfactory method performance as well as
guarantee the long term availability of all components necessary to successfully perform the test.

 For rapid test procedures, the quality control cr iteria needed to verify and maintain acceptable
method performance and to determine that a test k it is operating properly must be provided.
Information to verify proper test data interpretation associated with the quality control criteria must be
specified. A standard curve prepar ed for the analyte of interest of known purity is needed. A typical
analytical curve prepared by for tifying blank test material with the analyte of interest must be
provided.

 Data from uncontaminated, fortified, and dosed test material is required to show that the
method meets the specificity, precision, systematic e rror, and accuracy attributes for its intended use.
Test samples should be fortified at 0.5 (where practical), 1 and 2 times the MRLVD. Additional
samples within these concentration limits may be included.

 Data from inter-laboratory studies should be provided on the analytical worksheet developed
for evaluating methods for Codex MRLVDs. The method should be tested in three or more
laboratories for ease in evaluating multi-laboratory study reports. Each laboratory should analyze
samples fortified as stated previously and shoul d test biologically incurred samples containing the
analyte at the same concentrations.

 Test kits should utilize simple, unambiguous pr ocedures. The analytical procedures designed
into test kits to be used by field personnel shoul d be successfully evaluated by at least ten trained
individuals in a properly designed study before being placed into general use. The study environment
must be similar to that expected for routine use of the test. The design should provide sufficient data
for a statistical description of false positive and false negatives, and allo w determination of the
analytical limits of the test. Participants should include those individuals who have been trained by
the developer of the test to determine that training procedures are sufficient to provide acceptable
method performance.

STANDARD REFERENCE MATERIALS FOR VETERINARY DRUG RESIDUE ANALYSIS

 At the present time it is usually not practical to develop standard reference materials for
determination of residues of veterinary drugs in foods. There are specific difficulties in developing
standard reference materials for international use as noted below.

 Some drugs are not sufficiently stable in test materials at ordinary freezer temperatures.
Veterinary drug residue concentrations commonly de plete with time, dependent upon the analyte and
test material, at ordinary freezer temperatures. These test materials must be stored and shipped at
ultra-cold temperatures or use lyophilized, irradi ated, or treated otherwise to reduce enzymatic
activity and prevent loss of analyte. The relevant studies for most compounds of interest to CCRVDF
have not been published at this time, so it is not known whether treatments noted above will affect the
extent to which the drugs of interest are bound to the tissues, whether drug residues remain stable in
tissues, or whether they might chemically alter the trace residues.

 Recognized standard reference materials are ge nerally very expensive and, considering their
other limitations, they are generally not cost eff ective for residue analysis. Commercial reference
standards for veterinary drugs have limited availability at the present time. Because of these and other
limitations, such as analytical variability of a method versus the concentration of the analyte (i.e., low
mg/kg to µg/kg), standard reference materials are generally inappropriate.

ANNEX 11

Melengestrol acetate (CCRVDF chronology)

CCRVDF (session) Discussion/Status
11th CCRVDF (1998) Added melengestrol acetate (MGA) to the priority list for evaluation
or re-evaluation at the 54th JECFA27
12th CCRVDF (2000) Agreed to not cons ider the recommendations of the 54th JECFA.28
13th CCRVDF (2001) Advanced the temporary MRL for MGA to Step 5 and noted that
MGA was scheduled for re-evaluation by the 58 th JECFA for a
practical analytical method for monitoring residues at the
recommended MRL.29
14th CCRVDF (2003) Decided to retain the MRLs at Step 6 and requested JECFA
re-evaluation based on new informat ion and additional data to be
submitted.30
15th CCRVDF (2006) Was informed of an inaccu racy in the calculation of the TMDI for
MGA and decided to request JECFA to reassess the recommended
MRLs from the 62
nd JECFA and to circulate for comments at Step 6
the MRLs from the 66th JECFA for consideration at it next session.31
16th CCRVDF (2006) Considered the MRLs for MGA recalculated by the 66 th JECFA.
However, because of the lack con sensus on the further advancement
of the MRLs, the Committee agreed to retain the MRLs at Step 7 for
further consideration at its next session (scheduled in 2007).32

28 ALINORM01/31, para. 61.
29 ALINORM 03/31, para 43.
30 ALINORM 03/31A, paras 48 and 113 and Appendix VII.
31 ALINORM 05/28/31, paras 61-62.
32 ALINORM 06/29/31, para. 73, Appendix III.

ANNEX E-2

REPLIES OF THE JOINT FAO/WHO JECFA SECRETARIAT
TO CERTAIN QUESTIONS POSED BY THE PANEL
TO INTERNATIONAL ORGANIZATIONS

Introduction

Risk Analysis is a process consisting of three components: risk assessment, risk management and risk
communication. Risk management activities for veteri nary drugs within Codex are carried out by the
CCRVDF, which prepares draft standards, guidelines and recommendations for consideration by the
CAC. Risk assessment activities are performed by JECFA, which is an independent scientific expert
body, which advices CCRVDF, but also Members and WHO and FAO directly. JECFA provides
independent advice and as such is not part of Code x. Risk communication is the responsibility of all
involved parties. JECFA has provided scientific advice on veterinary drug residues since 1982. The
separation of tasks is illustrated in the graph below.

Annex 1 gives a brief fact sheet on JECFA, which has been meeting since 1956, i.e. it predates Codex.

3. Please identify any international guidance documents relevant to the conduct
 of a risk
assessment with respect to veterinary drug residu es. Since when have they been available?
Please also indicate if there is any relevant ongoing work at Codex.

The elaboration and application of risk assessmen t principles are within the responsibility of the
scientific expert bodies. Codex bodies elaborate risk assessment policies as they relate to their
respective areas of work for the risk assessment bodies in terms of th e respective roles and tasks and
general guidance on the type of scientific advice requested.

Risk Analysis Paradigm

Risk
Assessment
Risk
Management
Risk
Communication
Scientific advice and
information analysis
JECFA
Regulation
and control
CCRVDF & CAC
Dialog with
all stakeholders

The following lists the key interna tional risk assessment documents relevant to the assessment of
veterinary drug residues in food:

– The basis for JECFA risk assessments of veterinary drug residues in food: Environmental
Health Criteria 70: Principles for the Safety Assessment of Food Additives and Contaminants
in Food, World Health Organization, Geneva 1987.
http://www.inchem.org/documents/ehc/ehc/ehc70.htm
. Subsequently, these principles have
been further elaborated, clarified and updated in JECFA meetings dealing with veterinary
drug residues in food. These agreed updates are reported under 'General Considerations' in
each report. This is a continuing effort to have up-to-date risk assessment principles and
methods applied. These principles have been developed over the years of evaluation of
different chemical substances, including veterinary drugs.

– Consolidation of all these principles and harm onization between the assessment of veterinary
drug residue and pesticide residue, to the extent useful, within the 'Project to update the
principles and methods for the assessment of chemicals in food', to be published by the end of
2006. http://www.who.int/ipcs/food/principles/en/

– Principles and methods for the derivation of ma ximum residue limits of veterinary drugs in
food as elaborated by JECFA have been compile d in a format easily accessible to the public
in the following document: Procedure for reco mmending maximum residue limits – residues
of veterinary drugs (2000) ftp://ftp.fao.org/es/esn/jecfa/2000-06-
30_JECFA_Procedures_MRLVD.pdf

– The data requirements for the assessment of the residues of veterinary drugs have been
detailed by the Committee at the 32
nd (1987) and 42nd (1994) meetings. These are contained in
the above publication. Furthermore, a more complete description of these procedures is
available from a recent expert FAO/WHO/RI VM workshop on the update of principles and
methods of risk assessment: Maximum Residue Li mits (MRLs) for pesticides and veterinary
drugs (report available at the following website
ftp://ftp.fao.org/ag/agn/jecfa/bilthoven_2005.pdf

– Several other documents rega rding various aspects for the risk assessment of chemicals as
developed and published by the In ternational Program on Chemical Safety, in particular (but
not exclusively):

• Guidance values for health-based exposure limits. Assessing human health risks of
chemicals: Derivation of guidance values for health-based exposure limits (EHC
No 170, 1994) http://www.inchem.org/documents/ehc/ehc/ehc170.htm
• Biomarkers In Risk Assessment: Validity And Validation, Environmental Health
Criteria 222, 2001. http://www.inchem.org/documents/ehc/ehc/ehc222.htm
• IPCS Conceptual Framework for Evalua ting a Mode of Action for Chemical
Carcinogenesis. Regulatory Toxicology and Pharmacology Volume 34 (2001)
146-152. http://www.who.int/ipcs/publications/methods/harmonization/en/index.html

• Harmonization Project Document No. 2, Chemical-specific adjustment factors for
interspecies differences and human variability: guidance document for use of data in
dose/concentration–response assess ment, WHO, Geneva 2005.
http://whqlibdoc.who.int/publications/2005/9241546786_eng.pdf
• Guidance on acute reference dose setting. Fo od and Chemical Toxicology 43 (2005)
1569–1593 http://www.who.int/ipcs/food/jmpr/arfd_guidance.pdf

All these documents are the outcome of international expert meetings and represent the agreed views
of the participating experts and several of those ha ve also been published in the scientific literature.
There is a continuous effort to update and harm onize on an international level risk assessment
methodologies for chemicals.

4. The European Communities states that there is "no Codex standard specifically on the
risk assessment of effects of residues of veterina ry drugs" but a general one on microbiological
assessment. Is this correct? Which guidelines or principles have been used by JECFA in the
conduct of its risk assessments with respect to th e hormones at issue? [see para. 192 of EC
Rebuttal Submission (US case)]

As outlined under question 3 above, the elaboration a nd application of risk assessment principles are
within the responsibility of the scientific expert bodies. Regarding the principles for the risk
assessment of chemicals in food, including of veteri nary drug residues in food, please refer to the list
of international risk assessment guideline documents above.

6. Please briefly describe the four steps of a risk assessment (hazard identification, hazard
characterization, exposure assessment and risk characterization) as identified by Codex,
indicating any relevant sources.

Risk assessment comprises of four steps, as defined by many national and international bodies:

Hazard identification
: identification of potential adverse health effects as inherent property of a
compound.

Hazard characterization
: includes dose-response assessment, c onsiderations on species sensitivity,
relevance of specific effect for humans etc.

Exposure assessment
: estimation of dietary intake

Risk Characterization
: integration of the hazard characterization and exposure assessment for a
qualitative or quantitative estimate of risk.

Main reference: Application of risk analysis to food standards issues: report of the Joint FAO/WHO
Expert Consultation, 1995.

7. Please comment on the EC statement made in para. 140 of the EC Replies to Panel
Questions that "which ever approach of a risk a ssessment is followed, they are all based on a
deterministic approach to risk characterization [and that they] have serious limitations in non-
linear situations, such as in the current case regarding hormones". Are these situations
addressed by the risk assessment guidance cur rently available from the Codex Alimentarius
Commission? [see Canada's comments in para. 72 of its Rebuttal Submission]

There are no risk assessment guidelines available from the Codex Alimentarius Commission, which
applies to the assessment principles and procedures of JECFA. JECFA is an expert committee which
has been called into existence by the Director Generals of FAO and WHO. The constitutions and rules
of both organizations for such committees are in particular considered in Article VI of the
Constitution of FAO and the Regulations for Expert Advisory Panels and Committees of WHO lay
down the basic rules which assure excellence and independence of expert committees which provide
scientific advice to both organizations.

Throughout its existence JECFA has continued to develop principles for the safety assessment of
chemicals in food (see answer to question 3 above).

In general, most risk assessments of chemical s today on a national and international level are
deterministic, i.e. they use a point estimate for the toxicological endpoint and a point estimate for the
exposure assessment. This is not considered a limi tation of the risk assessment process, but often a
necessity due to the information at hand. Un certainties around these point estimates should be
considered in the risk assessment process. The current risk assessment process, which includes
consideration of sensitive subpopula tions, is considered to be suffi ciently conservative to be public
health protective.

Increasing efforts are under way, also within the International Program on Chemical Safety, to
explore methods to perform probabilistic risk assessme nt, i.e. include distributions rather than point
estimates in the risk assessment process. In th e area of exposure assessment probabilistic methods
have been developed and are increasingly applied, also by JECFA, however probabilistic methods in
the toxicological assessment are not yet internati onally agreed and are not yet commonly applied.
Moreover, the outcome of a probabilistic risk assessme nt is much more difficult to interpret and apply
by risk managers.

Probabilistic or deterministic approaches can be applied, independent if a compound is assumed to act
via a threshold mechanism, i.e. non-linear, or not. JECFA's assessment process is based on the
mechanism of action of the compound to be evaluate d, non-linearity is assumed if the adverse effect
of a compound is caused via a mechanism with a thr eshold of effect. In such a case, as for the
hormones, a no-effect-level can be determined from which an ADI can be established.

JECFA has in its reports and in the toxicological monographs on the safety assessment of the
hormones used risk assessment principles particularly targeted to the evaluation of such substances.
JECFA has distinguished between hormones that ar e identical to those occurring naturally in food-
producing animals and human bei ngs, i.e. endogenously produced hormones and substances with
hormonal activity, which are either synthetic or na turally occurring but which are not identical with
human endogenous hormones. As is standard practice, all toxicological effects of the hormones have
been considered by JECFA in th e risk assessment, including the hormonal no-effect-levels (the dose
at which no effects are found) and other relevant toxicological end-points, such as reproductive
toxicity, genotoxicity and potential carcinogenici ty. The conclusion of the risk assessments are
detailed in the respective report and monographs of JECFA.

8. Do JECFA or Codex materials confirm Cana da's statement in para. 80 of its Rebuttal
Submission that "... while international risk a ssessment techniques suggest that a dose-response
assessment is optional for biological or physica l agents when the data cannot be obtained, a
dose-response assessment should always be cond ucted for chemical agents ..."? [see Exhibit
CDA-25]

Dose-response assessment is an integral part of each assessment and is an essential part of the hazard
characterization step. This can be done in a quantita tive or a qualitative way. In the qualitative sense
this is the determination of a no-effect-level (NOEL or NOAEL) from an experimental or
epidemiological study. For the hormones JECFA used this approach. In some cases, for contaminants
(e.g. aflatoxins), JECFA has applied a quantitative dose-response assessment.

The International Programme on Chemical Safety (IP CS) has recently held an international workshop
to further elaborate the principles of dose-respon se assessment. The final report will be published in
the Environmental Health Criteria Series: Prin ciples for Modelling Dose-Response for the Risk
Assessment of Chemicals. Specifically as relevant to chemicals in food, part of the report will also be
included in the updated principles document on the risk assessment of chemicals in food (see under
question 3). The draft report was made availabl e for public comment, and is accessible under:
http://www.who.int/ipcs/methods/harmonization/draft_document_for_comment.pdf

9. Please provide definitions for the followin g terms: Acceptable Daily Intake (ADI) and
Maximum Residue Limit (MRL).

ADI: acceptable daily intake: An estimate of the amount of a substance in food or drinking water,
expressed on a body-weight basis, that can be ingested daily over a lifetime without appreciable risk
(standard human = 60 kg). The ADI is listed in units of mg per kg of body weight.
Source: JECFA glossary of terms: http://www.who.int/ipcs/food/jecfa/glossary.pdf
 (based on
EHC 70)

ADI: Estimated maximum amount of an agent, expressed on a body mass basis, to which individuals
in a (sub)population may be exposed daily over their lifetimes without appreciable health risk.
Related terms: Reference dose, Tolerable daily intake
Source: IPCS Risk Assessment Terminology
http://www.who.int/ipcs/methods/harmonization/areas/ipcsterminologyparts1and2.pdf

MRL: Residues of veterinary drugs is defined as follows in the Procedural Manual of the Codex
Alimentarius Commission: Residues of veterinary drugs include Parent compounds and/or their
metabolites in any edible portion of the animal product, including associated impurities of the
veterinary drug concerned, which may be of signi ficance to human health. On a recommendation to
harmonize the definitions of residues of veterinary drugs and pesticides from the conclusions of the
FAO/WHO workshop on updating the principles a nd methods of risk assessment: MRLs for
pesticides and veterinary drugs (see answer to qu estion 3 above), a modified definition was adopted
by the 66 th meeting of JECFA as follows: Parent compounds and/or their metabolites, including
associated impurities of the veterinary drug concerned, in any edible portion of the animal product,
which may be of significance to human health.

10. Please describe the procedure followed by JECFA in the identification of ADIs and the
development of recommendations on MRLs. Please also identify and describe any steps that are
taken in the risk assessment process to build a margin of safety into to the final
recommendation.

Establishment of ADI

Source: EHC 70:

 5.5. Setting the ADI

 Almost any substance at a high enough test leve l will produce some adverse effect in animals.
Evaluation of safety requires that this potential adverse effect be identified and that adequate
toxicological data be available to determin e the level at which human exposure to the
substance can be considered safe.

 At the time of its first meeting, JECFA recogni zed that the amount of an additive used in
food should be established with due attention to "a n adequate margin of safety to reduce to a
minimum any hazard to health in all groups of consumers" (9, pp. 14-15). The second
JECFA, in outlining procedures for the testing of intentional food additives to establish their
safety for use, concluded that the results of animal studies can be extrapolated to man, and
that

 "some margin of safety is desirabl e to allow for any species difference in
susceptibility, the numerical differences between the test animals and the human
population exposed to the hazard, the greater variety of complicating disease

processes in the human population, the difficu lty of estimating the human intake, and
the possibility of synergistic action among food additives" (10, p. 17).

 This conclusion formed the basis for establis hing the "acceptable daily intake", or ADI, which
is the end-point of JECFA evaluations for inten tional food additives. In the context in which
JECFA uses it, the ADI is defined as an esti mate (by JECFA) of the amount of a food
additive, expressed on a body weight basis, that can be ingested daily over a lifetime without
appreciable health risk.

 The ADI is expressed in a range, from 0 to an uppe r limit, which is considered to be the zone
of acceptability of the substance. JECFA expr esses the ADI in this way to emphasize that the
acceptable level it establishes is an upper limit and to encourage the lowest levels of use that
are technologically feasible.

 Substances that accumulate in the body are not su itable for use as food additives (39, p. 8).
Therefore, ADIs are established only for those compounds that are substantially cleared from
the body within 24 h. Data packages shoul d include metabolism and excretion studies
designed to provide information on the cumulative properties of food additives.

 JECFA generally sets the ADI of a food add itive on the basis of the highest no-observed-
effect level in animal studies. In calculating the ADI, a "safety factor" is applied to the no-
observed-effect level to provide a conservativ e margin of safety on account of the inherent
uncertainties in extrapolating animal toxicity da ta to potential effects in the human being and
for variation within the human species. When results from two or more animal studies are
available, the ADI is based on the most sens itive animal species, i.e., the species that
displayed the toxic effect at the lowest dose, unless metabolic or pha rmaco-kinetic data are
available establishing that the test in the other species is more appropriate for man
(section 5.5.1).

 Generally, the ADI is established on the basis of toxicological information and provides a
useful assessment of safety without the n eed for data on intended or actual use and
consumption. However, in setting ADIs, an attempt is made to take account of special
subpopulations that may be exposed. Therefore, general information about exposure patterns
should be known at the time of the safety assessme nt (section 5.5.6). For example, if a food
additive is to be used in infant formulae, the safety assessment is not complete without
looking carefully at safety studies involving exposure to very young animals.

 JECFA uses the risk assessment process when se tting the ADI, i.e. the level of "no apparent
risk" is set on the basis of quantitative extrapolation from animal data to human beings.

The above described procedure and principles are equa lly applied to residues of veterinary drugs by
JECFA.

Establishment of the ADI follows the following steps:

– determination of a no-observed-effect level

– application of safety factors

A safety factor has been used by JECFA since its inception. It is intended to provide an adequate
margin of safety for the consumer by assuming that th e human being is 10 times more sensitive than
the test animal and that the difference of sensitivity within the human population is in a 10-fold range.

In determining an ADI, a safety factor is applied to the no-observed-effect level determined in an
appropriate animal study.

JECFA traditionally uses a safety factor of 100 (10 x 10) in setting ADIs based on long-term animal
studies, i.e., the no-observed-effect level is divided by 100 to calculate the ADI.

Deviation from the default safety factor can be cons idered when e.g. the in adequacy of database may
justify a larger safety factor, or when a no-observed effect level is derived from adequate human data
a smaller safety factor may be applied. More over, recently the concept of chemical specific
adjustment factors (CSAF) has been applied if appropriate data were available. (Chemical-specific
adjustment factors for interspecies differences a nd human variability: guidance document for use of
data in dose/concentration–respon se assessment, WHO, Geneva 2005.
http://whqlibdoc.who.int/publications/2005/9241546786_eng.pdf

Residue evaluation:

Derivation and recommendation of maximum residue limits (MRLs)

JECFA has specified the data requirements that ar e intended to adequately identify and characterize
the veterinary drug being evaluated for toxicology and residue considerations. Specific information is
requested on mode of administration, dose and formulation, pharmac okinetic, metabolic and
pharmacodynamic studies, residue depletion studies with radiolabelled dr ug and non-radiolabelled
drug in target animals at appropriate times of w ithdrawal, information on major residue components
for determining a marker residue and target tissue. In addition, information is requested regarding free
and bound residues (including bioa vailability), routine analytical methods and appropriate method
performance factors and information on antimicrobial assays for those compounds for MRL
considerations on antimicrobial end points. The above data are requested for all relevant food animal
species and tissues, as well as milk, eggs and honey using good veterinary practice. The JECFA has
developed a mathematical model to account for bou nd residues in tissue. In consideration of MRLs,
the JECFA also reviews the comparative metabolism between laboratory animals and food animals to
determine qualitative or quantitative similarities or differences in metabolites across species.

The JECFA does not recommend MRLs when the th eoretical maximum daily intake (TMDI) of
residues substantially exceeds the ADI. The TMDI is the upper limit consideration in recommending
MRLs. For purposes of recommending MRLs, the JECFA uses a theoretical food basket that consists
of 300 g muscle, 100 g liver, 50 g kidney, 50 g fat, 1500 g milk, 100 g for eggs and 20 g for honey.
Considerations in MRLs are based on the adequacy of the data. Where a large database is available,
statistical approaches to MRLs may be used.

JECFA uses radiolabelled parent drug studies in inte nded host animal species as well as additional
studies with non-radiolabelled parent drug for recommending MRLs and a marker residue compound
and appropriate target tissues for residue analysis . Dose treatments preferably considered are those
conducted at the maximum approved dose. Residues are generally determined in all four edible tissues
– muscle, liver, kidney and fat as well as milk and eggs, where the data are sufficient. JECFA
identifies the appropriate stable compound that can be used as the marker residue and indicates the
most appropriate tissues for analysis, considering needs of national authorities for domestic residue
control programs and product intended for intern ational trade. These studies also provide the
necessary information to determine consideration of bound residues and relationships between the
marker residue and total residues of concern as determined by the ADI.

JECFA has recognized that the use of veterinary drugs in food producing animals can result in
residues that are neither extractable from tissue nor readily characterized using mild extraction
procedures. The Committee has developed a proce dure to estimate the maximum daily intake of

residues of a drug that has a bound residue component. It takes into account the toxicological potency
and bioavailability of the residues.

Residues = Free residues + Bioavailable bound residues.
Bound residue = Total residue - (extr actable fraction + endogenous fraction).

Residues = P
0 + Σ
nx
n=n1
(Mn × An) + (Bound residue × fraction bioavailable × Ab) ........ (1)
where
P0 = amount of parent drug per kg of tissue.
n1..nx = different metabolites of the parent drug.
Mn = amount of (unbound) parent drug metabolite n per kg of tissue.
An = toxicological potency of n relative to that of parent drug.
Ab = estimated relative toxicological potency of the metabolites in the bound
 residue (when no information is available, use A b = 1)

JECFA considers that in the absence of other data , a bound residue should be considered of no greater
toxicological concern than the compound for which the ADI was established. In considering the safety
of bound residues, JECFA acknowledges that a suitable extractable residue analyte may be selected as
a marker compound and used for recommending an MRL if bound residues make up an insignificant
portion of the total residue. Where bound residues become a significant portion of the total residues of
toxicological significance, then the procedure described may be used to assess their safety. The use of
residue data for the purpose of safety assessment is evaluated on a case-by-case basis.

JECFA make final recommendations for MRLs of a veterinary drug in appropriate food animal
species and tissues when there are adequate data and compatible with the ADI. Temporary MRLs may
be recommended when there is a full ADI yet ad equate residue or met hod performance data are
lacking or when the ADI is temporary. The Committee may recommend MRLs "not specified" or
"unnecessary" when there is a wide margin of saf ety of residues when compared with the ADI).
Finally, JECFA may determine that MRLs cannot be recommended because of significant
deficiencies in either residue data or available analytical methods or when an ADI is not established.

JECFA has devoted a significant effort to analytical methods performance because of the strong role it
has in recommending MRLs. JECFA has developed analytical methods performance factors for
consideration as suitable for determining co mpliance with a recommended MRL. Major
considerations include accuracy (recovery), precision, reproducibility, sensitivity (dose-response), and
selectivity, among others. Use of common laboratory instruments and solvents that do not have
environmental or health consid erations are important factors. Guidance for analytical method
performance factors has been described in individua l reports. Methods are considered in cooperation
with the Codex Committee on Residues of Veterinary Drugs in Food (CCRVDF) ad hoc Working
Group on Methods of Analysis and Sampling.

JECFA has devoted efforts recently to develop statis tical tools for data analysis to derive MRLs. A
JECFA paper has been prepared as well as a set of proposed statistical tools for JECFA experts to
apply for recommending a set of MRLs. The approach has to meet two specific criteria: 1) the time
point selected to recommend the MRLs is compatible with registered uses (Good Practice in the Use
of Veterinary Drugs), and 2) that it does not resu lt in a theoretical residue exposure in excess of the
ADI.

A summary of the JECFA procedures for recommending MRLs is described below.

GPVD
Marker residue
JECFA Residue Evaluation
Total residue
Ratio marker/total residue
Metabolism &
Distribution Studies
Field trials & Depletion curve &
confidence interval
MRL
F
1. estimate
ADI
TMDI < ADI TMDI > ADI
2. estimate accept MRL;
option to adjust MRL
adjust MRL or
MRL not recommend
Marker residue
JECFA Residue Evaluation
Total residue
FMetabolism &
Distribution Studies
Field trials & Depletion curve &
confidence interval
MRL
F
1. estimate
ADI
TMDI < ADI TMDI > ADI
2. estimate accept MRL;
option to adjust MRL
adjust MRL or
MRL not recommend
Intake assessment
Model food basket (TMDI)

The MRL recommendation procedure is an iterative pr ocess. The MRL is not derived directly from
the ADI. If the ADI is based on toxicological end-poi nts, all residues of toxicological relevance are
considered, if the ADI is based on microbiological end-points, all residues of microbiological
relevance are considered. The MRL recommendation procedure also takes into account the conditions
of use (e.g. use of the veterinary drug according to good practice in the use of veterinary drugs
GPVD) and the residues that result from such use (e.g . residue depletion studies). It also considers
results of radiolabel residue studies, the bioavailabili ty of bound residues, the identification of target
tissues and a marker residue, the availability of practical analytical methods, estimated exposure
resulting from recommended MRLs and consideration of extension of the MRLs to tissues, eggs and
milk of other species.

The initial consideration in recommending an MRL is whether it is sufficiently protective of human
health. If the use of the veterinary drug yields an estimated intake of ve terinary drug residues
consistent with the ADI, the recommended MRLs ma y then be adjusted accordingly when taking into
account the other factors noted above. As a gene ral principle, the Committee will not normally
recommend an MRL that results in residue levels th at lead to dietary intake exceeding the ADI based
on toxicological or microbiological considerations.

11. Please confirm or comment on the following Canadian statement: "it is recognized that
JECFA only allocates an ADI for a food additi ve or veterinary drug under review when JECFA
considers that its scientific data base is comple te and that there are no outstanding scientific
issues". [see para. 68 of Canada Rebuttal Submission]

If there are substantial data gaps and important information missing, JECFA can not establish an ADI.
However, JECFA can allocate a temporary ADI when da ta are sufficient to conclude that use of the

substance is safe over the relatively short period of time required to genera te and evaluate further
safety data, but are insufficient to conclude that us e of the substance is safe over a lifetime. A higher-
than-normal safety factor is used when estab lishing a temporary ADI and an expiration date is
established by which time appropriate data to resolve the safety issue should be submitted to JECFA.
The temporary ADI is listed in units of mg per kg of body weight. Source: JECFA glossary of terms:
http://www.who.int/ipcs/food/jecfa/glossary.pdf

12. In paras. 129 and 168 of its Replies to the Panel's questions, the European Communities
states that "JECFA's traditional mandate does no t allow it to examine all risk management
options but restricts it to either propose MRLs or not." Does Codex have risk management
options other than (1) the establishment of an MRL, (2) the establishment that an MRL is not
necessary, or (3) no recommendation?

JECFA is the risk assessment body and only consider s health impact of specific risk management
options when specifically requested by CCRVDF, e. g. JECFA could estimate the impact on exposure
of different MRLs, if asked to do so. Consid eration of risk management options is in the
responsibility of the risk management body, hence CCRVDF.

13. With respect to the data used in the eval uation of chemical substances, such as the
hormones at issue, what are the data requi rements for JECFA's work and how are they
determined? Who provides data for such eval uations? Are any records/archives kept by
JECFA? Do any confidentiality rules apply to da ta submitted to JECFA or should all data be
publicly available? If confidentiality rules apply, in which circumstances? [see paras. 95-96 of
EC Rebuttal Submission (US case), paras. 78-79 of EC Rebuttal Submission (Canada case),

Data requirements:

In the public call for data for submission to th e Joint FAO/WHO JECFA Secretariat that precedes
each JECFA meeting, governments, interested or ganizations, producers of these chemicals, and
individuals are invited to subm it data relating to the compounds listed in agenda. The data
requirements are detailed in the call for data and include the following:

Data relevant to the evaluation of veterinary drug residues in food products of animal origin,
including:

1. chemical identity and properties of the drug;

2. its use and dosage range;

3. pharmacokinetic, metabolic, and pharmacodynamic studies in experimental and food-
producing animals, and in humans when available;

4. short-term toxicity, long-term toxicity/carcinogenicity, reproductive toxicity and
developmental toxicity studies in experimental animals and genotoxicity studies;

5. special studies designed to investigate speci fic effects, such as those on mechanisms of
toxicity, no-hormonal-effect levels, immune responses, or macromolecular binding;

6. for compounds with antimicrobial activity, st udies designed to evaluate the possibility that
residues of the compound might have an adverse effect on the microbial ecology of the
human intestinal tract; and

7. studies providing relevant data on the use of and exposure to the drug by humans, including
studies of effects observed after occupationa l exposure and epidemiological data following
clinical use in humans

8. pharmacokinetic and metabolic studies in expe rimental animals, target animals, and humans
when available (information required by both FAO and WHO);

9. residue-depletion studies with radiolabelled dr ug in target animals from zero withdrawal time
to periods extending beyond the recommended wit hdrawal time (these studies should provide
information on total residues, including fr ee and bound residues, and major residue
components to permit selection of a marker residue and target tissue);

10. residue-depletion studies with unlabelled drug fo r the analysis of marker residue in target
animals and in eggs, milk, and honey (these should include studies with appropriate
formulations, routes of application, and species, at doses up to the maximum recommended);

11. a description of the analytical procedures used by the sponsor for the detection and
determination of parent dr ug residues with information on validation and performance
characteristics; and

12. a review of routine analytical methods that may be used by regulatory authorities for the
detection of residues in target tissue, includi ng information on quality assurance systems and
sampling procedures recommended.

Additional information can be found in the procedural guidelines for JECFA:

Guidelines for the preparation of toxicological working papers for the Joint FAO/WHO Expert
Committee on Food Additives: Residues of vete rinary drugs in food, Geneva, August 1996
http://www.who.int/ipcs/food/jecfa/en/guidelines_vet_drugs.pdf
 a n d
ftp://ftp.fao.org/es/esn/jecfa/2000-06-30_JECFA_Procedures_MRLVD.pdf

In the particular case of the hormones, JECFA also detailed in the respectiv e report, the additional
data needed to perform a complete risk assessment of the individual hormones under review.

Data submissions:

Data are mainly provided by companies who pr oduce the compounds, additional data are sometimes
provided by national authorities, such as data on levels analyzed in foods.

Records and archives – confidentiality rules:

The submitted data may be published or unpublished and should contain detailed reports of laboratory
studies, including individual animal data. Refere nce should be made to related published studies,
where applicable. Summaries in the form of monogra phs are helpful, but they are not in themselves
sufficient for evaluation. Unpublished confidential st udies that are submitted will be safeguarded and
will be used only for evaluation purposes by JE CFA. Neither FAO nor WHO have facilities for
storing printed data for long periods of time, so confidential data will either be returned to the
submitter at the submitter's expense or destroyed af ter the evaluations have been completed. Key
material can be stored up to five years and will then be destroyed.

Public accessibility of JECFA assessments:

It is important to note that JECFA evaluations are completely publicly available, and a detailed
description of the data evaluated is accessi ble through the monographs. Specific information
regarding the manufacturing process of substances, which are considered confidential for commercial
purposes may be excluded from the reports and monographs, if agreed by the Joint FAO/WHO
Secretariat.

Short explanation of JECFA publications:

– WHO Technical Report Series (TRS)
 These reports, published by the World Health
Organization, contain concise toxicological ev aluations and the chemical and analytical
aspects of each substance reviewed by JECFA, as well as information on the intake
assessment. Reports reflect the agreed view of the Committee as a whole and describe the
basis for their conclusions.

– WHO Food Additive Series (FAS)
 These monographs, published by the World Health
Organization, contain detailed descriptions of the biological and toxicological data considered
in the evaluation, as well as the intake assessment, including detailed literature references.

– Compendium of FAO Veterinary Drug Residue Monographs
 These monographs, published
by the Food and Agriculture Organization, contain the data and the evaluations used to
recommend MRLs for veterinary drug residues. They were originally published as the FAO
Nutrition Meetings Report Series, and late r as FAO Food and Nutrition Papers. The
information from these publications has been updated and compiled into FAO Food and
Nutrition Paper 41. Individual, fully updated evaluations are also available here in a combined
online compendium, searchable by both drug name and functional class. New monographs
will be published in the FAO JECFA Monograph series from 2006 onwards.

14. How are experts involved in JECFA's work selected? What are the selection criteria?

Detailed procedures are outlined in the procedural guidelines:
WHO procedural guidelines for JECFA:
http://www.who.int/ipcs/food/jecfa/procedural_guidelines%20_drugs.pdf

FAO procedural guidelines for JECFA:
ftp://ftp.fao.org/es/esn/jecfa/2002-09-24_Vet_Drugs_Proc_Guidelinesb.pdf

Guideline for selection of experts to serve on the roster of JECFA: These guidelines are governed by
Procedural rules of FAO and WHO (see response to question 7, first pa ragraph). Article VI
(sections 2, 3 and 7) of the Constitution of FAO and the Regulations for Expert Advisory Panels and
Committees of WHO lay down the basic rules of JECF A. All members and associated drafting
experts of JECFA act strictly in their own capacity. Declarations of interest are signed by each expert
in advance of the meeting and considered by the Joint FAO/WHO JECFA Secretariat.

JECFA is not a standing committee, the selection of members for each meeting is made after a careful
consideration of the scientific credentials of th e various candidates, and a balance of scientific
expertise and other experience that is considered es sential considering the items on the agenda of the
meeting. The selection process respects as we ll FAO and WHO policies on regional representation
and gender balance. FAO and WHO meet the costs of experts' attendance at JECFA meetings. Being a
joint committee of FAO and WHO, the organizationa l framework of JECFA complies with the rules
of both organizations. The selection process for expe rts is undertaken in mutual consultation by the
Joint Secretariats. When calling for and selecting experts, FAO and WHO assure that selections

complement each other. Both organizations establis h listings of experts, called rosters; appointments
are for a period of five years. Experts are select ed from those rosters for each meeting, in which
capacity they either attend the meeting as members or assist the Secretariat with preparatory work
before the meeting and usually par ticipate in the meeting itself. Each member invited by WHO must
also be a member of a WHO Food Safety Advisory Pa nel and is appointed by the Director General of
WHO. Invitations to each meeting by FAO is decided by the Director General of FAO.

17. Is the table in Exhibit CDA-32 outlining th e chronology of JECFA's assessment of the
hormones at issue and the resulting documentation complete?

The document describes the published documentation relating to the risk assessment of the individual
hormones, reports and monographs, adopted by JE CFA and published by WHO and FAO. The list is
complete (in some instances page numbers are given only as the first page and in other as the page
numbers of entire section in question), with the exception of the summary and conclusions of the 66 th
JECFA meeting held 20 - 28 February, 2006 (page 3). In this meeting, the Committee further
deliberated on the MRLs previously proposed for me lengestrol acetate, at the request of CCRVDF
(ftp://ftp.fao.org/ag/agn/jecfa/jecfa66_final.pdf.

18. What happens if new evidence or studies throw into doubt a Codex standard? What are
the procedures for incorporating more recent developments into Codex work? Has the
European Communities approached Codex for th is purpose with respect to the hormones at
issue in this case?

In general, there is a clear procedure for placi ng compounds on the agenda of JECFA to perform or
update a risk assessment. If new scientific data beco me available that may impact on an existing risk
assessment, there are several possibilities for a compound to be scheduled for re-evaluation by
JECFA.

Requests for the evaluation of certain veterinary drug s and consideration of issues of a general nature
by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) may come from a number of
sources:

1. Codex committees

The Codex Committee on Residues of Veterinary Dr ugs in Foods (CCRVDF) refers substances to
JECFA based on priorities that it establishes using criteria that it has developed that are in accord with
accepted procedures of the Codex Alimentarius Commission.

2. FAO and WHO Member States

FAO and WHO Member States may request the incl usion of veterinary drugs on the agenda of
JECFA through a direct request to the FAO and WHO Secretariats. Such a request must be
accompanied by a commitment to provide the necessary data 6-7 months before the meeting.

3. Sponsors

For veterinary drugs not previously evaluated by JECFA, an industry sponsor may forward a request
for evaluation through the government of a Member State to CCRVDF, with a commitment to provide
the relevant data. Requests for the re-evaluation of a veterinary drug that has been reviewed by
JECFA previously may be forwarded directly to the JECFA Secretariat. As with all other substances
on the agenda, the Joint Secretariat includes the substance in the call for data for the meeting to ensure
that all interested parties have the opportunity to submit data.

4. JECFA Secretariat

The JECFA secretariat may place a veterinary drug on the agenda for re-evaluation even though no
outside request has been received.

5. JECFA itself

The Committee often establishes a temporary ADI or recommends temporary MRLs, with a request
for further data by a certain time. These veteri nary drugs, which have the highest priority for
evaluation, are placed on the agenda of the appropriate meeting by the Joint Secretariat.

Source: WHO procedural guidelines for JECFA, Annex 1:
http://www.who.int/ipcs/food/jecfa/procedural_guidelines%20_drugs.pdf

19. What would be the procedures for requesting JECFA to re-evaluate its
recommendations in light of new concerns/eviden ce? How would an amendment be adopted?
Has the European Communities approached JECF A for this purpose with respect to the
hormones at issue in this case? [see Exhibit EC-63]

Regarding the procedures for a compound to be re-evaluated please refe r to the response under
question 18 above.

The re-evaluations of compounds follow the same pr ocedure as an evaluation performed for the first
time, with clear identification of the new data th at were assessed. Data from previous assessments
relevant for the evaluation are also described, a nd the final assessment published in the report and if
relevant also as a monograph addendum. JECFA reports are adopted before the close of the meeting,
i.e. the final report for each meeting, including the general considerations as well as the assessments
for all compounds on the agenda, are adopted at the meeting before it is adjourned. After that only
editorial changes are made.

European Union has not asked the JECFA Secretariat to bring their data referred to in the report of the
11
th session of CCRVDF (see below point 1 of question 20) before JECFA for review. The studies
referred were finalised later than the 52nd JECFA meeting and the Secretariat has not scheduled these
substances on the agenda of JECFA since that meeting.

20. What were the reasons for the re-evaluati on by JECFA of the three natural hormones in
1999? Were the residues data used for the three natural hormones in 1999 the same as those
used in 1988? What additional information was used for the JECFA evaluation in 1999 of the
three natural hormones which was not available in 1988? How did the conclusions differ? What
led JECFA to establish ADIs for the three natura l hormones? What are the implications of
establishing ADIs? Why were JECFA's more recent recommendations not considered by
CCRVDF? What is the status of these recommendations? [see paras. 96-97 of EC Rebuttal
Submission (US case), paras. 79-80 of EC Rebuttal Submission (Canada case)]

(1) What were the reasons for the re-evaluati on by JECFA of the three natural hormones in
1999?

The natural hormones were placed on the agenda fo r re-evaluation by the JECFA secretariat, as
documented in the report of the 11th Session of CCRVDF:

From the report of the 11
th Session of CCRVDF, ALINORM99/31:

125. The question was raised as to why the natu ral hormones (estradiol-17b, progesterone, and
testosterone) had been placed on the agenda of th e JECFA for reevaluation. It was pointed out that
they were placed on the agenda at the initiative of th e JECFA Secretariat to ensure that all the latest
information had been evaluated. On the evaluati on of natural hormones, the European Commission
pointed out that it had written to the JECFA Secretar iat in order to make JECFA aware that a number
of substantial studies were currently being prepar ed by the EU and had requested that the JECFA
evaluation be deferred to a later JECFA meeting. The European Community therefore reiterated the
request to defer the JECFA consideration.

ALINORM 99/31
APPENDIX VIII
PRIORITY LIST OF VETERINARY DRUGS REQUIRING EVALUATION OR
REEVALUATION

1. Substances scheduled for evaluation or reevaluation at the fifty-second meeting of JECFA in
February 1999:

Substances on the previous priority list of
CCRVDF

Substances recommended for reevaluation
by JECFA (temporary ADI and/or MRLs)
or by the JECFA Secretariat

Deltamethrin (residues) – toxicological
evaluation by 2000 JMPR
Permethrin (residues) – toxicological evaluation
by 1999 JMPR
Phoxim
Porcine somatotropin
Carazolol

Abamectin (residues; referral from JMPR)
Azaperone (analytical method)
Dihydrostreptomycin/streptomycin (residues)
Doramectin (residues)
Natural hormones (estradiol-17
β, progesterone,
and testosterone)
Thiamphenicol

JECFA can decide to reevaluate previous assessment when the Committee is made aware that there is
new data which may be pertinent to the risk assess ment of the substances in question. The European
Union had claimed in the 1997 WTO hormone dispute that new evidence showed that oestradiol-17ß
is a directly acting genotoxic carcinogen. Also for the other substances a substantial amount of new
studies had been published since the 32nd meeting. Also the 32nd Meeting produced no toxicological
monograph for the three nature-identical hormones. The toxicological/endocrinological/
epidemiological data for the 52nd Meeting were retrieved by means of an exhaustive literature survey.

(2) Were the residues data u sed for the three natural hormones in 1999 the same as those
used in 1988?

In the 1988 evaluation, the data has been descri bed in FAO Food and Nutrition Paper 41/1 (1988). In
the 1999 evaluation, new information for the three natural hormones was provided, including the
complete dossier submitted to the US Food and Drug Administration. FDA kindly permitted the FAO
expert to the Committee to search all their relevant files for data. A more complete and transparent
assessment of all data, including statistical ev aluation, was made (FAO Food and Nutrition Paper
42/12, 2000, p. 37-90). Most of the studies were th e same. However, a few additional investigational
studies were also reviewed. JECFA also performed a more detailed thorough review of the validity of
the analytical methods used in the studies and used only data generated using valid methods. It also
performed more detailed statistical and graphical analyses of the data. Since the FAO FNP 41/12

monograph provides all raw data used (in graphical form) and all the calculations performed, the
document is also more transparent than the corresponding monograph produced by the 32nd Meeting.

(3) What additional information was used for the JECFA evaluation in 1999 of the three
natural hormones which was not available in 1988?

From the report of the 52nd JECFA meeting, TRS 893:

Estradiol-17β, progesterone and testosterone were re-evaluated at the pr esent meeting to take into
consideration any data that had b een generate since their previous review and to make a quantitative
estimate of the amounts that could be consumed safely.

Toxicological data

Estradiol-17β. The Committee considered published data from studies on the oral bioavailability,
metabolism, short-term toxicity, reproduc tive toxicity, genotoxicity and long-term
toxicity/carcinogenicity of exogenous estrogens. Numerous reports on studies of the use of exogenous
estrogens in women were considered, as were studi es in experimental animals on the mechanism of
action of estradiol-17β. The extensive database derived from the results of epidemiological studies in
women taking oral contraceptive preparations c ontaining estrogens or postmenopausal estrogen
replacement therapy was also used to evaluate the safety of estradiol-17β.

Progesterone. The Committee considered published data from studies on the oral bioavailability,
metabolism, short-term toxicity, reproduc tive toxicity, genotoxicity and long-term
toxicity/carcinogenicity of progesterone. Numer ous reports of studies on progesterone in humans
were considered. In addition, the extensive data base derived from women taking progesterone as a
component of oral contraception, as inject able progestogen-only c ontraception, and in
postmenopausal hormone replacement therapy was used to support the safety evaluation.

Testosterone. The Committee considered published data fro m studies on the oral bioavailability,
metabolism, short-term toxicity, reproduc tive toxicity, genotoxicity and long-term
toxicity/carcinogenicity of testosterone. Reports of studies on testosterone in humans were also
considered.

Residue studies for the three hormones. Please see answer to point 2 above.

(4) How did the conclusions differ?

Estradiol-17β

Estradiol was reviewed previously by the Committe e, at its thirty-second meeting (1988), when it
concluded that the establishment of an acceptable residue level and an ADI was 'unnecessary', based
on the conclusion that this is a hormone that is produced endogenously in human beings and shows
great variation in level according to age and sex. This conclusion was based on studies of the patterns
of use of estradiol for growth promotion in cattle, the residues in animals, analytical methods,
toxicological data from studies in laboratory animal s, and clinical findings in human subjects. The
Committee further concluded that estradiol residue s resulting from its use for growth promotion in
accordance with good husbandry practices were unlikely to be a hazard to humans.

On the basis of its safety assessment of residues of estradiol-17 β, and in the view of the difficulty of
determining the levels of residues attributable to the use of this hormone as a growth promoter in
cattle, the Committee concluded that it was unnecessary to establish an Acceptable Residue Level.

At its 52
nd meeting in 1999, estradiol-17 β was re-evaluated to take into consideration any data that
had been generated since the previous review and to make a quantitative estimate of the amount that
could be consumed safely. The Committee establis hed an ADI of 0-50 ng/kg bw on the basis of the
NOEL of 0.3 mg/day (equivalent to 5 µg/kg bw per day) in studies of changes in several hormone-
dependent parameters in postmenopausal women. A safety factor of 10 was used to account for
normal variation among individuals, and an additio nal factor of 10 was added to protect sensitive
populations.

Progesterone

Progesterone was reviewed previously by the Committee, at its thirty-second meeting (1988). The
Committee then concluded, that the amount of exogen ous progesterone ingested from meat of treated
animals would not be capable of exerting hormonal a effect, and therefore any toxic effect, in human
beings. The Committee deemed it 'unnecessary' to set an ADI for a hormone that is produced
endogenously in human beings and shows marked phys iological variation in levels according to age
and sex. The Committee concluded that residues aris ing from the use of progesterone as a growth
promoter in accordance with good animal husbandr y practice are unlikely to pose a hazard to human
health.

On the basis of its safety assessment of residues of progesterone, and in the view of the difficulty of
determining the levels of residues attributable to the use of this hormone as a growth promoter in
cattle, the Committee concluded that it was unnecessary to establish an Acceptable Residue Level.

At its 52
nd meeting in 1999, progesterone was re-evaluated to take into consideration any data that had
been generated since the previous review and to make a quantitative estimate of the amount that could
be consumed safely. The Committee established an ADI of 0-30 µg/kg bw for progesterone on the
basis of the LOEL of 200 mg/day (equivalent to 3.3 mg/kg bw) for changes in the uterus. A safety
factor of 100 was used to allow for extrapolati on from a LOEL to a NOEL and to account for normal
variation among individuals.

Testosterone

Testosterone was reviewed previously by the Committee, at its thirty-second meeting (1988). The
Committee the considered an ADI 'unnecessary' fo r a hormone that is produced endogenously in
human beings and shows marked ph ysiological variation in levels according to sex and age. The
Committee concluded that residues resulting from the us e of testosterone as a growth promoter in
accordance with good animal husbandry practice are unlikely to pose a hazard to human health.

On the basis of its safety assessment of residues of testosterone, and in the view of the difficulty of
determining the levels of residues attributable to the use of this hormone as a growth promoter in
cattle, the Committee concluded that it was unnecessary to establish an Acceptable Residue Level.

At its 52
nd meeting in 1999, testosterone was re-evaluated to take into consideration any data that had
been generated since the previous review and to make a quantitative estimate of the amount that could
be consumed safely. The Committee established an ADI of 0-2 µg/kg bw for testosterone on the basis
of the NOEL of 100 mg/day (equivalent to 1.7 mg/kg bw per day) in the study of eunuchs and a safety
factor of 1000. The large safety factor was used in order to protect sensitive populations and because
of the small number of subjects in the study from which the NOEL was identified.

Conclusions in residues evaluation of all three hormones

The conclusions concerning residues were equivalent in the 1988 evaluation and the 1999 evaluation,
but were based on a more deta iled discussion. The 52nd JECFA performed a detailed theoretical
intake assessment based on a worst case scenario (all animals are slaughtered at the time of the
highest hormone levels - this time point differs largely from the time point at which the benefit due to
the anabolic effect is greatest). In this assessment intake estimates for preferential meat eaters were
performed on the basis of the hormone levels of treated animals in comparison with the corresponding
levels in untreated animals and the additional "burden" or "excess intake" was calculated.

For total estrogens the highest excess intakes from approved uses calculated this way were in the
order of magnitude of 30-50 ng/person/day. This range of intake is less than 2% of the ADI for
estradiol-17β established by JECFA at the 52 nd meeting. For certain experimental studies carried out
with experimental combinations resulted in an excess intake of around 4% of the ADI.

The highest excess intake of progesterone, the onl y relevant hormonal active residue from treatment
with progesterone, was below 500 ng/person/day fo r the approved uses of this hormone. This
corresponds to 0.003% of the ADI for progesterone established by JECFA.

For testosterone, the highest intake of the free hormone was approximately 60 ng/person/day for all
approved uses of this hormone. Th is represents around 0.2% of the ADI for testosterone established
by JECFA.

JECFA also noted that hormone concentrations found in individual populations of treated animals,
although they were typically statistically significan t higher than untreated controls, were well within
the physiological range of these substances in bovi ne animals. The data assessed and the worst case
scenario calculations made indicated a wide marg in of safety of consumption of residues from
animals treated in accordance with good practice of use of the veterinary drugs containing the
hormones in question. JECFA therefore concluded that there was no need to specify numerical
maximum residue levels for the three hormones and recommended MRLs not specified in bovine
tissues.

(5) What led JECFA to establish ADIs for the three natural hormones?

The additional data reviewed and the need to establish and ADI as quantitative estimate for a safe oral
intake. The exposure assessment perfo rmed would then allow the comparison of the estimated intake
with the ADI. This can mean that maximum residue s limits are recommended or if the margin of
safety is wide that there is no necessity to derive numerical values.

(6) What are the implications of establishing ADIs?

An ADI is an estimate of a quantity of a substan ce that can be consumed over life-time without any
appreciable health risk, i.e. it is a measure for a sa fe chronic intake level. The ADI can be used to
estimate the safety of proposed maximum residue le vels in food and the resulting intake estimates.
The ADI can then be compared to actual or estima ted intake levels, which are calculated from actual
or estimated occurrence data in food times the amount of food consumed. This then leads to
conclusions on the safety of the food supply, or of specific foods, including tissues of animal origin.
JECFA uses a standard food basket for foods of animal origin, which includes 500 g of meat to be
eaten every day of life.

Sufficient new data from observations in humans were available to the 52nd JECFA which were
suitable to derive ADIs. The ADI not only provide s an estimate of daily intakes which can be

accepted over life time without appreciable health ri sks, it also enables a quantitative comparison of
the excess intakes calculated on the basis of the above mentioned worst case scenario (see point
4 above). The Committee found that the excess intake was in the order of only 0.02 to 4% of the ADI
depending on the substance and the product used for the treatment of the animals.

Moreover, the establishment of an ADI implies that there is a threshold of effect for such a compound,
below which now toxicological effects occur.

(7) Why were JECFA's more recent recomm endations not considered by CCRVDF?

From 12th CCRVDF report, ALINORM 01/31
under report from JECFA : MRLs for estradiol-17 β, progesterone and testosterone were
recommended as "not specified".

Under MRLs

Estradiol-17β, Progesterone and Testosterone

84. Recognizing that this Committee had not request ed the re-evaluation of these substances and
that the new MRLs recommended by the 52nd JECF A did not differ significantly from the current
MRLs, the Committee decided not to consider these new recommendations. The MRLs not specified
adopted by Codex were the same as those recommended by JECFA at the 52nd meeting.

ANNEX 1

Food and Agriculture Organization
of the United Nations
World Health
Organization

FACT SHEET - WHAT IS JECFA?
(9 February 2006)

Introduction

The Joint FAO/WHO Expert Committee on Food Add itives (JECFA) is an international expert
scientific committee that is administered jointly by the Food and Agriculture Organization of the
United Nations (FAO) and the World Health Organi zation (WHO). It has been meeting since 1956,
initially to evaluate the safety of food additiv es. Its work now also includes the evaluation of
contaminants, naturally occurring toxicants and residues of veterinary drugs in food.

To date, JECFA has evaluated more than 1500 fo od additives, approximately 40 contaminants and
naturally occurring toxicants, and residues of appr oximately 90 veterinary drugs. The Committee has
also developed principles for the safety assessment of chemicals in food that are consistent with
current thinking on risk assessment and take account of recent devel opments in toxicology and other
relevant scientific areas such as microbiology , biotechnology, exposure assessment, food chemistry
including analytical chemistry and assessment of maximum residue limits for veterinary drugs.

JECFA normally meets twice a year with individu al agendas covering either (i) food additives,
contaminants and naturally occurring toxicants in food or (ii) residues of veterinary drugs in food. The
membership of the meetings varies accordingly, with different sets of experts being called on
depending on the subject matter.

History and Background

The evaluation of food additives at the interna tional level was initiated as a result of a Joint
FAO/WHO Conference on Food Additives held in Geneva, Switzerland in 1955. The Conference
recommended to the Directors-General of FAO and WHO that one or more expert committees should
be convened to address the technical and administrati ve aspects of chemical additives and their safety
in food. This recommendation provided the basis for the first meeting of JECFA. As of January 2006
the committee has met 65 times and the 67
th meeting in June 2006 marks the 50 th anniversary of
JECFA.

Purpose

JECFA serves as an independent scientific comm ittee which performs risk assessments and provides
advice to FAO, WHO and the member countries of both organizations. The requests for scientific
advice are for the main part channelled through the Codex Alimentarius Commission (CAC) in their
work to develop international food standards and guidelines under the Joint FAO/WHO Food

Standards Programme. The main purposes of this Pr ogramme are protecting health of the consumers
and ensuring fair trade practices in the food trade. The advice to CAC on food additives, contaminants
and naturally occurring toxicants is normally pr ovided to the Codex Committee on Food Additives
and Contaminants (CCFAC) and advice on residues of veterinary drugs to the Codex Committee on
Residues of Veterinary Drugs in Food (CCRVDF).

All countries need to have access to reliable risk as sessment of chemicals in food, but not all have the
expertise and funds available to carry out separate risk assessments on large numbers of chemicals.
JECFA performs a vital role in providing a reliable and independent source of expert advice in the
international setting, thus contributing to the settin g of standards on a global scale for the health
protection of consumers of food and for ensuring fa ir practices in the trade in safe food. Some
countries use information from JECFA in the es tablishment of national food safety control
programmes and CCFAC and CCRVDF develop standards based on evaluations by JECFA.

Under the terms of the Sanitary an d Phytosanitary agreement (SPS), scientific, risk based standards
established by CAC should be employe d in international trade of food. Therefore, governments are
likely to request advice from Codex committee s, and consequently from JECFA and other
international scientific bodies, on the implementation of national sta ndards and legislation related to
food safety.

Membership of the Committee

FAO and WHO have complementary functions in se lecting experts to serve on the Committee. FAO
is responsible for selecting members with chemical expertise for the development of specifications for
the identity and purity of food additives, for the assess ment of residue levels of veterinary drugs in
food, and to assess the quality of the monitoring da ta. WHO is responsible for selecting members for
the toxicological evaluations of the substances under consideration, in order to establish acceptable
daily intakes (ADIs), or other relevant guidance values, or to give a quantitative estimate of the health
risk. Both FAO and WHO invite members who are responsible for assessing exposure. Both
organizations establish listings of experts, called
rosters; appointments are for a period of five years.
Experts are selected from those rosters for each m eeting, in which capacity they either attend the
meeting as members or assist the Secretariat with preparatory work before the meeting and usually
participate in the meeting itself. The selection of members for each meeting is made after a careful
consideration of the scientific credentials of th e various candidates, and a balance of scientific
expertise and other experience that is considered es sential considering the items on the agenda of the
meeting. FAO and WHO meet the costs of experts’ attendance at JECFA meetings.

Being a joint committee of FAO and WHO, the or ganizational framework of JECFA complies with
the rules of both organizations. The selection proce ss for experts is undertaken in mutual consultation
by the Joint Secretariats. When calling for and selecting experts, FAO and WHO assure that selections
complement each other. The selection process re spects as well FAO and WHO policies on regional
representation and gender balance.

Terms of Reference of the Committee

For food additives, including enzymes and flavouring agents, contaminants and naturally occurring
toxicants, the Committee

 (i) elaborates principles for evaluating their safety and for quantifying their risks;

 (ii) conducts toxicological evaluations and es tablishes acceptable daily intakes (ADIs) or
tolerable intakes for chronic exposure and other guidance values for acute exposure;

 (iii) assess the performance, quality and applicability of analytical methods;

 (iv) prepares specifications of purity for food additives; and

 (v) assesses exposure of populations to chemical substances in food.

For residues of veterinary drugs in food, the Committee

 (i) elaborates principles for evaluating their safety and for quantifying their risks;

 (ii) establishes ADIs and other guidance values for acute exposure

 (iii) recommends maximum residue limits (MRLs) for target tissues; and

 (iv) determines appropriate criteria for and evaluates methods of analysis for detecting
and/or quantifying residues in food.

Risk assessment

For food additives and veterinary drug residues, JECFA normally establishe s ADIs on the basis of
available toxicological data and other information. Specifications for the identity and purity of food
additives are also developed, which help to ensu re that the commercial product is of appropriate
quality, can be manufactured consistently, and is equi valent to the material that was subjected to the
toxicological testing.

For contaminants and naturally occurring toxicants, levels corresponding to ‘tolerable’ intakes such as
the provisional maximum tolerable daily intake (P MTDI) or the provisional tolerable weekly intake
(PTWI) are normally established when there is an identifiable no-observed-effect level. When a no-
observed-effect level cannot be identified, the Co mmittee aims to provide other advice depending on
the circumstances and the data available.

For veterinary drug residues, maximum residue limits (MRLs) in target animal tissues, milk and eggs
are developed taking into account Good Practice in the use of Veterinary Drugs. The application of
these MRLs provides assurance that when the drug has been used properly, the intake of residues
from animal produce is unlikely to exceed the ADI.

JECFA experts are expected to conduct extens ive literature searches on the substances for
consideration by the committee, in addition to th e review of information submitted by sponsors and
national governments.

JECFA also develops general principles and methods for the risk assessment of chemicals in food. To
keep abreast in the variety of scientific discip lines necessary for the conduct of up-to-date risk
assessments, continuous review and update of the evaluation processes are necessary. Moreover,
JECFA plays an important role in the international harmonization of risk assessments of chemicals in
food.

Reports and publications

An electronic summary with the main findings and conclusions of the meeting is published by the
Joint Secretariat shortly after each meeting. Usua lly, the information is mainly in tabular format,
including the details of ADIs and MRLs recommended . This is available on the website of JECFA at
FAO and WHO.

The concise description of the key data used in th e assessments, the evaluation of these data and the
conclusions of the committee are published by WHO in the Technical Report Series. These reflect the
view of the committee as a whole, albeit in rare events where one or more members cannot agree to
the conclusions, the positions of the dissenting expe rt(s) and the reason for the disagreement will be
recorded in the report.

Toxicological and exposure assessment monographs are published in the WHO Food Additive Series
(FAS). These monographs contain the detailed desc ription and evaluation of all the biological and
toxicological data considered in the evaluation and provide references to the cited literature. A
detailed exposure assessment is also included in the monographs.

The reports and toxicological monographs ar e available from the WHO JECFA website
http://www.who.int/ipcs/publications/jecfa/en/

Specifications monographs on the identity and purity of food additives developed at meetings and
agreed on have been published in the Compendium of Food Additive Specifications (Food and
Nutrition Paper 52) and are available from the FAO JECFA website
http://www.fao.org/ag/agn/jecfa/database/cover.htm
. A new Combined Compendium replaces the
earlier edition and incorporates all the additions an d revisions made since 1992, up to and including
those contained in FNP 52 Addendum 13. It is being published as the first document under a new
publication series, the FAO JECFA Monographs as Vo lume 1 - 3. Volume 4 of this first Monograph
series will provide a reference for analytical methods and test procedures used in and referenced by
the specifications and which replaces the previous Food and Nutrition Paper 5.

Monographs on veterinary drug residues, which summa rize the data and the evaluations used for the
recommendation of MRLs, have been published in the Food and Nutrition Paper Series 41 and are
available from the FAO JECFA website http://www.fao.org/ag/agn/jecfa/jecfa_vetdrug_en.jsp
. New
monographs will be published in the FAO JECFA Monograph series from 2006 onwards.

Information on the activities and output from JECFA m eetings are available at the dedicated JECFA
websites at FAO http://www.fao.org/ag/agn/jecfa/index_en.stm
 and WHO
http://www.who.int/ipcs/food/jecfa/en/ .

ANNEX E-3

REPLIES OF THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER
TO CERTAIN QUESTIONS POSED BY THE PANEL
TO INTERNATIONAL ORGANIZATIONS

21. What is the mandate of the Intern ational Agency for Research on Cancer?

 According to the statute of the Internationa l Agency for Research on Cancer, "The objective
of the International Agency for Research on Cancer shall be to promote international collaboration in
cancer research. The Agency shall serve as a means through which Participating States and the World
Health Organization, in liaison with the Interna tional Union against Cancer and other interested
international organizations, may c ooperate in the stimulation and s upport of all phases of research
related to the problem of cancer." One of the Ag ency's functions is "the collection and dissemination
of information on epidemiology of cancer, on cancer research and on the causation and prevention of
cancer throughout the world."

22. Who are the members of the IARC?

 According to the statute of the Internationa l Agency for Research on Cancer, "The Agency
shall comprise: (a) the Governing Council; (b) the Scientific Council; (c) the Secretariat." The
Governing Council shall be composed of one repr esentative of each Participating State and the
Director-General of the World Health Organization. In June 2006, the Participating States of the
Agency are Australia, Belgium, Canada, Denmark, Fi nland, France, Germany, India, Italy, Japan,
Norway, the Netherlands, the Republic of Korea, Spain, Sweden, Switzerland, the United Kingdom,
and the United States. The Scientific Council is co mposed of a maximum of twenty highly qualified
scientists, selected on the basis of their technical competence in cancer research and allied fields. The
Secretariat consists of the Director of the Agency and such technical and administrative staff as may
be required.

23. What are IARC Monographs? How are they prepared?

 The IARC Monographs are a series of scientific review s that identify environmental factors
that can increase the risk of human cancer.

 IARC convenes an international, interdiscip linary Working Group of expert scientists to
develop each volume of
IARC Monographs . The Working Group writes a critical review of the
pertinent scientific literature and an evaluation of each agent's potential to cause cancer in humans.

IARC Monographs are developed during an 8-day meeting whose objectives are peer review
and consensus. Before the meeting, the Working Group searches the scientific literature and writes
preliminary working papers for the critical review. At the meeting, four subgroups (exposure, cancer
in humans, cancer in experimental animals, and m echanistic and other relevant data) review these
working papers and develop consensus subgroup dr afts. Then the Working Group meets in plenary
session to review the subgroup drafts and develop a consensus evaluation. After the meeting, IARC
scientists review the final draft for accuracy and clarity before publication.

 The evaluation is developed in steps. The subgroup of epidemiologists proposes an
evaluation of the evidence of cancer in humans as sufficient evidence , limited evidence, inadequate
evidence, or evidence suggesting lack of carcinogenicity . A subgroup of toxicologists and
pathologists proposes an evaluation of the evidence of cancer in experimental animals, choosing one
of the same descriptors. Combination of these tw o partial evaluations yields a preliminary default
evaluation that the agent is either:

 –
Carcinogenic to humans (Group 1)
 – Probably carcinogenic to humans (Group 2A)
 – Possibly carcinogenic to humans (Group 2B)
 – Not classifiable as to its ca rcinogenicity to humans (Group 3)
 – Probably not carcinogenic to humans (Group 4)

 When the epidemiological evidence is sufficient, the final evaluation is carcinogenic to
humans, regardless of the experimental evidence. In other cases, the mechanistic and other relevant
data are considered to determine whether the de fault evaluation should be modified, upwards or
downwards. A subgroup of experts in cancer mechanis ms assesses the strength of the mechanistic
data and whether the mechanisms of tumour form ation in experimental animals can operate in
humans. The overall evaluation is a matter of scientific judgement, reflecting the combined weight of
the evidence.

 Working Groups are selected on the basis of (1) knowledge and experience and (2) absence of
real or apparent conflicts of in terests. Consideration is given also to demographic diversity and
balance of scientific findings and views. Each potential participant completes the World Health
Organization's Declaration of Interests, which IARC assesses to determine whether there is a conflict
that warrants some limitation on participation. An e xpert with a real or appa rent conflict of interests
may not draft text that describes or interprets cance r data, participate in the evaluations, or serve as
chair. IARC strives to ensure that the Working Group is free from all attempts at interference, before
and during the meeting. This includes lobbying, wr itten materials, and meals or other favours offered
by interested parties. Workin g Group Members are asked not to discuss the subject matter with
anyone outside the meeting and to report all attempts at interference.

24. Please briefly explain the groupings that a re used to categorize "potentially carcinogenic
agents"? What are the implications when an "agent" is placed in one of the IARC categories?

 IARC uses the following groupings to ch aracterize potentially carcinogenic agents:

Carcinogenic to humans (Group 1). This category is used when there is sufficient
evidence of carcinogenicity in humans.
Probably carcinogenic to humans (Group 2A). This category is generally used when
there is limited evidence in humans and sufficient evidence in experimental animals.
Possibly carcinogenic to humans (Group 2B). This category is generally used when
there is limited evidence in humans or sufficient evidence in experimental animals, but
not both.
Not classifiable as to its carcinogenicity to humans (Group 3). This category is
generally used when there is inadequate evidence in humans and inadequate or
limited evidence in experimental animals. Agents that do not fall into any other group
are also placed in this category.
Probably not carcinogenic to humans (Group 4). This category is generally used
when there is evidence suggesting lack of carcinogenicity in humans and in
experimental animals.
Mechanistic and other relevant data also contribute to the grouping. Further details can be found in
the Preamble to the IARC Monographs (http://monographs.iarc.fr).

25. Which of the six hormones at issue in this dispute (oestradiol-17 β, progesterone,
testosterone, trenbolone acetate, zeranol, and me lengestrol acetate) have been evaluated by the
IARC? Have any specific risks from the consumption of meat from cattle treated with these
growth promotion hormones been assessed by the IARC?

 IARC has evaluated steroidal estrogens as carcinogenic to humans (Group 1); for
oestradiol-17β there is sufficient evidence of carcinogenicity in experimental animals (Volume 21,
1979; Supplement 7, 1987; Volume 72, 1999).

 IARC has evaluated progestins as
possibly carcinogenic to humans (Group 2B), based on
sufficient evidence of carcinogenicity in experimental animals (Volume 21, 1979; Supplement 7,
1987).

 For testosterone, IARC has determined that there is
sufficient evidence of carcinogenicity in
experimental animals and advised, "In the absence of adequate data in humans, it is reasonable, for
practical purposes, to regard testosterone as if it presented a carcinogenic risk to humans"
(Volume 21, 1979).

 Trenbolone acetate, zeranol, and melengestrol acetate have not been evaluated by IARC, nor
have the specific risks from the consumption of me at from cattle treated with these growth promotion
hormones.

26. How does the work of the IARC feed into the work of national regulatory agencies or
international bodies, in particular with respect to assessments of risks from the consumption of
meat from cattle treated with the six growth promoting hormones at issue in this dispute?

 The IARC Monographs are used by national and internati onal health agencies as a source of
information on potential carcinogens a nd as scientific support for their actions to prevent exposure to
potential carcinogens. The Monographs are used by such national a nd international authorities to
make risk assessments, formulate decisions con cerning preventive measures, provide effective cancer
control programmes, and decide among alternative options for public health decisions.