The document discusses regulations around renewing approvals for active substances in pesticides. It focuses on regulations in the EU and US that require periodic review and reapproval of both active substances and pesticide products. In the EU, active substances undergo renewal processes known as Annex I Renewal programs, with over 200 substances currently part of the AIR4 program. In the US, the EPA conducts registration reviews of all registered active substances every 15 years to ensure they still meet safety standards. The document provides guidance on successfully navigating the renewal process, including forming consortiums, starting early, addressing data gaps, interacting with regulators, and responding to evaluation questions.

1. 1
PRESERVING LIFECYCLES
PRESERVING
LIFECYCLES:
Renewing Existing Plant
Protection Active Substances

2. 2
PRESERVING LIFECYCLES
Introduction 3
Current Agrochemicals Market Backdrop 3
Active Substances Review and Re-Approval Regulation 4
Steps to Achieve Successful AS Renewal 11
Summary 15
References 16
Terminology 17
CONTENTS

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With the rise in the use of such
products came increasing concerns
about their effect on health and the
environment. In the USA, specific
regulation of such chemicals first
appeared in the early 1900s, but it was
not until 1970 that the Environmental
Protection Agency (EPA) was
created, with the remit of protecting
the environment, and the health of
humans and other animals. In Europe,
the European Council (EC) issued its
first directive on pesticide residues in
1976, with extensive regulatory activity
beginning in the early 1990s.
We have been using
chemicals to protect
plants from pests and
diseases since 2,500 BC,
when, as records show,
ancient Sumarians used
sulfur to control mites/
insects; however, it was
really towards the end
of the 19th century that
the industrial usage of
inorganic products and
those derived naturally,
such as pyrethrum,
became common
and widespread.1
In 2017, the regulation that governs
the marketing, sale and use of plant
protection products (PPPs) is just
a fact of life and a standard part of
international agrochemical business.
However, the standards imposed by
regulation are constantly evolving as
our scientific insight and knowledge
increases, so active substances (ASs)
and PPPs previously approved as safe
may need to be reviewed against
new standards.
INTRODUCTION
This informational e-book is
designed to examine how existing
ASs are managed through the
current regulatory renewal
systems in the EU and USA.

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The annual growth
rate for PPPs (2017
to 2022) is estimated
to be 5.79%.2
CURRENT AGROCHEMICALS MARKET BACKDROP
On a broader political front, the
EU is reviewing its current legislation
through the REFIT program, while
in the USA, President Trump’s
reforms to the EPA may also impact
the regulatory environment.
Challenges and opportunities
also exist in the plant protection
market. Important patent expiries
are expected in the coming year,
and merger and acquisition activity
among agrochemical companies is
changing the competitive landscape;
for example, the merger of Dow
Chemical and DuPont has required
divestment of certain parts of each
company’s business, with the
USA requiring DuPont to shed
its herbicide/insecticide business
(acquired by FMC), and Brazil’s CADE
(Administrative Council for Economic
Defense) requiring Dow to divest part
of its corn hybrid seed business, which
it has sold to China’s Citic Agri Fund.3
Against this backdrop, the history,
knowledge and insight about
established active substances could
get ‘lost’, and such changes may pose
risks for reauthorization of PPPs.
The growth in the market will mainly
be driven by increasing food demand
from a growing global population
and the need to increase crop yields.

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In major global markets, regulatory
approval usually constitutes two parts:
first, approval of the so-called AS
or technical-grade active ingredient
(TGAI) and, second, approval of the
actual end-use or formulated PPPs
containing one or more approved
ASs. Approvals are usually time limited;
therefore, both the ASs and the PPPs
must be reapproved and reauthorized
once approval lapses.
The most sophisticated and developed programs for review
and re-approval of ASs and PPPs are in the major US
and European markets. This e-book focuses on the review
programs in use by those regions, while recognizing that
other important markets, such those in Japan, Australia
and New Zealand, Canada and Brazil, have well-developed
crop protection legislation to ensure safety to humans
and the environment when PPPs are authorized for use
in their territories.
US REGULATION OF ASs AND PPPs
The EPA Office of Pesticide Programs handles most
of the regulatory issues pertaining to PPPs, using
authority from the Federal Insecticide, Fungicide,
and Rodenticide Act (FIFRA). All PPPs being sold
or distributed in the USA must be registered with
the EPA. The EPA evaluates the PPP’s proposed usage
and labeling, to ensure it will not have unreasonable
adverse effects on humans or the environment.
AS REVIEW AND RE-APPROVAL REGULATION
Both the ASs and the PPPs must be reapproved
and reauthorized once approval lapses.

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The EPA reviews each registered AS
at least every 15 years to determine if
it meets current FIFRA standards for
registration. ASs registered before 1984
have been re-evaluated initially under
the re-registration program. These ASs
are also subject to registration review.4
REGISTRATION REVIEW PROGRAM
The EPA plans to review all ASs registered on or before
1st October 2007 by 1st October 2022. Schedules of reviews
and consultations before reviews are published and
updated annually. New ASs will be added to the schedules
as they approach 15 years’ post-registration. The EPA
is planning to start 70 or more new registration reviews
in 2017.4
Reviews are structured into review ‘cases’ that group ASs
together for a number of possible reasons, including their
chemical class or structure, mode of action or use.

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PRESERVING LIFECYCLES
A detailed description of the process and
procedures can be found on the EPA website
under registration review procedures.
FIGURE 1: EPA REGISTRATION
REVIEW AS OF JANUARY 1, 20164
165COMPLETED
interim or
final decisions
~724registration review cases
>550inACTIV
E
registration
review
>630OPENregistr
ation review cases
~1,140
active
ingredients

8. 8
PRESERVING LIFECYCLES
FIGURE 2: THE EPA REGISTRATION REVIEW PROCESS4
DOCKET
OPENING
FOCUS
MEETING
REGISTRATION
REVIEW
DECISION
CASE
DEVELOPMENT
Summarizes the
pesticide information
and the review plan.
Typically initiated with
affected registrants and
other stakeholders early
in the process.
EPA assesses changes
in law/regulation
since last review.
EPA issues a draft
decision with a 60-day
comment period.
It contains:
Acts about the pesticide
and its use
The anticipated risk
assessment and data needs
An estimated review timeline.
The preliminary workplan
undergoes public consultation
for 60 days after which a final
workplan is published.
If new assessment is needed,
data gaps are identified and
registrants asked for data
call-in (DCI).
Risk assessment or risk/benefit
analysis is undertaken if needed.
The public and regulatory
partners are consulted.
After this point, a final decision
is issued on which the registrant
must act.
In some situations, interim
decisions are issued before
the final decision. This may
require risk mitigation
measures, call for new data,
and outline schedules for
subsequent data submission
and review.
The focus is to identify
information needs and provide
an opportunity to address areas
of uncertainty affecting the
risk assessment and risk
management decisions.
Although not mandatory,
they are recommended.

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PRESERVING LIFECYCLES
The legislation concerning
the placing of PPPs on the
European single market
is included in Regulation
(EC) No. 1107/2009,
with the specific data
requirements for ASs
and PPPs contained
in Regulations (EU)
No. 283/2013 and
No. 284/2013.
The authorization of ASs generally
expires after ten years. To enable
continued marketing and sales
of PPPs, a renewal of authorization
of the ASs must be sought.
This renewal procedure is covered
by Commission implementing
Regulation (EU) No. 844/2012.5
and is a European-level process.
Article 43 of Regulation (EC)
No. 1107/2009 also provides the
framework for the renewal of PPPs
following the re-approval of an AS.
This process is further elaborated on
in a European Commission guidance
document.6 The renewal of PPPs is
the responsibility of the individual
European Member States.
EUROPEAN REGULATION
RENEWAL PROGRAMS
The programs for renewal of
ASs in the EU are known as
Annex I Renewal (AIR) programs.
ASs are assigned to a program, group
and/or batch, based on their expiration
dates and level of priority, in order
to manage and spread the workload
of the renewal process. The AIR
programs also assign each AS a
‘Rapporteur Member State’ (RMS)
to undertake the task of evaluating
the renewal application.
The legislation concerning the placing
of PPPs on the European single
market is included in Regulation
(EC) No. 1107/2009

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THERE ARE FOUR AIR PROGRAMS, AS OUTLINED IN TABLE 1.
TABLE 1: THE AIR PR GRAMS, AS OF FEBRUARY 2017
AS EXPIRY DATES NUMBER OF ASs REGULATION NOTES
AIR1 7 (pilot project) EC NO. 737/2007 All substances were renewed for expiry
on December 31, 2021, so they are due for
second renewal under AIR4 and as such,
are due for second renewal under AIR
AIR2 2011–2012 31 EU NO. 1141/2010 29 renewal dossiers were submitted.
It was necessary to extend the expiry
dates for 23 of the ASs
AIR3 January 1, 2013 –
December 31, 2018
150 EU NO. 844/2012
EU NO. 1107/2009
Applications split into batches,
with extensions for some to allow
for sufficient time for dossier preparation
by companies and/or balance workload
in reviewing States
AIR4 January 1, 2019 –
December 31, 2021
214 EU NO. 844/2012
EU NO. 1107/2009
Prioritized into four groups
(SANTE-2016-10616),
Details of the latest updates for renewal programs,
AIR3 and AIR4, can be found on the EC website

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For the current AIR4 substances,
applicants must apply for renewal
three years before the expiry date
of an approved AS.
Article 17 of Regulation 1107/2009
allows for extensions to the expiry
dates of ASs, where it would not
be possible to take a decision before
the current expiry date, for reasons
beyond the control of the applicant.
THE MAIN REASONS THESE
EXTENSIONS ARE REQUIRED ARE:
▶▶ Delays in assessment
▶▶ Delays in decision-making –
this is true for highly complex cases
▶▶ Facilitation of the review through the Member States
by balancing capacity – this is the case for AIR4.
TIMELINES AND EXTENSIONS

12. 12
PRESERVING LIFECYCLES
FIGURE 3: THE AIR RENEWAL PROCESS7
APPLICATION
(36 months
before expiry)
SUBMISSION
(30 months
before expiry)
RAR
EVALUATION
(RAR issued
12 months post
submission)
PEER
REVIEW
(Review
8 1/2 – 11
months)
RENEWAL
DECISION
(~9 months
duration)
APPLICATION
REVIEW
Registrants submit
an application containing
limited information
to indicate their intent
of submitting a dossier
to pursue active
substance renewal.
RMS conducts
admissibility check.
Registrant must
respond within 14 days
to calls for missing
information.
Registrants create
and submit
a renewal dossier.
For most ASs, the dossier
must be submitted 6
months post-application.
For AIR4, some groups’
expiry dates have been
extended by 1 to 3 years
to allow more time
for dossier submission.
RMS conducts an initial
review check; registrants
must respond to any
data requests within
14 days.
A draft Renewal
Assessment Report (RAR)
is issued 12 months
after dossier submission.
Requests for additional
information may be made.
The RAR is passed to the
European Food Safety
Authority for publication
and consultation.
The final decision is made
by a vote of the Standing
Committee on the Food
Chain and Animal Health.
Renewal is officially adopted
by the Commission and
the results are published.

13. 13
PRESERVING LIFECYCLES
In the final section of this
e-book, we will provide
some practical advice
to help companies tackle
the renewal process.
FORM A TASKFORCE
OR CONSORTIUM
A major difference between the
application for marketing authorization
of a new AS and that for renewal of
an existing substance is that renewals
are likely to involve more than one
applicant and take the form of a
joint submission. In fact, there is an
expectation that stakeholders with an
interest in the AS will reach agreement
to cooperate in the re-approval process
and submit a joint dossier.
For joint submissions to work
efficiently, it is important to establish
a task force or consortium of all
companies that have an interest in an
AS used in specific PPPs. With many
older chemicals out of patent, the list
of interested companies could be large.
By establishing a consortium, the
division of the costs for dossier creation
and submission can be shared within
a clear legal framework. Once renewal
is gained, all parties share the data,
which can be used for the renewal
of individual PPP registrations.
STEPS TO ACHIEVE SUCCESSFUL ‘AS’ RENEWAL
PLAN AHEAD
AND START EARLY
From experience, we know that
you need to start well before the
application date for an AS renewal.
In the EU, where applications are
required three years before the expiry
date, however it is recommended to
start the process at least two years
before that – that is, five years before
expiry. This gives sufficient time for
the following important activities:
▶▶ Assess data gaps: it is essential
to review the data available for
the AS against the current data
requirements and guidance, to
identify what data are missing or
suboptimal. Past experience and
learning from substances that have
already been, or are being, evaluated
as part of earlier AIR submissions
can also be taken into account.

14. 14
PRESERVING LIFECYCLES
▶▶ Identify a costed plan for addressing
gaps in data: once data gaps are
established, the next step is creating
a plan to address them. This plan
should identify what studies could
be defended and what new studies
may need to be carried out. The
challenge when consortia reach
this stage is balancing the
expenditure of new studies against
the overall return from the AS.
Having both regulatory and
scientific expertise under one roof
enhances decision-making and
prioritization at this stage.
▶▶ Conduct studies: by starting
two years before the application
deadline for renewal, it is possible
to conduct two seasons of field
studies if required.
▶▶ Organize a pre-submission
meeting with the RMS: this is the
opportunity to have an open and
frank discussion with the RMS
about your AS, and the plans and
strategy for renewal. It is important
that particular areas of concern are
discussed. Experience has shown
these meetings are invaluable
for both parties, with many
questions answered.
▶▶ Prepare and submit the renewal
application and updating statement:
this should include a reference list
detailing the new studies that are
intended to be submitted in the
supplementary renewal dossier.
▶▶ Prepare and submit the
supplementary renewal dossier:
the dossier should be written up
to the appropriate standards and
following the templates required.
It is important to build a case
that will resonate with regulatory
reviewers, anticipating and
answering their concerns.
The dossier is prepared and
submitted in CADDY format.
▶▶ Respond to RMS questions during
their evaluation: the time for
preparing responses is usually
limited, and it is important to
have a clear understanding what
is being asked, so seek clarification
if necessary. Try to answer as fully
as possible.
▶▶ Comment on RAR: it is important
to be prepared to respond to the
RARs when they are issued a year
after dossier submission. Review
them objectively, and be prepared
to defend studies and provide
comprehensive answers to
any questions.

15. 15
PRESERVING LIFECYCLES
Application
(36 months before expiry)
RAR
(12 months after
submission)
Submission
(30 months before expiry)
-5 -4 -3 -2 -1 EXPIRY
PROPOSED REGISTRANT ACTIVITY TIMEFRAME
EU REGULATORY RENEWAL TIMEFRAME
Renewal decision
Pre-submission meeting
(sometime before application)
Defend
dossier and
respond
to RAR
Data gap
analysis
Prepareand
submitdossier
Study
plan
Conduct studies –
allowing 2 seasons of field studies
FIGURE 4: THE ROUTE THROUGH AS RENEWAL

16. 16
PRESERVING LIFECYCLES
Given the complexity of managing
these long-term, regulatory renewals
and study programs, it can be of great
added value to work with a partner
who has experience in all the stages
of the process.
WORK WITH AN EXPERIENCED PARTNER
TRUSTED PARTNERS CAN PROVIDE
NUMEROUS ADVANTAGES THROUGHOUT
THE RENEWAL PROCESS, INCLUDING:
▶▶ Wide experience covering multiple AS chemistries
and activities
▶▶ A consultancy team with a background in industry,
authorities, Contract Research Organizations (CROs)
and other consulting companies
▶▶ Thorough understanding of the crop protection market
▶▶ Strategic focus and industry perspective
▶▶ Experience and proven track record
▶▶ Flexible approach and close partnership
▶▶ Detailed planning and project management
▶▶ Timely communication
It is important to remember that once the AS has been
re-authorized, the process of product renewal begins,
following the procedures laid down in Article 43.

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PRESERVING LIFECYCLES
▶▶ Literature review: A comprehensive literature
search, that meets the criteria in the EFSA Guidance
(is required.8-11
A tiered approach is taken in order
to identify those papers that are both relevant
and reliable, and therefore merit inclusion and
consideration of the results in the renewal dossier.
▶▶ Harmonized classification and labeling (CLH) of
ASs is the responsibility of the European Chemicals
Agency (ECHA). This requires preparation of dossiers
(including IUCLID technical dossiers) for CLH under
Regulation (EC) No. 1272/2008 (CLP Regulation),
preparation of expert statements on technical
and scientific issues regarding toxicity of ASs
and supporting clients at ECHA risk assessment
committee meetings.
OTHER IMPORTANT ELEMENTS OF EU ‘AS’ REVIEW
▶▶ Maximum residue levels (MRLs): It is important to
have appropriate MRLs (and/or import tolerances [ITs])
in place for all uses, not just the representative uses
included in the renewal dossier. MRL application and
setting is covered by Regulation (EC) No. 396/2005.10

18. 18
PRESERVING LIFECYCLES
The renewal process
in the EU for existing
ASs requires advance
planning and careful,
attentive management.
SUMMARY
FOUR KEY PIECES
OF ADVICE ARE:
▶▶ Start early and plan ahead: do
not leave planning for your renewal
to the last minute. You need to
start planning at least five years
before the AS expiry date to give
you time to establish, if necessary,
a task force or consortium and
agree your strategy, budget
working practices and study
program for the renewal process.
▶▶ Communicate clearly and work
collaboratively with others: effective
working partnerships with other
stakeholders, such as task force
members, consultants and CROs,
requires good communication
and clear agreement of roles
and responsibilities. Engage with
the renewing authority early to
establish possible issues and scope.
▶▶ Be bold but realistic: review the
data for your AS and characterize
data gaps comprehensively;
however, do not be afraid to look
at your existing studies and plan
a robust defense of them, while
always having a contingency.
▶▶ Remember this is an ongoing
process: renewal of approval is
only a step towards meeting your
commercial objectives, and the
next stage of renewal of products,
introduction of new products
and extensions of use of existing
products are just as important
and require careful planning
and management.

19. 19
PRESERVING LIFECYCLES
1
Aspinal A. Pesticide usage in the United
States: Trends During the 20th Century.
Center for Integrated Pest Management.
CIPM Technical Bulletin 2003; 105.
2
Mordor Intelligence. Crop protection
chemicals (Pesticides) Market - Global
Industry Growth, Trends and Forecasts
(2017 - 2022). Published February 2017.
www.mordorintelligence.com/industry-
reports/global-crop-protection-chemicals-
pesticides-market-industry
3
Reuters. BRIEF-Dow to divest portion
of its corn hybrid seed business in Brazil
to CITIC Agri Fund for $1.1 bln. July 11,
2017 http://uk.reuters.com/article/
brief-dow-to-divest-portion-of-its-corn-
idUKASA09WQR
4
United States Environmental Protection
Agency. Registration Review Process.
www.epa.gov/pesticide-reevaluation/
registration-review-process
REFERENCES
5
EFSA. Applications helpdesk – Renewal
of approval under AIR programme:
application procedure. www.efsa.europa.
eu/sites/default/files/applications/
RenewalApprovalActSubPro.pdf
6
European Commission.
SANCO/2010/13170 rev. 14.
Guidance Document on the Renewal
of Authorizations according to Article 43
of Regulation (EC) No 1107/2009. 2016.
October 7, 2016. https://ec.europa.eu/
food/sites/food/files/plant/
docs/pesticides_aas_guidance_
renewal_1107-2009.pdf
7
1107 Vademecum, Fourth Edition,
Pappas & Associates, Brussels, 2017
8
EFSA. Submission of scientific peer-
reviewed open literature for the approval
of pesticide active substances under
Regulation (EC) No 1107/2009. EFSA
Journal 2011; 9(2): 2092. https://efsa.
onlinelibrary.wiley.com/doi/epdf/
10.2903/j.efsa.2011.2092
9
European Union. Regulation (EC) No.
1107/2009 of the European Parliament
and of the Council of 21 October 2009
concerning the placing of plant protection
products on the market and repealing
Council Directive 79/117/EEC
and 91/414/EEC. Official Journal
of the European Union L 309,
November 24, 2009. https://eur-lex.
europa.eu/legal-content/EN/TXT/
PDF/?uri=OJ:L:2009:309:FULL&from=EN
10
European Parliament, Council of the
European Union. Regulation (EC) No.
396/2005 of the European Parliament
and of the Council of 23 February 2005 on
maximum residue levels of pesticides
in or on food and feed of plant and
animal origin and amending Council
Directive 91/414/ EEC. Official
Journal of the European Union L
70, March 16, 2005. https://eur-lex.
europa.eu/legal-content/EN/TXT/
PDF/?uri=OJ:L:2005:070:FULL&from=EN
11
European Commission. Renewal of
approval. https://ec.europa.eu/food/
plant/pesticides/approval_active_
substances/approval_renewal_en

20. 20
PRESERVING LIFECYCLES
AIR Annex I Renewal
AS Active substance
CLH Harmonized classification and labeling
CLP Classification, Labeling and Packaging
CRO Contract research organization
DCI Data call-in
EFSA European Food Safety Authority
EPA Environment Protection Agency
EU European Union
FIFRA Federal Insecticide, Fungicide,
and Rodenticide Act
TERMINOLOGY
IT Import tolerance
MRL Maximum residue level
PPP Plant protection product – a term often used
interchangeably with the term pesticide;
however, pesticide is broader and also covers
non-plant or crop use (for example, biocides)
RAR Renewal Assessment Report
RMS Rapporteur Member State – the member
state of the EU that acts as the lead reviewer
of renewal dossiers
TGAI Technical-grade active ingredient

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