Joint Research Centre (JRC) Tobias...

IHCP - Institute for Health and Consumer ProtectionIspra - Italy

http://ihcp.jrc.ec.europa.eu/http://www.jrc.ec.europa.eu/

Joint Research Centre (JRC)

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Tobias Porsbring

Effect assessment of biocide mixtures

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Content of presentation

• Biocides as mixtures

• Biocides legislation on mixtures

• Principles and approaches for the ecotoxicological effect assessment of chemical mixtures

• Outline of discussions and proposals for EU guidance on mixture toxicity for the environmental risk assessment of biocidal products

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Biocidal products as mixtures

• Often combinations of two or more active substances- to increase efficacy, decrease potential for resistance

• Additives (solvents, colouring agents etc.)- may or may not be “substances of concern”

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Biocides as environmental mixtures

• High use - estimated global use 330,000 tonnes active substances per year- market estimated to 25% of market value for agricultural pesticides

• Many uses means many exposure routes to the environment- STPs, land run-off, leaching, direct application in the environment

• Many different active substances- around 300 substances in the Review Program

• Often persistent or semi-persistent

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use

clas

s re

l. do

min

ance

(no.

of c

ompo

unds

)

Modified from Götz et al, 2010. Environ Sci Pollut Res 17, 341-354

Probable environmental mixtures in surface waters

continuousexposure

Biocides

Pharmaceuticals

Industrial chemicals

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use

clas

s re

l. do

min

ance

(no.

of c

ompo

unds

)

Modified from Götz et al, 2010. Environ Sci Pollut Res 17, 341-354

Probable environmental mixtures in surface waters

Bio

Pharma

Ind

Pesticides

Biocides

Industrial chemicalsVeterinary pharmaceuticals

pulsedexposure

continuousexposure

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Biocides legislation on mixtures

Directive 98/8/EC and the upcoming new Regulation

• An overall assessment for the biocidal product itself(active substance(s) + substance(s) of concern)

• Taking into account synergistic effects

• Taking into account cumulative effects

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Biocides legislation on mixtures

Glossary

• Synergistic effects- legislative: combination effects- scientific: higher than expected effects

• Cumulative effects- effects from combined exposure to the same substance used in different products

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Mixture assessments: How to do it?

• Direct testing of the product or comparison to similar mixtures

• Component based approach

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Direct test with mixture

• The product itself “straight out of the can”

• Leachate (e.g antifouling paint, wood water storage)

Incorporates the full chemical complexity of the product

…but can only cover the initial release stage

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Mixture 1

Mixture 2

Mixture 5

Mixture 4

Mixture 3

The composition of the initial mixture will change!

• Concentrations• Compounds incl. residues

Picture modified from van Hattum et al, 2002, MAM-PEC v1.4

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Component based approach

- Prediction of the mixture toxicity

Taking into account

• The effects and concentrations of the mixture constituents

• A plausible assumption on their combined toxicity

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• Circumvents testing

• Can be prospective

• If effect and exposure data on the single compounds are available, any mixture can be assessed!

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Mixture 1

Mixture 2

Mixture 5

Mixture 4

Mixture 3


• Circumvents testing

• Can be prospective

• If effect and exposure data on the single compounds is available, any mixture can be assessed!

?High demands on environmental fate data to define the

mixture(s)!

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Concentration Addition (CA)

• Reference for the joint toxicity of chemicals with a similar mechanism of action

• Each single chemical contributes to the overall toxicity in relation to its concentration and potency

• Each chemical contributes to a joint effect, even if present at a concentration low enough to not provoke an effect on its own

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Faust et al, 2001. Aq Tox 56, 13-32

Mixture toxicity from similarly acting toxicants

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Independent Action (IA)

• Reference for the joint toxicity of chemicals with dissimilar mechanisms of actions

• Probabilistic: taking into account that a chemical in the mixture has a certain probability to exert an effect of a certain magnitude

• Only chemicals present in concentrations high enough to provoke an effect on their own contribute to a joint effect

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Mixture toxicity from dissimilarly acting toxicants

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Mixture toxicity from dissimilarly acting toxicants

Overestimation by CA (in effect concentrations): a factor of 3


CAIA

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Ecotoxicological experience with CA and IA

• Even for mixtures of dissimilarly acting substances, CA and IA predicts roughly equal mixture toxicities (within a factor of 5)

• CA typically predicts a higher mixture toxicity than IA

• IA requires low effect data for the individual substances as input

• CA can be used with only e.g. EC50 values

Kortenkamp et al, 2009. State of the art report on mixture toxicity

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Protein – inhibition, function

Individual - disease, reproduction, activity, death

Population – size, structure, activity

Community – species interactions, function, structure

Ecosystem – biodiversity, services

Level MoAs, Effects, Endpoints

?

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Extrapolation “Biochemical MoA” to “Ecological MoA”

• Protection goals and ecologically relevant effects and MoA-targets are high-order ones; reproduction, activity, community and ecosystem species structure and function

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Extrapolation “Biochemical MoA” to “Ecological MoA”

• Protection goals and ecologically relevant effects and MoA-targets are high-order ones; reproduction, activity, community and ecosystem species structure and function

• Considerable knowledge gaps on chemicals´ MoAs and effects with respect to these issues

Extrapolation of chemicals´ grouping according to MoA on a biochemical level is probably extremely difficult

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• Not possible to group chemicals according to mode of action similarity/dissimilarity in the environment

• A major knowledge gap is mode of action information

SCHER, 2011. Draft Opinion on combination effects

Syberg et al, 2009. Hum & Ecol Risk Ass 15, 1257-1272

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• CA should be used as a default

• In the case of insufficient mode of action information, CA should be used


Syberg et al, 2009. Hum & Ecol Risk Ass 15, 1257-1272

Kortenkamp et al, 2009. State of the art report on mixture toxicity

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Proposed guidance and related discussions on mixture toxicity within the ERA of biocidal products

Tiered approach considering- Product composition and use- Data quantity and quality- Suspected interactions (synergism)

Utilising, for example:- Testing (product, leakage)- Mixture Assessment Factor (MAF)- PEC/PNEC summation- CA- IA

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Possible Tier options

Tier 0• Mixture assessment necessary? (product use, composition, suspected

synergism?)

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synergism?)

• Possible additive effect of concern?

i, max = the highest PEC/PNEC ratio of any single component in the product/mixture10 = default assessment factor, i.e., “Mixture Assessment Factor”

110max,

iPNECPEC ?

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synergism?)

• Possible additive effect of concern?or

i, max = the highest PEC/PNEC ratio of any single component in the product/mixturen = number of (considered) components in the product

1max,

n

PNECPEC

i?

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synergism?)• Possible additive effect of concern?

Tier 1• PEC / PNEC summation• Testing with the product / leakage

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Testing the mixture

• Includes the full chemical profile of the product

• If prediction of mixture toxicity is available, testing can reveal interactions (synergism / antagonism)

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PEC / PNEC summation

...C

C

B

B

A

A

PNECPEC

PNECPEC

PNECPECproduct

PNECPEC

Where A, B, and C are the individual components

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PEC / PNEC summation

...C

C

B

B

A

A

PNECPEC

PNECPEC

PNECPECproduct

PNECPEC

Where A, B, and C are the individual components

• Use of the most sensitive species for each compound A, B and C…

• Conceptual similarity to CA

• Violates CA (Different species, tests, endpoints, extrapolation values for deriving PNEC)

• Conservative

• Possible to combine with additional MAF for non-considered compounds

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PEC / PNEC summation – Refinement approaching CA

• Use of the same species for each compound A, B and C…

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Tier 1• MAF (in case of low data availability, default value=10)• PEC / PNEC summation• Testing with the product / leakage

Tier 2• Concentration Addition

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Concentration Addition• Single substance data based on the same test, same species and the

same endpoint; same assessment factor

• No need for full concentration-response curves at first stage; possible to use on the basis of only e.g. NOEC and EC50 values

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Tier 1• MAF (in case of low data availability, default value=10)• PEC / PNEC summation• Testing with the product / leakage

Tier 2• Concentration Addition

Tier 3…• e.g. Independent Action

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Independent Action• Grouping according to MoA(s) difficult and potentially controversial

• Need for defining low-dose effects of the single compounds means high data demand; costly, resource demanding

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Interactions• Deviation of observed from predicted mixture toxicity

• Deviation from CA means not concentration additive• Independent Action, synergism, antagonism?• Proposed deviation factor from CA-prediction for “not additive”: 5

• Deviation could also result from non-considered additives, solvents etc. in the product

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Interactions• Deviation of observed from predicted mixture toxicity

• Deviation from CA means not concentration additive• Independent Action, synergism, antagonism• Proposed deviation factor from CA-prediction for “not additive”: 5

• Deviation could also result from non-considered additives, solvents etc. in the product

• Synergism considered rare and dose-dependent(i.e. less likely and less severe at low effect levels)


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SynergismMight be more prevalent to occur in certain chemical combinations

• e.g. pyrethroids combined with inhibitors of cytochrome P450 mediated enzymes:

cypermethrin (insecticide; sodium channel modulator)

+piperonyl butoxide (“intentional” synergist)

and/or

propiconazole (fungicide; inhibitor of sterols biosynthesis)

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Summary• The use of a concentration additive approach supported by

- Experimental evidence- Protective- Relatively low demands on data quantity, assumptions and

calculations in first Tiers

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Summary• The use of a concentration additive approach supported by

- Experimental evidence- Protective- Relatively low demands on data quantity, assumptions and

calculations in first Tiers

• A major challenge is the exposure assessment

Mixture 1

Mixture 2

Mixture 5

Mixture 4

Mixture 3

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Food and feed area disinfectants

Antifouling products

Wood preservatives

Insecticides, acaricidesand to control other arthropods

Preservatives for liquid-coolingand processing systems

Slimicides

Masonrypreservatives

Rodenticides

Veterinary hygiene biocidal products

In can preservatives

Avicides

Preservatives for Food and feedstock

Control of vertebratesHuman hygiene biocidal products

Molluscicides

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Outlook

On October 4 EP voted for this amendment to BPR Article 8.3 “Evaluation of applications”:

“Where the evaluating competent authority considers that there are concerns with regard to the cumulative effects from the use of biocidal products containing the same active substance, or different substances with similar or common effects on the same endpoints, whether by the same or different mechanism of action, it shall document its concerns … and include this as part of its conclusions.”

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Thank You!

Date post:	30-Mar-2021
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