JOURNAL TRANSCRIPT
BUNDESINSTITUT FÜR RISIKOBEWERTUNG
Legal and Practical Aspects of the Cut-off Criteria for Reproductive Toxic and Endocrine Disrupting Effects for Approval and Classification of Pesticides in Europe
Roland Solecki, Rudolf Pfeil Federal Institute for Risk Assessment, Berlin, Germany
CUT – OFF CRITERIA for substances with reproductive toxic and endocrine disrupting effects (points 3.6.4. and 3.6.5 of ANNEX II of REGULATION (EC) 1107/2009)
Legal and practical issues that still need to be resolved Possible procedures for implementing the cut – off Criteria for C&L for reproductive toxicity Consideration of hazard-based & risk-based cut - off Reproductive toxicity Endocrine Disrupting Properties (ED) Co-ordination between the new Regulations for Pesticides and CLP
Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Current approval criteria: risk assessment Directive 91/414/EEC concerning the placing of plant protection products on the market
Risk assessment for pesticide approval … Directive 91/414/EEC concerning the “placing of plant protection products on the market” entered into force on 15 July 1991. Dir. 91/414/EEC stipulates that a.s. contained in PPP must be assessed regarding the possible risk for humans, animals ….. Only when this risk assessment confirms that their use does not constitute a risk …, the a.s. entered in the EU positive list. This means that preparations with these active substances may be approved in the individual Member States of the EU. Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Current approval criteria: risk assessment Dose-response relationship – Threshold Concept 10 0 FX 90 80 %
70 60 50 40 10
100
1 000 p pm
1 000 0
NOAEL for parental effects
Hazard Absorption, Assessment identification NOAELs for bioavailability Factor reproductive effects Exposure assessment A
External ARfD ADI Route specific AEC
Exposure assessment B Exposure assessment Z
Systemic AOEL
Risk Characterisation
No concern Annex I inclusion Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
Concern No Annex I inclusion Seite 4
Legal and practical issues that still need to be resolved Directive 91/414/EEC vs. Regulation (EC) No. 1107/2009 concerning the placing of plant protection products on the market
Approval of pesticides should not depend primarily on carcinogenic, reprotoxic and endocrine disrupting properties when, instead, threshold values can be established above which a health risk is to be expected. The potential exposure of consumers, operators, workers and bystanders should also be taken into account. Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Legal and practical issues that still need to be resolved
Substances should … present a clear benefit for plant production and … not expected to have any harmful effect on human or animal health ... … the decision on acceptability or non-acceptability of such substances should be taken at Community level on the basis of harmonised criteria. These criteria should be applied for the first approval of a substance under this Regulation. For active substances already approved, the criteria should be applied at the time of renewal or review of their approval. Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Future approval criteria: Cut-off for CMR Cat 1 and ED PPP - Regulation (EC) No. 1107/2009 concerning the placing of plant protection products on the market An active substance, safener or synergist shall only be approved if … … it is not or has not to be classified as … mutagen category 1A or 1B. carcinogen category 1A or 1B …* toxic for reproduction category 1A or 1B …* is not considered to have endocrine disrupting properties that may cause adverse effects in humans …* …* unless ... exposure of humans is negligible …
Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Possible procedures for implementing the cut-off criteria Definitions “Negligible exposure” for C & R & ED … the product is used in closed systems or in other conditions excluding contact with humans and where residues of the active substance, safener or synergist concerned on food and feed do not exceed the default value set in accordance with Article 18(1)(b) of Regulation (EC) No 396/2005 Closed systems do not exclude necessarily exposure of bystanders and residents. A MRL of 0.01 mg/kg food for all compounds (PPP regulation) is not a health-based scientific decision criterion to protect consumers. A pragmatic and science-based definition of negligible exposure might be based on TTC concept or Exposure < 10 % (< 1%) ADI, ARfD, AOEL NOAEL reprotox & carcinogenicity / 1000 Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Future approval criteria: Cut-off for CMR Cat 1 and ED
Hazard identification Exposure assessment
Risk Characterisation
Classification and labelling for Carcinogenicity Mutagenicity Reproductive Toxicity ….
Annex I Inclusion Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Classification for reproductive toxicity
CLP - Regulation (EC) No. 1272/2008 on classification, labelling and packaging of substances and mixtures Harmonised classification and labelling for active substances used in plant protection products and biocidal products
In this classification system, reproductive toxicity is subdivided under two main headings: (a)
Adverse effects on sexual function and fertility;
(b)
Adverse effects on development of the offspring
Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Hazard categories for reproductive toxicants Category 1A: Known human reproductive toxicants The classification is largely based on evidence from humans. Category
1B: Presumed human reproductive toxicants
The classification is largely based on data from animal studies. clear evidence of an adverse effect … in the absence of other toxic effects, or adverse effect is considered not to be a secondary non-specific consequence. mechanistic information raises doubt about relevance for humans, classification in Category 2 may be more appropriate.
Category 2: Suspected human reproductive toxicants some evidence from humans or experimental animals, possibly supplemented with other information, and evidence is not sufficiently convincing to place the substance in Category 1. effects in the absence of other toxic effects, or considered not to be a secondary non-specific consequence. Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Classification for fertility effects
Adverse effects on sexual function and fertility Any effect of substances that has the potential to interfere with sexual function and fertility. This includes, but is not limited to, alterations to the female and male reproductive system, adverse effects on onset of puberty, gamete production and transport, reproductive cycle normality, sexual behaviour, fertility, parturition, pregnancy outcomes, premature reproductive senescence, or modifications in other functions that are dependent on the integrity of the reproductive systems.
Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Classification for developmental effects (1)
Adverse effects on development of the offspring Developmental toxicity includes, in its widest sense, any effect which interferes with normal development of the conceptus, either before or after birth, and resulting from exposure of either parent prior to conception, or exposure of the developing offspring during prenatal development, or postnatally, to the time of sexual maturation … Therefore, for pragmatic purpose of classification, developmental toxicity essentially means adverse effects induced during pregnancy, or as a result of parental exposure …
Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Classification for developmental effects (2)
Adverse effects on development of the offspring The major manifestations of developmental toxicity include: •
death of the developing organism,
•
structural abnormality,
•
altered growth, and
•
functional deficiency.
Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Classification for developmental effects (3)
Maternal toxicity Developmental effects which occur even in the presence of maternal toxicity are considered to be evidence of developmental toxicity, unless it can be unequivocally demonstrated on a case-by-case basis that the developmental effects are secondary to maternal toxicity. Moreover, classification shall be considered where there is a significant toxic effect in the offspring, e.g. • irreversible effects such as structural malformations, • embryo/foetal lethality, • significant post-natal functional deficiencies.
Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Classification for developmental effects (4)
Maternal toxicity Classification shall not automatically be discounted for substances that produce developmental toxicity only in association with maternal toxicity, even if a specific maternally-mediated mechanism has been demonstrated. In such a case, classification in Category 2 may be considered more appropriate than Category 1. …when a substance is so toxic that maternal death or severe inanition results, or the dams are prostrate and incapable of nursing the pups, it is reasonable to assume that developmental toxicity is produced solely as a secondary consequence of maternal toxicity and discount the developmental effects.
Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Consideration of hazard-based cut-off criteria Reproductive toxicity CLP - Regulation (EC) No. 1272/2008 Annex I; 3.7 Reproductive toxicity For the purpose of classification hazard classes Reproductive Toxicity are differentiated into: CAT 1 may damage fertility or unborn child
CAT 2 suspected of damaging fertility or unborn child Additional category effects on or via lactation Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Consideration of hazard-based and risk-based cut off criteria Reproductive toxicity Cat. 1 2 10 0 FX 90 80 %
70 60
NOAEL for Hazard-based parental effects Absorption, Assessment Classification NOAELs for bioavailability Factor reproductive effects 50 40
10
100
1 000
1 000 0
p pm
10X
Exposure assessment A
External ARfD ADI
Exposure assessment B Exposure assessment Z Risk Characterisation
Route specific AEC Systemic AOEL
TTC
No concern Concern Decision on approval Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Consideration of hazard-based cut-off criteria Reproductive toxicity ec.europa.eu/sanco_pesticides/public/index.cfm If the criteria … applied at the time of renewal or review of their approval.
Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Consideration of hazard-based cut-off criteria Endocrine Disrupting Properties PPP - Regulation (EC) No. 1107/2009 By 14 December 2013, the Commission shall present … a draft of the measures concerning specific scientific criteria for the determination of ED properties to be adopted ... Pending the adoption of these criteria, substances that are or have to be classified, in accordance with the provisions of Regulation (EC) No 1272/2008, as carcinogenic category 2 and toxic for reproduction category 2, shall be considered to have endocrine disrupting properties. In addition, substances such as those that are or have to be classified, in accordance with the provisions of Regulation (EC) No 1272/2008, as toxic for reproduction category 2 and which have toxic effects on the endocrine organs, may be considered to have such endocrine disrupting properties. Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Joint DE-UK Proposal for potency-based cut-off criteria Endocrine Disrupting Properties Evaluate all available toxicological data of the substance
Are there adverse effects potentially related to ED in intact organisms in acceptable studies?
Substance is classified as CMR Cat 1A or 1B under the CLP Reg.? NO
YES
Does the available evidence demonstrate that ED mode of action in animals is plausible?
NO
YES
Are the effects judged to be relevant to humans?
NO
YES
Are serious ED effects observed at or below the STOT-RE Cat 1 guidance values of the CLP Regs$?
Substance is not deemed an ED of regulatory concern: Proceed with standard risk assessment
NO
YES
Substance is an ED for regulatory purposes Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Joint DE-UK Proposal for potency-based cut-off criteria Endocrine Disrupting Properties Analysis of relevance for humans
Use IPCS human relevance framework for robust and transparent conclusion (Boobis et al., 2008); If no information, assume human relevance; If effects not relevant to humans, they could still be relevant to non-target species in the environment.
Can human relevance be reasonably excluded on the basis of fundamental qualitative differences in key events between animals and humans? NO YES
MOA not relevant
Can human relevance be reasonably excluded on the basis of fundamental quantitative differences in key events between animals and humans? NO
Potential ED with relevance to humans Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Coordination between PPP– and CLP–Regulation Workshop on Harmonised Classification and labelling (CLH) of active substances in Plant Protection Products 12. April and 13. April 2011 at the BfR in Berlin Cooperation at the European level in the assessment of human health hazards of active substances in Plant Protection Products (PPP) under the Regulation (EC) No 1107/2009 and the harmonised classification and labelling of active substances under the Regulation (EC) No 1272/2008
Goals of the Workshop: to finalise discussion on how the two processes can most efficiently be linked between RMS, EFSA and ECHA. to raise awareness in MSs (CAs for PPP evaluation and for C&L) and to communicate importance of the issue and the possible solutions. to discuss and recommend solutions regarding formatting problems a (how to facilitate compilation of PPP and C&L dossiers in form and content). to discuss possibilities and practicalities for submission of IUCLID 5 dossiers to support technical preparation of dossiers for C&L and Annex I inclusion. to improve harmonised interpretation and reporting for of CMR studies, discuss scientific principles of interpretation to avoid conflicting interpretations e.g. for Reproductive Toxicity .. Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Workshop Classification of Pesticides Break out group 1 Scope streamlining and integration of the procedures for active substances in PPP for Annex I inclusion under the Reg. (EC) No 1107/2009 and for Classification and Labelling (C&L) .
Main goals how 2 processes could most efficiently be linked between RMS, EFSA, ECHA as prepared by ECHA discussion paper and reflected in the outline paper to consider the anticipated workloads stemming from the PPP programmes in relation to the capacity of the ECHA process with a view to ensuring appropriate planning, management and prioritisation procedures. to raise awareness in Member States and to communicate the importance of the issue and possible solutions. to prepare a draft working document on the both processes. Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Workshop Classification of Pesticides Break out group 2 Scope scientific and practical issues in assessment and interpretation of CMR studies and requirements concerning adequate scientific content according to Reg. (EC) No 1107/2009 and Reg. (EC) No 1272/2008.
Main goals how to facilitate compilation of CLH dossiers by the RMS; how to integrate additional relevant documents from the pesticide process, to facilitate the harmonised preparation of dossiers for both procedures. to improve harmonised interpretation and reporting of CMR studies, including Reproductive Toxicity to discuss scientific principles of interpretation of relevant studies, e.g., Reproductive Toxicity to avoid conflicting interpretations and different reporting of same studies, e.g., Reproductive Toxicity. Toxicity Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Workshop Classification of Pesticide Company One set of data, Submission of IUCLID 5
RMS
CoC
Registry of Intentions
Hazard Characterisation
EFSA
DAR
CLH Dossier
DAR to EFSA
C&L Dossier Submission
EFSA Public Consultation EFSA Opinion Building EFSA Conclusion
ECHA ECHA Public Consultation
Mutual engagement, Manual of Decisions, Information exchange
RAC Opinion Building RAC Opinion
DG SANCO
DG ENV & DG ENTR
Decision on Approval
Decision on C&L
Inclusion in Annex I, PPP Reg.
Inclusion in Annex IV, CLP Reg.
Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Coordination between PPP Regulation and CLP Concluding remarks C&L Workshop (1) Aim: Proposals for C&L from EFSA and ECHA should be identical, at best. How to reach this aim? 1. Improvement of procedural issues 2. Improvement of scientific issues Procedural issues: 1. Processes (PPP, CLP) should be run in cooperation. 2. Revision of the DAR is necessary in order to meet CLP requirements. 3. IUCLID-file should also be submitted for PPP assessment in order to save work for RMS. Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Coordination between PPP Regulation and CLP Concluding remarks C&L Workshop (2) Scientific issues: 1. Identical data base (for PPP and CLP decisions) is essential for receiving identical conclusions. 2. Harmonized application of CLP criteria is essential for receiving identical conclusions. Workshop output: Publication of results: CIRCA and COM SANCO website save all background documents of the workshop and the report in a public folder in CIRCA at the following address: http://circa.europa.eu/Public/irc/sanco/eccoman1/library?l=/new_section Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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Coordination between the Regulations for PPP & biocides Proposal for a regulation of the European Parliament and of the Council concerning the placing on the market and use of biocidal products New: Hazard based “exclusion criteria” for the biocide approval Article 5 1) The following active substances shall not, …, be included in Annex I: a) … classified as, carcinogen category 1A or 1B; b) … classified as, mutagen category 1A or 1B; c) … classified as, toxic for reproduction category 1A or 1B; d) … identified … as having endocrine disrupting properties; e) … fulfill the criteria for being PBT or vPvB … f) … are persistent organic pollutants ….. 2) However … included in Annex I … if .. one of the following conditions is met: a) … exposure of humans … in a biocidal product…, is negligible, in particular … used in closed systems or strictly controlled conditions; b) … active substance is necessary to control a serious danger …; c) … not including … would cause disproportionate negative impacts Roland Solecki & Rudolf Pfeil – DevTox Workshop Berlin 2011
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