Renewal of Chlorpyrifos-Methyl under Regulation

1107/2009
How a rushed scientific assessment of an active substance could lead to an
unreliable & non-transparent regulatory process

Regulation 1107/2009: a precautionary-based and science driven legislation?

A higher level of protection of human/animal health and the environment but also the reinforcement
of the internal market for plant protection products and the competitiveness of European agriculture
were the basic policy principles which guided the review of Directive 91/414. Indeed, the previous
legislation did not guarantee a uniformed implementation of the EU legislation, reason why a
Regulation was adopted instead of a new Directive.

Harmful organisms affect widely and increasingly the productivity of agriculture due to climate change.
In the EU, it is estimated that about 30% of our agricultural production is lost because of pests. This
means that some land currently used could fulfill other goals (biodiversity, green areas) if the
productivity would reach 100% on the land cultivated. Clearly, the current technologies, whether in
crop protection, seeds, fertilisers or machinery are not sufficient and more innovation is needed.

In this context, the precautionary principle plays a fundamental role. While it is an overarching driver
of the EU policies and should indeed be implemented whenever appropriate, it´s interpretation and
use should not lead to a “risk adverse society” in which the room for science and innovation would be
severely limited. Speculative thinking about worst-case scenarios undermines probabilistic traditional
risk assessments.

The current discomfort of society as regards certain types of scientifical and technological progress
leads to emotional reactions and fears, given the inability of today’s society to provide full certainty.
Paradoxically, the greater knowledge our societies develop on a certain area, the more society
questions decision-making in such area, notably at EU level, and in particular in the field of chemicals
and agro-chemicals, where trust in our EU institutions and evaluating authorities is at its lowest ever.
Magnification of uncertainties by the media, for pure dogmatic or business interests, should be
discarded if the EU wants to guarantee a constructive dialogue on how the precautionary principle
should be implemented.

Chlorpyrifos-methyl evaluation or when media drives science and regulatory

agenda

Similarly to the Glyphosate case, it seems that the recent (and noisy) NGO activities on Chlorpyrifos-
ethyl and Chlorpyrifos-methyl (though, very likely NGOs do understand the differences) have
pressured the European Commission and some Member States to suddenly over-react. Indeed, the
review process was proceeding ordinarily (as usual, including the normal delays), when the European
Commission suddenly issued a mandate to EFSA, just before the summer break, to make a statement
on both active ingredients. The facts:

 The peer review (experts) by EFSA of the Renewal Assessment Report (‘RAR’) by the
Rapporteur Member State (Spain) started on 18 October 2017. On 4 July 2018, EFSA requested
the Applicant to provide further information which was submitted, evaluated and included in
an updated 2019 Report by Spain. The proposal by the RMS was for renewal approval.

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  In April 2019, EFSA organised a Peer review meeting to further discuss toxicology and conduct
a hazard assessment largely based on the structural similarity of CHP-methyl with CHP-ethyl.
EFSA never issued an EFSA Conclusion Report regarding this peer review!

 On 1 July 2019, the Commission suddenly issued a mandate to EFSA asking it to review the
human health assessment and to publish a statement as to whether CHP-methyl (as well as
CHP-ethyl) can be expected to meet the human health approval criteria.

 On 31 July 2019, EFSA sent to the Commission its statement, concluding that CHP-methyl
cannot be expected to meet the approval criteria because of the following:
 It was stated that CHP-methyl ‘would’ meet the criteria for classification as
toxic for reproduction category 1B.
 Due to the fact that the genotoxic potential of CPH-methyl remains unclear,
toxicological reference values could not be established.
 Significant uncertainties were linked to the neurodevelopmental toxicity
study. These concerns were supported by the available epidemiological
evidence related to developmental neurological outcomes in children. In the
absence of toxicological reference values, a risk assessment for consumers,
operators, workers, bystanders and residents cannot be conducted. This issue
represents a critical area of concern for CPH-methyl.

To add to the sudden general improvisation, specific to CHP-methyl and never experienced so far, the
EFSA Statement added that the read-across to CHP-ethyl for the hazard identification would be re-
discussed at a later expert meeting (September) and that the outcome of those discussions "might
impact on the assessment of the specific studies, on the possibility to identify a classification as well
on the setting of reference values for Chlorpyrifos-methyl". Despite this admission that the conclusion
in the Statement could still be changed, the latter was made public and published on the EFSA website
on 2 August 2019.

Furthermore, and without even awaiting that the September experts meeting takes place and
concludes, and that the final EFSA Opinion is finalised and released, the Commission informed the
Applicant that it already prepared a Draft Review Report and Draft Regulation where the overall
conclusion is almost, a word for word, copy of the overall conclusions in the draft non-renewal report
for CHP-ethyl. All Member States received those documents, mid-August and were already asked to
comment, to secure a vote at the December Meeting of the Standing Committee on Plants, Animals,
Food and Feed.

It is also worth noting that within 2 days, the European Commission changed its invitation to the
applicant to comment (On 12 August 2019, invitation to comment by 9 September 2019 and on 14
August 2019, by 30 August!) adding to the confusion.

Serious procedural flaws

When looking at the review process of CPH-methyl, it is clear, as also confirmed to Member States,
that the European Commission is looking for an adoption of a non-approval before the expiry of the
current approval, i.e. January 2020. In order to achieve this goal by all means, the ordinary procedure
for assessment of active substances, as foreseen under Regulation 1107/2009, is not being respected,
to the detriment of the legitimate expectations of the applicant as regards a fair review.

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Concretely, it is common practice in the review of active substances that:
 The applicant receives the final RAR for information, which did not take place in the
present case.
 EFSA reviews all parts of the dossier, toxicology and eco-toxicology. The applicant was
never informed that it would not be the case after EFSA reviewed the toxicology part, in
April. Such approach is contrary to the principle of transparency, which applies to every
public authority in the EU.
 Under Article 13 of Regulation (EU) No 844/2012, EFSA has an obligation to adopt a
conclusion, which it must communicate to the applicant who should be given the
possibility to request confidential treatment of certain submitted data. It did not happen
in the case of CPH-methyl, and there is no precedent of such flaw in the process, to our
knowledge.
 Finally, the EFSA short statement on CPH-methyl is based on a read-across data from
CHP-ethyl, which is a different active substance. In other words, it seems that the
specific data submitted for CHP-methyl and is available in its dossier, was not evaluated
by EFSA, as it based its statement on a read-across from CHP-ethyl. Indeed, the EFSA
Statement noted that the Peer Review Expert conclusions on CHP-methyl are
preliminary and that the experts are also not sure about the read-across conclusions.
The above clearly indicates that the European Commission is rushing without serious scientific grounds
and without leaving the time for a proper review, as done with all other active substances. The
communication towards all Member States, mid-August of not only the Draft Review Report proposing
the non-approval but also Draft Regulation, infringes on the Better Regulation principles quite clearly.

Is the EFSA statement so negatively different than many other cases to justify
not respecting the rules of procedure?

When looking at the issues raised by EFSA in its statement, those are not different or particularly worse
than in many other cases which follow a ‘normal review procedure’. In fact, in many instances, at least
2 out of the 3 concerns are directly challengeable, based on principles only:

EFSA proposed Classification as Repro 1B:

 Over the past 5 years, there has been an increase of cases where EFSA proposed a classification for
a substance (Art. 12 of Regulation No. 1107/2009), during its scientific evaluation, even if legally it
does not have the competence to decide on classification. Indeed, ECHA is the only EU body legally
entrusted with the competence to propose harmonised classification of substances. More
precisely, as confirmed by Art. 115 of Regulation (EC) No. 1907/2006 (REACH) and Regulation (EC)
No. 1272/2008 (CLP), ECHA is the competent body to provide scientific advice on the process of
classification of substances, with its Risk Assessment Committee (RAC) being the only competent
advisory body assisting the Commission in taking decisions on classification.

What is more, in an increasing number of dossiers (Flutianil, Isoxaflutole, and even recently at the
March RAC meeting, Flumioxazin and Thiophanate-methyl), the EFSA proposal was challenged by
the ECHA RAC, concluding differently than the latter. It shows that the EFSA proposal is not always
scientifically correct and therefore needs to be always revised and confirmed by the ECHA RAC, the
competent authority on classification. In this sense, the European Commission has, in fact, decided
not to use the EFSA proposed classification in a number of cases, e.g. Amitrole & Isoproturon given
the legal uncertainty.

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 Last but not least, it should be taken into account that RMS Spain did not consider that CHP-Methyl
would meet the criteria to change the existing harmonised classification as “not reprotoxic” when
it submitted its draft RAR, reason why it did not considered necessary to submit a new CLH parallel
dossier to ECHA for a new harmonised classification. Any new classification should therefore be
based on ECHA and not on EFSA, following a submission by RMS Spain.
Genotoxicity – a broader methodological problematic beyond CHP-methyl

Only in November 2017, and following a request by the European Commission for clarification, EFSA
published a scientific opinion1 in which it provides recommendations on the adequacy of specific tests
to establish (or exclude) the genotoxic potential of substances, and advised on using data in a weight-
of-evidence approach to conclude on genotoxicity and whether or not it is possible to set safe levels
for substances. The Commission´s request originated in the multiple cases for which EFSA could not
finalise its assessment as regards genotoxicity and the difficult situation this was creating for risks
managers.

Indeed, CHP-ethyl and CHP-methyl are not the first cases in which EFSA cannot conclude its scientific
assessment as regards the genotoxicity potential of a given active or metabolite. On the contrary, it is
just the latest case of a large series of more than 18 active substances which are facing a similar issue:
due to this internal change in EFSA´s methodology to evaluate genotoxicity concerns, the agency is not
able to conclude its scientific assessment and is incapable of proposing reference values.

In all of these cases, a similar pattern has taken place: 1) RMS did not consider necessary to conduct
additional vertebrate studies; 2) applicant was therefore not allowed to conduct and submit these, 3)
RMS concludes there is no genotoxicity concerns in its own evaluation; 4) At the end of the evaluation
process, EFSA cannot finalise its assessment on genotoxicity without those studies and does not
propose any reference values. In all these cases, RMS excluded genotoxicity concerns, contrary to
EFSA´s conclusion. For CHP-Methyl, the situation is further aggravated, as the conclusion on
genotoxicity is based on a read-across from CHP-ethyl, and not even on its own data-set.

While a case-by-case approach to each substance is necessary, it is clear that we are not facing a
consumer safety concern but rather a systemic procedural issue related to which methodology is
used to conduct genotoxicity assessment. The current approach, to justify an approval, is to
distinguish between a suspected genotoxicity and inconclusive results. In the current EFSA statement,
we fall clearly in the 2nd category which led, for instance, to the approval of Cyflometofen or even
more recent, the setting of MRLs for Imazalil on citrus. Therefore, reference values must be established
and the risk assessment finalised leading to no critical area of concern.

The Obvious Conclusion

Given all the above, there is no other conclusion but that the Better Regulation principles, highly
praised at the start of this Commission, are far from being respected in the present case and that the
European Commission is acting against the rules of procedure of Regulation No 1107/2009, preventing
the applicant from having a fair review, probably guided by strong NGO and media pressure.
Science only must be the driver of any regulatory decision. In this sense, the applicant for CHP-methyl
expects to receive a final EFSA Opinion on which, as always, it will comment and provide a sanitized
version. Only then, the European Commission should prepare a Draft Review Report to be discussed
by Member States based on the merits of the case and not of another active substance (CPH-ethyl).

1 EFSA Journal 2017; 15(12):5113.

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Moreover, the final EFSA Opinion should not be based on a challengeable read-across from CHP-ethyl,
given that the expert meetings concluded that "it reconsidered the read-across approach applied for
the hazard identification after a full comparison of the available toxicological data: it was agreed to re-
discuss this issue in an experts’ meeting”. The outcome of the discussions might impact on the
assessment of the specific studies, on the possibility to identify a classification as well as on the setting
of reference values for Chlorpyrifos-methyl.
CPH-methyl is not classified as a Reprotoxic 1b substance under the CLP Regulation nor was it proposed
to be by the Rapporteur Member State, Spain. The genotoxicity uncertainties are due to a data gap
resulting from a procedural issue, common to many other cases where an approval was confirmed
given the absence of a suspicion.
Finally, the communication to Member States, during the summer break, of a Draft Review Report &
Regulation was clearly premature, not based on an EFSA Opinion or final consultation of scientific
experts, and could lead to unjustifiably impact the views of authorities.
Is this way of proceeding what outgoing President Juncker had in mind when it rolled-out its ambitious
Better Regulation agenda in 2014?

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ANNEX: key differences between Chlorpyrifos ethyl and methyl

1. Identification

Chlorpyrifos-methyl Chlorpyrifos-ethyl

Common name (ISO) Chlorpyrifos-methyl Chlorpyrifos

Chemical names

O,O-dimethyl-O-3,5,6-trichloro-2- O,O-diethyl O-3,5,6-trichloro-2-

IUPAC
pyridyl phosphorothioate pyridyl phosphorothioate

O,O-dimethyl-O-(3,5,6-trichloro-2- O,O-diethyl O-(3,5,6-trichloro-2-

CA
pyridinyl) phosphorothioate pyridinyl) phosphorothioate

CAS, EINECS Numbers and CIPAC

CAS No. 5598-13-0 2921-88-2

EEC No. 227-011-5 220-864-4

CIPAC No. 486 221

Molecular formula, molecular mass and structural formula

Molecular mass 322.53 g/mol 350.6 g/mol

Empirical formula C7H7Cl3NO3PS C9H11Cl3NO3PS

Structural formula

Relevant impurities

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Name: Sulfotemp Sulfotep

Sulfotemp-ester

2. Physical and Chemical information

Chlorpyrifos-methyl Chlorpyrifos-ethyl

Melting point 46ºC 42ºC

Decomposition/ Sublimation
233.6°C 170-180°C.
temperature

Volatility (Henry’s Law MODERATELY VOLATILE (0.235 Pa MODERATELY VOLATILE (0.478 Pa m

constant) m3 /mol) 3/mol)

Solubility in water Low (2.74 mg/L) Low (1.05 mg/L)

Metabolites

TCP; TMP; Desethyl-chlorpyrifos- TCP; TMP; Desmethyl-chlorpyrifos-

methyl; N-methyl TCP methyl
Name:

3. Mammalian Toxicology

Chlorpyrifos-methyl Chlorpyrifos-ethyl

Acute Toxicity

Acute oral LD50

Not classified

H301: Toxic if swallowed

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 Chlorpyrifos-methyl Chlorpyrifos-ethyl

Dermal LD50

Not classified

H312: Harmful in contact with skin

Inhalation LC50 Not classified Not classified

Skin sensitization

No sensitizer

H317: May cause an allergic skin

reaction

Genotoxicity

Not genotoxic Potential genotoxic

Chronic toxicity / carcinogenicity

Not classified Not classified

Reproductive and developmental toxicity

Not classified Not classified

Neurotoxicity

Not neurotoxic Potential neurotoxic

ED

Not classified Not classified

ADI / ARfD / AOEL / AAOEL

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 Chlorpyrifos-methyl Chlorpyrifos-ethyl

ADI 0.01 mg/kg bw/day b) 0.001 mg/kg bw/day

AOEL 0.01 mg/kg bw 0.001 mg/kg bw/day

ARfD = AAOEL 0.1 mg/kg bw/day 0.005 mg/kg bw/day

b)
RAR (2017)

4. Ecotoxicology

Chlorpyrifos-methyl Chlorpyrifos-ethyl

Birds

Birds acute LD50 LOW TOXIC (923 mg/kg) HIGH TOXIC (39 mg/kg)

Aquatic organisms

Fish Acute Toxicity LD50 MODERATE TOXIC (0.410 mg/L) HIGH TOXIC (0.025 mg/L))

Aquatic invertebrate Acute HIGH TOXIC (0.00062 mg/L) HIGH TOXIC (0.00017 mg/L)
Toxicity EC50

Effects on bees

Honeybees acute oral LD50 HIGH TOXIC (0.50 μg a.s./bee) HIGH TOXIC (0.068 μg a.s./bee)

Honeybees acute contact LD50 HIGH TOXIC (0.25 μg a.s./bee) HIGH TOXIC (0.15 μg a.s./bee)

Effects on non-target soil meso- and macro fauna

Earthworms chronic effects MODERATE TOXIC (12.5 mg a.s/kg HIGH TOXIC (0.075 mg a.s /kg soil)
NOEC soil)

5. Environmental behavior parameters

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 Chlorpyrifos-methyl Chlorpyrifos-ethyl

Aerobic Soil Half-Life

Lab studies DT50– Parent NON-PERSISTENT (7.64 days) PERSISTENT (110.3 days)

Field soil dissipation NON-PERSISTENT (2.17 d) MODERATELY-PERSISTENT

studies DT50- Parent (88.89 d)

Adsorption SLIGHTLY MOBILE (Koc = 1376) SLIGHTLY MOBILE (Koc =

3954)

FAST DEGRADATION (3.25 d) FAST DEGRADATION (29.93 d)

Water/Sediment Study

Chlorpyrifos-methyl, TCP, TMP, Chlorpyrifos, TCP, TMP, DCP

Soil:
DCP, N-methyl TCP

Chlorpyrifos-methyl, Desmethyl Chlorpyrifos, Desethyl

Surface
chlorpyrifos-methyl, TCP, TMP, chlorpyrifos, TCP, TMP, DCP
water:
DCP, N-methyl TCP

Residues
requiring Chlorpyrifos-methyl, Desmethyl Chlorpyrifos, Desethyl
further Sediment: chlorpyrifos-methyl, TCP, TMP, chlorpyrifos, TCP, TMP, DCP
assessment DCP, N-methyl TCP

Ground Chlorpyrifos-methyl, TCP, TMP, Chlorpyrifos, TCP, TMP, DCP

water DCP, N-methyl TCP

Chlorpyrifos-methyl, TCP, Chlorpyrifos, TCP, TMP,

Air: Chlorpyrifos-methyl oxon. Chlorpyrifos-oxon.

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