boundaries in risk –sharing experiences · 2019. 12. 19. · Denaturants Indelible identification of feed materials. EFSA@10 Challenging boundaries in risk assessment – sharing

Jürgen M. GroppEFSA Scientific Conference

Challenging boundaries in risk assessment – sharing experiences7 – 8 November 2012, Parma, Italy

Assessment of efficacy – technological, sensory and nutritional feed additives

Regulation (EC) No 1831/2003 on additives for use in animal nutritionArticle 5 (3) describes rather indirectly:

No direct definition available !

The feed additive shall:(a) favourably affect the characteristics of feed,(b) favourably affect the characteristics of animal products

Article 5 (3) describes rather indirectly:

(b) favourably affect the characteristics of animal products,(c) favourably affect the colour of ornamental fish and birds,(d) satisfy the nutritional needs of animals,(e) favourably affect the environmental consequences of animal production,(e) favourably affect the environmental consequences of animal production,(f) favourably affect animal production, performance or welfare, particularly by

affecting the gastro‐intestinal flora or digestibility of feedingstuffs, or(g) have a coccidiostatic or histomonostatic effect.

EFSA@10 Challenging boundaries in risk assessment – sharing experiences 7 – 8 November 2012, Auditorium Paganini, Parma, Italy


should be determined by specific endpoints,derived from the additive category or functional group

All additives which have an effect on the feed (or water for drinking) should be studied in vitro (most technologicals, some sensory).

All additives which exert their effect(s) in the animal should be studied d i i di i i d d f h iunder in‐vivo conditions independent from the sometimes erroneous

description of a functional group.



During the authorisation process, for most additives only the potential of an additive to be efficacious can be assessed, since number and extent of efficacy studies to be submitted is limited.is limited.

Consequently, efficacy assessment provides only a YES or NO answer; comparative qualitative considerations are neitheranswer; comparative qualitative considerations are neither possible nor wanted (by applicants).



The requirement for efficacy studies is given by a legal framework (Regulation (EC) 429/2008) and EFSA/FEEDAP guidance.

Only a rough estimate of the probability of efficacy can be made.

If only one or two studies are provided, even this is completely impossible.

Therefore, a minimum of three studies with significant positive effects is required for an efficacy assessment.



Studies should be designed to demonstrate the efficacy of the additive – normally of the lowest recommended dose – by targeting sensitive parameters in comparison y g g p pto a negative and, optionally, a positive control group.

A dose‐titration study is recommended to provide the rationaleA dose titration study is recommended to provide the rationale for the selection of the recommended dose or dose range.

Also additives for which an in vitro testing is considered satisfactory for demonstration of efficacy need certain rules on how the tests should be performed (particularly for additives which have never been assessed before as


for additives which have never been assessed before as feed additives).


TECHNOLOGICAL ADDITIVESTECHNOLOGICAL ADDITIVESF ti l E d i t f d t ti f ffiFunctional group End‐points for demonstration of efficacy

Preservatives Inhibition of microbial growth, particularly that of known pathogenic and spoilage organisms.

Antioxidants Protection against oxidative damage of key nutrients/componentsAntioxidants Protection against oxidative damage of key nutrients/components during feed processing and/or storage.

Emulsifiers Formation/maintenance of stable emulsions of otherwise immiscible or poorly miscible feed ingredients.

S bili M i f h h i h i l f f di ffStabilisers Maintenance of the physico‐chemical state of feedingstuffs. Thickeners Viscosity of the feed materials or feedingstuffs. Gelling agents Formation of a gel resulting in a change in the texture of the feed. Binders Pellet durability or performance of pellet formation. y p pAnti‐caking agents Flow ability. Acidity regulators pH and/or buffering capacity in feedingstuffs. Denaturants Indelible identification of feed materials.


The period for which an effect is claimed should be demonstrated.


SILAGE ADDITIVESSILAGE ADDITIVES

Improved production of silage calculated dry matter loss (corrected for volatiles); pHpH concentration of volatile fatty acids and lactic acid concentration of alcohols ammonia nitrogen

Inhibition of undesirable microorganisms

Reduction of effluents

Improved aerobic stability


Improved aerobic stability


SILAGE ADDITIVESSILAGE ADDITIVES

For additives intended for the preparation of silage from all (or unspecified) forages, separate tests should be made with one example of each of the categories:

easy to ensile forage (>3 % soluble carbohydrates in the fresh material),

moderately difficult to ensile forage (1.5‐3.0 % solublemoderately difficult to ensile forage (1.5 3.0 % soluble carbohydrates in the fresh material) and

difficult to ensile forage (<1.5 % soluble carbohydrates in the fresh material)fresh material).

Within each test, a minimum of three replicates is required. This requires in turn the use of non parametric methods for statistical evaluation


in turn the use of non‐parametric methods for statistical evaluation.


TECHNOLOGICAL ADDITIVESTECHNOLOGICAL ADDITIVES

Substances for control of radionuclides: Evidence of reduced contamination of food of animal origin.

Substances for the reduction of contamination of feed by mycotoxins

Suppression or reduction of absorption of mycotoxinsmycotoxins Increased excretion of mycotoxins/reduced deposition in tissues or products


In vivo !


MYCOTOXIN BINDERSMYCOTOXIN BINDERSl / b l f /In general, mycotoxin/metabolites excretion in faeces/urine,

concentration in blood/plasma/serum, tissues or products (milk or eggs) or other relevant biomarkers should be taken as end‐points.

Specific endpoints

Aflatoxin B1 Aflatoxin M1 in milk/egg yolk

Deoxynivalenol DON/metabolites in blood serum

Zearalenone ZEA + α‐ and β‐zearalenol in plasma β pExcretion of ZEA/metabolites

Ochratoxin A OTA in kidney (or blood serum)

Fumonisins B1+B2 Sphinganine/sphingosine ratio in blood plasma


Fumonisins B1+B2 Sphinganine/sphingosine ratio in blood, plasma or tissues


MYCOTOXIN BINDERSMYCOTOXIN BINDERS

For additives intended to be used in all animal species except fish, studies should be performed in at least three major species, a poultry, a monogastric mammal and a ruminant p , p y, g

Target species/categories that should be included in an application for all animal species p

Mycotoxin(s) against which the additive isintended to act Species/category

Afl t i B1 D iAflatoxin B1 Dairy cow

Deoxynivalenol, Ochratoxin A, Fumonisins B1+B2 Pig

Zearalenone Piglet or gilt



SENSORY ADDITIVESSENSORY ADDITIVES

In the category ‘sensory additives’, the following functional groups are included:(a) colourants:( )

(i) substances that add or restore colour in feedingstuffs;

(ii) substances which when fed to animals add(ii) substances which, when fed to animals, add colours to food of animal origin;

(iii) substances which favourably affect the colour of ornamental fish or birds;

(b) flavouring compounds: substances the inclusion of which in feedingstuffs increases feed smell or


gpalatability.


SENSORY ADDITIVESSENSORY ADDITIVES

Substances which, when fed to animals, add colours to food of animal origin

The change in colour of products obtained from animals receiving the additive should be measured using the appropriate methodology (e.g., colour fan, reflectance spectroscopy). Evidence of efficacy can )be demonstrated in long term studies or, where the relationship between a particular substance and the colour of animal tissues/products is well documented, in short term studies (e.g., bioavailability).

It should be demonstrated that the use of the additive does not adversely


affect product stability or sensory and nutritional qualities of the food.


NNUTRITIONAL ADDITIVESUTRITIONAL ADDITIVES

The efficacy of nutritional additives (amino acids, vitamins, trace elements) is mostly assessed on the basis of literature.

Biochemical endpoints (biomarkers).

New compounds require in vivo studies.



FOOD ADDITIVES USED AS FEED ADDITIVESFOOD ADDITIVES USED AS FEED ADDITIVES

For additives which are also used in food (i.e. flavouring ( gsubstances and some colorants), and their function in feed is essentially the same as that in food, no further demonstration of efficacy is necessarydemonstration of efficacy is necessary.

Problem: the different matrix and dose in food and feed.


SAFETY FOR THE TARGET SPECIESSAFETY FOR THE TARGET SPECIESAssessment of safety for the target animal – sensory feed additives

SAFETY FOR THE TARGET SPECIESSAFETY FOR THE TARGET SPECIESFLAVOURING COMPOUNDSFLAVOURING COMPOUNDS

Substances the inclusion of which in feedingstuffs increases feed smell or palatability

Since minimum and maximum dose of flavourings is often arbitrarily chosen by the applicant and not based on efficacy studies, the maximum effective dose shown to be safe for the target animal indicates the effective use level.

Safety data for target animals is normally not available !


THE TOLERANCE STUDYTHE TOLERANCE STUDYAssessment of safety for the target species

THE TOLERANCE STUDYTHE TOLERANCE STUDY

d l d i h h i idFor new compounds, a tolerance study with the aim to provide a limited evaluation of short‐term toxicity of the additive to the target animals is necessary.

These studies require a detailed description of the experimental design, including endpoints and a certain duration of studies.

A graded system of endpoints is introduced depending on tolerance to overdoses.

If h li i i f ll i l i l di i d iIf the application is for all animal species, tolerance studies are required in only three major target species (a monogastric, a ruminant, poultry or a salmonid) provided that they show a comparable and wide margin of safety (at least ten)


(at least ten).

ENDPOINTSOFA TOLERANCE STUDYENDPOINTSOFA TOLERANCE STUDYAssessment of safety for the target species

ENDPOINTS OF A TOLERANCE STUDYENDPOINTS OF A TOLERANCE STUDY

I l T i l h ld b i l i d f i l id f li i lIn general: Test animals should be routinely monitored for visual evidence of clinical effects, performance characteristics, product quality where relevant, and for other parameters likely to be related to the biological properties of the additive. Critical endpoints known from the toxicological studies in laboratory animals should be

Safe at 10 times the maximum recommended dose/use level

p g yconsidered.

Safe at 100 times the maximum recommended dose/use level, No haematology or routine blood chemistry would be required.

Additional endpoints: haematology and routine blood chemistry

gy y q

Safe at < 10 times the maximum recommended dose/use level Additional end‐points by necropsy, histology if relevant, and other appropriate criteria


appropriate criteria

ALTERNATIVESALTERNATIVESAssessment of safety for the target species – sensory feed additives

ALTERNATIVESALTERNATIVESFLAVOURING COMPOUNDSFLAVOURING COMPOUNDS

For flavourings already authorised for use in food, the safety for target species may be assessed by a comparison between the level of intake by the target species from feed y g pand that by humans from food.

Default values for different animal species and categories are given withDefault values for different animal species and categories are given with respect to body weight, metabolic body weight and feed intake to harmonise calculations

If the use level in the target animals [expressed as quantity per metabolic body weight (usually mg/kg0.75)] is similar to that in humans (or less), no further studies are normally required.


ALTERNATIVESALTERNATIVESAssessment of safety for the target species – sensory feed additives

ALTERNATIVESALTERNATIVESFLAVOURING COMPOUNDSFLAVOURING COMPOUNDS

Where the proposed level of intake of the target animal is higher than that of humans, or when the compound is not authorised for use in food, the safety for target species may be assessed taking into account:

the feed concentration derived from the lowest NOAEL (or by benchmark dose procedure) of appropriate(or by benchmark dose procedure) of appropriate substance‐specific toxicological studies, applying a safety factor of 100, or

the thresholds of toxicological concern


CONSEQUENCESCONSEQUENCESAssessment of safety for the target species – sensory feed additives

CONSEQUENCESCONSEQUENCESFOOD ADDITIVES FOR FEEDFOOD ADDITIVES FOR FEED

Where efficacy is not demonstrated by studies in target animals because it is not necessaryanimals, because it is not necessary,

the maximum use level is determined (efficacy limited) by the maximum safe level derived frommaximum safe level derived from

(i) human consumption data,

(ii) laboratory animal data or(ii) laboratory animal data, or

(iii) the thresholds of toxicological concern.


Assessment of Assessment of efficacy and safety for efficacy and safety for the target speciesthe target species: : technologicaltechnological sensory and nutritional feedsensory and nutritional feed additivesadditivestechnologicaltechnological, sensory and nutritional feed , sensory and nutritional feed additivesadditives

In most cases, only the potential of an additive to be efficacious can be confirmed !

But efficacy assessment seems necessary to avoid ……..But efficacy assessment seems necessary to avoid ……..

Real efficacy will prove only after some years in practice!

FAVOURABLE shares a multitude of aspects !

The definition of “favourable effects” remains unclear !

p

FAVOURABLE shares a multitude of beneficiaries !

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boundaries in risk –sharing experiences · 2019. 12. 19. · Denaturants Indelible identification of feed materials. EFSA@10 Challenging boundaries in risk assessment – sharing