SOCIO-ECONOMIC ANALYSIS
Socio-Economic Analysis Use number: 1 Laboratoires Expanscience 1
SOCIO-ECONOMIC ANALYSIS
(SEA)
Legal name of applicant(s): Laboratoires Expanscience
Submitted by: Laboratoires Expanscience
Substance: 1,2-dichloroethane (EDC) – CAS No. 107-06-2
Use title: Use as process and extracting solvent in fine chemical
processes
Use number: 1
SOCIO-ECONOMIC ANALYSIS
Socio-Economic Analysis Use number: 1 Laboratoires Expanscience 2
CONTENTS
DECLARATION .......................................................................................................................................................... 5
1 SUMMARY OF SOCIO-ECONOMIC ANALYSIS .............................................................................................. 6
2 GENERAL INTRODUCTION – PRESENTATION OF EXPANSCIENCE ......................................................... 7
Presentation of the Company .......................................................................................................................... 7 2.1.1 Organization & products ..................................................................................................................... 7 2.1.2 International business .......................................................................................................................... 9
Focus on the production site ........................................................................................................................... 10
3 AIMS AND SCOPE OF SEA ................................................................................................................................. 13
Aims of SEA ................................................................................................................................................... 13
Geographical scope ......................................................................................................................................... 13
Scope related to timelines ............................................................................................................................... 13
Scope related to impacts ................................................................................................................................. 14
Stakeholders included in the impact assessment ............................................................................................ 14
4 DEFINITION OF “APPLIED FOR USE” SCENARIO ......................................................................................... 16
Presentation of Piascledine® 300 ................................................................................................................... 16
Piascledine® 300 production process description – From raw materials to patients ...................................... 17
Employment data ............................................................................................................................................ 18
Supply chain analysis ..................................................................................................................................... 19
Distribution network ....................................................................................................................................... 20
Rheumatology sales and profit forecasts (2015 – 2029) ................................................................................. 21
5 DEFINITION OF THE “NON-USE” SCENARIO AND THE “SHORT AUTHORISATION” VARIANT ........ 23
“Non-use” scenario: Closing of the Rheumatology Business ......................................................................... 24
“Short Authorisation” scenario: Relocation of Avocado and Soybean oil unsaponifiables production outside
E.U. ................................................................................................................................................................. 25
6 INFORMATION ON THE LENGTH OF THE REVIEW PERIOD ...................................................................... 27
7 ANALYSIS OF IMPACTS – “APPLIED FOR USE” SCENARIO – HEALTH AND ENVIRONMENTAL
IMPACTS ..................................................................................................................................................................... 28
Hazard profile of EDC .................................................................................................................................... 28
Exposed populations ....................................................................................................................................... 31 7.2.1 Worker population ............................................................................................................................... 31
SOCIO-ECONOMIC ANALYSIS
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7.2.2 General population living nearby the Épernon production site ........................................................... 31
Human health impacts on Expanscience’s workforce .................................................................................... 32 7.3.1 Exposure scenario................................................................................................................................ 32 7.3.2 Exposure levels ................................................................................................................................... 33 7.3.3 Calculation of excess cancer cases ...................................................................................................... 34 7.3.4 Distinction between potential number of additional fatal and non-fatal cancers among Expanscience’s
workforce ............................................................................................................................................ 36 7.3.5 Economic valuation of additional fatal and non-fatal cancer cases among Expanscience’s workforce 37
Human health impacts on general population ................................................................................................. 41 7.4.1 Exposure levels ................................................................................................................................... 41 7.4.2 Calculation of excess cancer cases ...................................................................................................... 42 7.4.3 Economic valuation of additional fatal and non-fatal cancer cases among the general population ..... 43
Environmental impacts ................................................................................................................................... 44 7.5.1 Monitoring and emission of EDC to the environment ......................................................................... 44 7.5.2 Aquatic releases ................................................................................................................................... 44 7.5.3 Atmospheric releases ........................................................................................................................... 46
Conclusion on health and environmental impacts .......................................................................................... 47
8 ANALYSIS OF IMPACTS – “NON-USE” SCENARIO: CLOSING OF THE WHOLE RHEUMATOLOGY
BUSINESS ................................................................................................................................................................... 48
Economic impacts of the closing of the Rheumatology business ................................................................... 48 8.1.1 Impact on Sales ................................................................................................................................... 49 8.1.2 Impact on profitability ......................................................................................................................... 50
Social impacts ................................................................................................................................................. 52 8.2.1 Impact on Expanscience’s workforce .................................................................................................. 52 8.2.2 Impact on suppliers ............................................................................................................................. 52 8.2.3 Impact on distributors .......................................................................................................................... 52
Wider economic impacts ................................................................................................................................ 53
Conclusions of the “Non-Use” Scenario (i.e. the closing of the Rheumatology business) ............................. 54
9 ANALYSIS OF IMPACTS – “SHORT AUTHORISATION” VARIANT: RELOCATION OF AVOCADO AND
SOYBEAN UNSAPONIFIABLES PRODUCTION OUTSIDE E.U. ......................................................................... 55
Economic impacts ........................................................................................................................................... 55 9.1.1 One-off costs ....................................................................................................................................... 55 9.1.2 Operating costs .................................................................................................................................... 56
Social impacts ................................................................................................................................................. 58 9.2.1 Impact on Expanscience’s workforce .................................................................................................. 58 9.2.2 Impact on third parties (suppliers & distributors) ................................................................................ 59
Wider economic impacts ................................................................................................................................ 59
Conclusions of the “Short Authorisation” variant (i.e. the relocation of the Avocado and Soybean
unsaponifiables production outside E.U.) ....................................................................................................... 60
10 COMBINED ASSESSMENT OF IMPACTS ......................................................................................................... 61
SOCIO-ECONOMIC ANALYSIS
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Comparison of impacts ................................................................................................................................... 61
Uncertainty analysis ....................................................................................................................................... 62 10.2.1 Health Impacts ..................................................................................................................................... 62 10.2.2 Economic Impacts ............................................................................................................................... 62
11 CONCLUSIONS ..................................................................................................................................................... 63
ANNEX – JUSTIFICATIONS FOR CONFIDENTIALITY CLAIMS ........................................................................ 64
APPENDIXES .............................................................................................................................................................. 65
APPENDIX A – Detailed process description ........................................................................................................ 65 A.1. Process description: used as a process and extracting solvent in fine chemical processes (i.e.
pharmaceutical) ................................................................................................................................... 65 A.2. Transport ................................................................................................................................................. 68 A.3. Storage .................................................................................................................................................... 69 A.4. Recycling ................................................................................................................................................ 70
APPENDIX B – Other pictures of the existing facility ........................................................................................... 71
APPENDIX C – Details on past investments on the new HEQ building ................................................................ 72
APPENDIX D – Details on hypotheses for Piascledine® 300 sales forecasts ........................................................ 72
APPENDIX E – Overview of Expanscience’s substitution strategy ....................................................................... 73
APPENDIX F – Details on labour costs outside E.U. ............................................................................................. 74
APPENDIX G – Measures taken to limit workers’ exposure to EDC .................................................................... 75
APPENDIX H ......................................................................................................................................................... 76 H.1 Methyl iso-butyl ketone (MIBK, CAS 108-10-1) .................................................................................... 76 H.2 Human Health .......................................................................................................................................... 77 H.3 Ecotoxicity ............................................................................................................................................... 81
SOCIO-ECONOMIC ANALYSIS
Socio-Economic Analysis Use number: 1 Laboratoires Expanscience 5
DECLARATION
We, Laboratoires Expanscience, request that the information blanked out in the “public version” of
the Socio-Economic Analysis is not disclosed. We hereby declare that, to the best of our knowledge
as of today (July 2nd, 2015) the information is not publicly available, and in accordance with the due
measures of protection that we have implemented, a member of the public should not be able to
obtain access to this information without our consent or that of the third party whose commercial
interests are at stake.
Signature: Date, Place: July 2nd, 2015, Courbevoie
JP. Berthomé, CEO of Expanscience
SOCIO-ECONOMIC ANALYSIS
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1 SUMMARY OF SOCIO-ECONOMIC ANALYSIS
Expanscience is a laboratory active in different complementary fields, ranging from osteoarthritis
treatment to skin care.
In particular, Expanscience launched in 1992 Piascledine® 300 in its Rheumatology business, a
drug to treat osteoarthritis which currently accounts for ca. % of Expanscience turnover and is
commercialized in 42 countries (see section 2.1 of the SEA). Piascledine® 300 is produced in
Expanscience’s only manufacturing facility in Épernon, France, and involves different steps of
production. One key step in this process requires the use of EDC as a major extraction solvent in a
liquid/liquid extraction unit operation. The company has already invested more than 23 M€ in 2010-
2012 to build a modern production tool including a HEQ building limiting risks for environment
and for workers linked to the use of EDC.
As mentioned in the Analysis of Alternatives (AoA), one substance appears as a potential candidate
to replace EDC but the technical and economic feasibility of this substitution are critical points
where some uncertainties remain to be lifted (see section 5.2 of the AoA).
In order to comply with the new REACH regulation and to substitute EDC, Expanscience requests a
12-year authorisation (“Applied for Use” scenario) after the sunset date (November 22nd, 2017) to
be able to use EDC in the production process of Piascledine® 300 until 2029, when the substitution
candidate will be fully qualified and when the new process should be fully deployed (see section 5.7
of the AoA). Substituting EDC will mean investing an additional ca. 51 M€ in the next few years.
Consequently the analysis of the socio-economic impacts was led for the 12-years period running
from 2018 to 2029. We considered a “Non-Use” scenario and a “Short Authorisation” variant,
which we compared to the “Applied for Use” scenario.
In the “Non-Use” scenario, Expanscience would have to close its Rheumatology business because
it would not be able to produce nor to sell Piascledine® 300 for 12 years in all the markets where
the product is currently sold. Piascledine® 300 indeed accounts for nearly % of Expanscience
Rheumatology sales (2014). This scenario would impact all Expanscience employees dedicated to
the Rheumatology business, as well as suppliers’. Therefore, we estimate that the closing of the
Rheumatology unit would mean suppressing 282 jobs at Expanscience and 27 at suppliers within
the European Union (plus a total of 120 workers outside EU). The NPV of EBIT losses for
Expanscience would be M€ over the 2018-2029 period. The scenario could possibly lead to the
bankruptcy of the whole Company, as the Rheumatology business generates roughly % of
Expanscience EBIT and 40% of its sales (see section 5.1 of the SEA).
The “Short Authorisation” variant has been considered in the case where Expanscience would
only be granted a 5-year authorisation. In that variant, Expanscience would have to relocate the
extraction step of the production (using EDC) in a country outside E.U. The 5-year authorisation
would allow for the set-up of a new site abroad and to obtain regulatory approvals while
maintaining the production in Épernon, France. In this variant, the social and economic impacts for
Expanscience and its suppliers would be limited to the extraction step representing a NPV of EBIT
losses of M€ over the 2018-2029 period (see section 5.2 of the SEA). The workforce reduction
would amount to 21 employees at Expanscience and 9 at suppliers within the European Union.
In parallel, we led a comprehensive cost analysis to monetize the health impact of additional cancer
development linked to the continued use of EDC after the sunset date. We demonstrated that, in the
“Non-Use” scenario, the socio-economic impact ( M€ over the 2018-2029 period) is about
M€ higher than the 0.0126 M€ of monetized benefits of avoiding potential additional cancer
cases over 12 years. In the “Short Authorisation” variant the socio-economic impact would be
M€ over the 2018-2029 period including the cost of additional cancer cases over 5 years.
SOCIO-ECONOMIC ANALYSIS
Socio-Economic Analysis Use number: 1 Laboratoires Expanscience 7
2 GENERAL INTRODUCTION – PRESENTATION OF EXPANSCIENCE
Presentation of the Company
2.1.1 Organization & products
Founded in 1950, Expanscience is a French, independently-owned pharmaceutical and dermo-
cosmetics laboratory. In 2014, the Company generated a turnover of € 272 million, 45% of which
was through export, and employed 893 people (770 in France).
Expanscience is structured around 3 main business units (see Figure 1 hereafter):
a) Pharmaceuticals including Rheumatology and Dermatology
b) Dermo-cosmetics
c) Cosmetic Active Ingredients
Figure 1 – Expanscience main business units
In 2014, Rheumatology & Dermo-Cosmetics accounted for around 95.5% of Expanscience total
sales.
SOCIO-ECONOMIC ANALYSIS
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a) Pharmaceuticals including Rheumatology and Dermatology
Rheumatology (~40% of sales in 2014) is one of Expanscience key area of expertise.
Piascledine® 300 is Expanscience flagship brand in Rheumatology. Initially
a leading brand in France, it is today marketed in 42 countries, in particular
in Latin America and Asia. In 2014, Piascledine® 300 accounted for nearly
% of total Rheumatology sales.
Expanscience’s osteoarthritis product range also includes a number of other medicines, namely
Hyalgan®, Flexea®, Fixical®, Takadol® and Nabucox®.
In addition Expanscience’s dermatology portfolio includes the following products: Doxylis®,
Procuta®, Effizinc® and Finhair®.
b) Dermo-cosmetics
Dermo-Cosmetics is another core business of Expanscience (~56% of sales in 2014), with two
marketed brands: Mustela® and Noviderm®.
Mustela®
As one of the European leading brands for baby care and stretch-mark
treatment commercialized through pharmacy distribution networks,
Mustela® has supported parents and baby care professionals for more than
60 years. Mustela® is designed to meet the needs of babies, young mothers
and mothers-to-be.
Noviderm®
Noviderm® is a specialty dermatological product which has helped
teenagers and adults tackle skin problems for over 15 years. Innovation and
continuous improvement have made Noviderm® more pleasant and
effective, winning the trust and acclaim of users and healthcare
professionals.
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c) Cosmetic Active Ingredients
Based on its expertise in lipid chemistry, molecular distillation and plant extraction, Expanscience
is a supplier of Cosmetic Active Ingredients to leading cosmetic brands in France and abroad. The
Company also produces Plant Extracts (plant oils, powders and butters) for other industry players.
2.1.2 International business
The Company has built up a solid international reputation as an innovator and as a specialist in skin
care and in the treatment of osteoarthritis. Expanscience products are sold in 97 countries, through
12 subsidiaries (Australia, Belgium, Brazil, France, Italy, Mexico, Poland, Portugal, Spain,
Switzerland, Turkey and USA), and through independent distributors in the other 85 countries.
In 2013, the International business accounted for ~45% of Expanscience revenues (see Figure 2
hereafter), and represents in the next years a major growth lever for the Company.
Figure 2 – Global turnover by geographical area (2013)
International (44.9%)
SOCIO-ECONOMIC ANALYSIS
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Focus on the production site
Expanscience has integrated the major part of its value chain – from research to production and
distribution. Ever since it was founded, Expanscience production facilities and R&D resources have
been based in Épernon, a small town of about 5,500 people in Eure-et-Loir, France.
The six activities that constitute Expanscience manufacturing facility are still located on the same
site in Épernon (see Figure 3 hereafter).
In 2013, nearly 57.8 million pharmaceutical and dermo-cosmetic products were manufactured in
Épernon, up from 56 million in 2012.
Figure 3 - Schematic view of Expanscience production facility in Épernon, France
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The Épernon facility encompasses the following activities:
R&D centre
Scientists from different backgrounds discover new active
ingredients and develop the innovative formulas of the future.
The safety, quality and efficacy division is responsible for
making sure products comply with regulatory and internal
requirements. There is one guiding principle: priority to
naturalness, safety and efficacy.
The R&D centre is located nearby the production site.
The production site itself is composed of 5 main units (see details below):
Naturally-sourced active ingredients production unit
This production unit ensures the industrial extraction and
production of the Active Pharmaceutical Ingredient (API) of
Piascledine® 300. Avocado and soybean unsaponifiables are
produced using an exclusive plant extraction process. This
production step uses EDC as a major extraction solvent in
a liquid/liquid extraction unit operation. This is the only
place in the whole plant where EDC is used.
As a part of its CSR (Corporate Social Responsibility) strategy, the Company invested more than
23 M€ in 2010-2012 to build a modern production tool, including a HEQ building limiting the
impact of production activities on people and on the environment (certification ISO 14001). Please
refer to Appendix C for more details on the investment costs.
In the same plant, but in a different facility, active ingredients are produced for other players in the
cosmetics industry.
Pharmaceutical production unit
This manufacturing facility produces the pharmaceutical
blisters and packs used for the packaging of
Piascledine® 300.
The production of Piascledine® 300 capsules (mixing, filling
and capping) is also performed within this unit.
In 2014, 337,500,000 capsules (22.5 million of boxes containing 15 caps each) of Piascledine® 300
were manufactured.
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Dermo-cosmetic production unit
This unit ensures the manufacturing of Mustela® and
Noviderm® dermo-cosmetic products.
Expanscience product range is very diverse and includes both
creams and liquids, representing 70 formulas altogether.
The packaging is performed in a separated unit (see activity
n°5 hereafter).
Dermo-cosmetic packing units
160,000 products (i.e. 32 tons of products) come out of eight
dermo-cosmetic packaging lines every day.
Quality and safety checks are carried out at every stage.
Warehousing and dispatching platform
Reception:
Every day, four trucks deliver 110 pallets to this platform.
Dispatching:
Six trucks leave every day, transporting 160 product pallets
to more than 70 countries.
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3 AIMS AND SCOPE OF SEA
Aims of SEA
Expanscience applies for a 12-year authorisation for the continued use of 1,2-dichloroethane
(EDC) after the sunset date (November 22nd, 2017) as defined in REACH Annex XIV.
The aim of this document is to assess and balance the overall socio-economic benefits of continuing
to produce Piascledine® 300 with EDC in comparison with the risks to human health and the
environment that would be associated with its continued use.
The Analysis of Alternatives (AoA) has shown that there may be a potential suitable substitute (i.e.
MIBK) for the use of EDC as an extraction solvent in the manufacturing of avocado and soybean
oil unsaponifiables (see section 5.6 of the AoA). Some critical technical and economic questions
remain to be answered about MIBK, which are currently investigated by Expanscience. In the
meantime, Expanscience is currently following a substitution plan that will end in 2029, should
every critical point be addressed (see section 5.7 of the AoA).
Geographical scope
EDC is used during the extraction step of the Active Pharmaceutical Ingredient (API)
manufacturing process of Piascledine® 300 in Épernon, France. The Company headquarters are
located in Courbevoie, France. If most of Expanscience employees are therefore located in France,
Piascledine® 300 is marketed all around the world, with specific marketing authorisations for each
country. The Company also deals with key suppliers in South Africa, Mexico and Peru. The
geographical scope of the SEA impact assessment is therefore global.
Scope related to timelines
The substitution plan detailed in the Analysis of Alternatives presents an estimated end date of the
substitution project in 2029 (see section 5.7 of the AoA). The Company is therefore requesting a 12-
year authorisation (after the sunset date on November 22nd, 2017) to complete the overall
substitution project. As a consequence, the period of time covered by the impact assessment ranges
from 2018 to 2029.
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Scope related to impacts
This socio-economic analysis will assess the following categories of impacts: economic, social,
wider economic, and health & environmental impacts.
Stakeholders included in the impact assessment
Expanscience has many suppliers, subcontractors and distributors all over the world, but not all of
them are affected by the scenarios defined in this SEA (see sections 5.1 and 5.2).
Throughout this socio-economic analysis we have considered the impacts on the following
stakeholders only:
- Departments of Expanscience involved in the Rheumatology activity (production, sales,
etc.)
- Suppliers, subcontractors and distributors who do more than 5% of their turnover with
the Expanscience Rheumatology activity, and/or have one or more employees dedicated to
the Expanscience Rheumatology activity
Figure 4 below shows key stakeholders of the Expanscience ecosystem taken into account in the
impact assessment.
Figure 4 - Mapping of stakeholders included in the impact assessment
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Piascledine® 300 production process description – From raw materials to patients
Expanscience is using EDC as a major extraction solvent in a liquid/liquid extraction unit
operation. The active substance (Active Pharmaceutical Ingredient) of our drug corresponds to a
blend of highly purified avocado and soybean oil unsaponifiable compounds. These families of
molecules obtained through extraction are purified separately from the two independent sources of
oil: avocado oil on one hand and soybean oil on the other hand. To reach adequate purity of
unsaponifiables, a specific proprietary and highly selective extraction and purification process has
been designed. This process involves a key liquid/liquid extraction step using EDC.
The overall Active Pharmaceutical Ingredient (API) manufacturing and distribution process is
described in Figure 5 hereafter.
Figure 5 – Piascledine® 300 – From raw materials to patients
Please refer to Appendix A of the present document for more details on the extraction process, and
also to section 2.1 of the Analysis of Alternatives (AoA) document.
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5 DEFINITION OF THE “NON-USE” SCENARIO AND THE “SHORT
AUTHORISATION” VARIANT
The purpose of this section is to present what would happen if Expanscience had to stop using EDC
after 2017, or would not be granted a 12-year authorisation. The most likely scenario is that
Expanscience would no longer be able to extract the unsaponifiables required in the manufacturing
of Piascledine® 300. As described in the Analysis of Alternatives, Expanscience uses EDC as an
extraction solvent during a key step of the overall manufacturing process of Piascledine® 300
(please refer to section 4.2 or to Appendix A for more details on the extraction process).
The substitution of EDC with a new extraction solvent will not be presented in this document. This
project is indeed described in detail in section 5 of the Analysis of Alternatives (AoA) document. A
global substitution plan has been designed with an end date in late 2029. This substitution scenario
therefore requires a 12-year authorisation. Please refer to the AoA document for more details.
In this context, two scenarios have been considered:
“Non-use” scenario: Closing of the Rheumatology business (potentially leading to the
bankruptcy of Expanscience)
“Short Authorisation” variant: Relocation of the Active Pharmaceutical Ingredient
(API) production in a country outside E.U. This variant would imply that Expanscience is
granted a 5-year authorisation to have time to set up a new site abroad (see section 5.2)
Figure 9 - Illustration of the two scenarios analysed in this document
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“Non-use” scenario: Closing of the Rheumatology Business
If no authorisation is granted to Expanscience for the use of EDC, the only potential “Non-Use”
scenario is that the Company will shut down the Rheumatology part of its production site in
Épernon, France.
This scenario would therefore result in the closing of Expanscience Rheumatology business.
The Company would maintain its activity in dermo-cosmetics but all functions and operations
related to Rheumatology would be closed and corresponding buildings destroyed. The destruction
of buildings and equipment would indeed be required to write-off the corresponding assets in the
Company’s books.
Figure 10 – Buildings to be dismantled in the Épernon facility in case of shut-down of the
Rheumatology business
Further details about impacts are discussed in section 8.
Destruction of all
Rheumatology-related
facilities
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“Short Authorisation” scenario: Relocation of Avocado and Soybean oil
unsaponifiables production outside E.U.
The other variant scenario considered in this impact assessment is the potential relocation of the
extraction step (using EDC) in a country outside E.U. to be able to continue to use EDC. EDC is
indeed involved in a crucial but limited step of the overall Active Pharmaceutical Ingredient (API)
production process. We have therefore only considered the relocation of the step involving EDC.
All other manufacturing steps would remain in Épernon, France (see Figure 11 hereafter).
Figure 11 - Step of the Active Pharmaceutical Ingredient (API) manufacturing process of
Piascledine® 300 to be relocated outside E.U.
Based on its previous experience with the construction of its new HEQ building (see details in
section 2.2), Expanscience has estimated that at least four years would be required to implement a
new production site abroad. Assuming a starting date of the construction work in 2017, the new
production site would not be fully operational before 2021.
In addition, Expanscience would have to file all the necessary variations requests to local healthcare
authorities to validate that the Active Pharmaceutical Ingredient (API) production outside E.U. does
not change the characteristics of the final drug. These filings would have to be done independently
in 42 different countries having independent health authorities. However, this variation process
would be less complex and time-consuming than for the substitution of EDC with MIBK (see
section 5.7 of the AoA). We have estimated that about 2 years on average (15-39 months) would be
required to obtain the approvals of our regulatory dossier amendment before the 42 local Health
Authorities (see Figure 12 for more details).
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6 INFORMATION ON THE LENGTH OF THE REVIEW PERIOD
Expanscience is applying for an authorisation to use EDC for 12 years as from the sunset date
(November 22nd, 2017).
This period is justified by the time needed for the necessary R&D, industrial and regulatory work to
substitute EDC with MIBK as an extraction solvent. At this stage of investigation, the technical and
regulatory suitability of MIBK is not fully proven. The first results are encouraging but lab trials
revealed critical points that still need to be fixed:
- Low selectivity of MIBK regarding avocado oil unsaponifiables (impact on quality and
yield)
- MIBK and ethanol recyclability
- Stability of MIBK in alkaline conditions
Time is therefore required to fully validate its compatibility with all acceptance criteria and then
implement it at industrial scale while modifying our pharmaceutical dossier.
The detailed timeframe of the substitution plan is discussed in sections 5.3 and 5.7 of the Analysis
of Alternatives (AoA). Please refer to this document or to Appendix E for more details.
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7 ANALYSIS OF IMPACTS – “APPLIED FOR USE” SCENARIO – HEALTH
AND ENVIRONMENTAL IMPACTS
In this section we will monetize the potential human health and environmental damages
caused by the use of EDC.
Hazard profile of EDC
EDC is classified as Carc. 1B (H350) and was proposed for inclusion in REACH Annex XIV
for this reason. Similarly, IARC categorised EDC as “possibly carcinogenic to humans
(Group 2B)” (IARC, 1999).
In general, the epidemiological evidence for carcinogenic activity in humans is considered
inadequate. Therefore, the classification and risk quantifications (see below) rely on
experimental data from rodent carcinogenicity studies. Three reliable long-term
carcinogenicity studies are available:
The chronic gavage study of NCI (1978) in mice and rats
Dermal study of Van Duuren et al. (1979) in ICR/Ha Swiss mice
The chronic inhalation study of Nagano et al. (2006) in mice and rats.
According to the RAC paper on the exposure-risk relationship of EDC, mammary gland
tumours as well as subcutaneous fibromas were consistently found in both species via the
different exposure routes applied. Furthermore, Nagano et al. (2006) detected liver and lung
tumours in mice and further tumours at several other locations. In the NCI (1978) study,
lymphoma, liver tumours, uterine cancer, and benign lung tumours were found in mice, and
hemangiosarcoma1 and forestomach tumours in rats. Van Duuren et al. (1979) detected
benign lung papillomas in ICR/Ha Swiss mice dermally exposed to EDC.
The toxicological evidence suggests that the carcinogenicity of EDC is dependent on
metabolic activation into genotoxic intermediates, by catalysis via cytochrome P450 and
glutathione S-transferase enzymes or conjugation with glutathione. The mutation frequency
of EDC in human cell lines in vitro has been correlated with glutathione S-transferase
activity, which is believed to be the most significant pathway. Formation of DNA adducts
with S-(2-chloroethyl) glutathione in B6C3F1 mice has corroborated this hypothesis.
IARC (1999) concluded that EDC induces gene mutation, micronuclei and unscheduled DNA
synthesis in mammalian cells in vitro. However, a clear picture for the mutagenic potential of
EDC is lacking, and a GLP-compliant in vivo OECD TG 489 Comet assay conducted by Dow
Chemical Company does not support a genotoxic/mutagenic mode of action for EDC. In lieu
of a historical database of demonstrated proficiency, the RAC excluded the contradictory
results of the Comet assay from the evaluation of EDC.
1 Hemangiosarcoma is a rapidly growing, highly invasive sarcoma arising from the lining of blood vessels.
SOCIO-ECONOMIC ANALYSIS
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Exposed populations
We will consider the impact of the use of EDC over two main groups of people:
1) Expanscience’s workers
2) The general population living nearby the facility (population of Épernon)
7.2.1 Worker population
EDC is only used at Expanscience, Épernon site. Therefore, only workers operating in this
plant might be exposed to the substances. However, only a few production steps may expose
workers to EDC. In total, the worker population potentially exposed to EDC is estimated at
49 employees. Please refer to Table 9 for more information on the number of workers
exposed for each exposure scenario.
7.2.2 General population living nearby the Épernon production site
In addition to Expanscience’s workforce, we might also consider the impact on general
population. Indeed, low levels of fugitive and vented EDC emissions from the production site
may expose inhabitants of Épernon and the general population around the site to a limited
potential additional cancer risk.
The village of Épernon where the production facility is located has a population of 5,451
inhabitants. As shown in Figure 13, the plant is located in a rural area with only a small
population surrounding the facility. As a conservative approach we have taken the total
population of Épernon even if the size of the village extends well beyond the 100m radius for
which inhalation daily dosage has been estimated (see section 7.4).
Figure 13: Aerial view of Épernon (source: Google Maps)
Exposure of patients is considered as non-relevant, as there are no consumer-related uses of
EDC and no discernible concentration of EDC is contained within the final Piascledine® 300
product (the concentration of EDC, if present at all, is under 5ppm as per the Marketing
Authorisation). This application for authorisation focuses on the industrial use of EDC as an
extraction solvent. Patients will therefore not be addressed in the calculation of the number of
potential additional cancer cases.
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Human health impacts on Expanscience’s workforce
7.3.1 Exposure scenario
Expanscience uses EDC in a closed batch process continuously, all year round (with only 3
weeks/year annual maintenance break). The process using EDC are taking place in closed
systems without direct handling of EDC by operators except for EDC sampling for quality
control, raw material unloading from road tankers (connecting/disconnecting flexible hoses)
and maintenance. In this SEA, we have considered 4 contributing scenarios (CS). Please refer
to the CSR document for more information on exposure scenarios:
CS1 – Production process, including storage, transfers, sampling, recycling,
waste transfers (PROC 2): this CS covers the complete operators shift working in
the plant production unit Building B2. The tasks done by operators are facility
supervision, control from the room panel control (most of the activity = 70%), visual
control routine on unit (1 or 2 per shift), EDC sampling for QC (1 per shift), final
product packaging (EDC < 5ppm in product). CS1 covers all tasks where EDC is used
or transferred in closed system equipment:
transfers from storage tank to first liquid/liquid extraction reactor
washing solvent reactor
falling film evaporator
transfers to skid unit
transfers from skid unit to recovered EDC storage tanks
There is one task during the entire shift that involves direct handling of EDC, which is
EDC sampling for quality control (QC)
CS2 – Receipt of EDC from road tank (PROC 8b): this CS covers the specific
operation of road tank EDC unloading. This operation is done once a year. Only
unloading team operators are involved in this operation
CS3 – Non-routine maintenance and cleaning (PROC 8b): this CS covers the
specific operation of small repairs in case of equipment malfunction (e.g. a pump)
CS4 – General maintenance and cleaning (PROC 8b): this CS covers the specific
operation of maintenance and cleaning of general equipment (e.g. reactors, vessels).
Regarding EDC, only the exposure to the substance itself is relevant. Other reaction products
originating from the presence of EDC are not taken into account. The most relevant route of
exposure for EDC is through inhalation. Oral uptake for workers is not relevant in general
and thus was not assessed. Dermal exposure via direct contact of liquid EDC has been taken
into account for workers. However, this risk is very limited due to applied risk management
measures like chemically resistant gloves or masks. Please refer to Appendix G for more
details on the measures taken by Expanscience to limit workers’ exposure to EDC.
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7.3.3 Calculation of excess cancer cases
Under the “Applied for Use” Scenario, the use of EDC in the production of Piascledine® 300
will continue after the 2017 sunset date for a total of 12 years (5 years in the “Short
Authorisation” variant scenario). Using the information presented in Table 7 (and the analysis
provided in the CSR document), the excess risk of cancer can be calculated using the ERF
(exposure response function, cf. CSR table 3 and 4) published by RAC. Some key
assumptions are made here:
Inhalation is the key route of exposure. As can be seen from the contributing scenarios
developed in the CSR and summarized in section 7.3.1, workers wear appropriate
Personal Protection Equipment (PPE) with a 95% efficiency value in those scenarios
where exposure of the skin is expected. Taking account the 50% dermal absorption
value for EDC as well as the low frequency of some of the contributing exposure
scenarios, it can safely be assumed that this exposure route is of negligible concern
when compared to inhalation exposure; nevertheless, as a conservative approach,
dermal exposure is considered in this comprehensive evaluation of worker health
impacts
The RAC utilized the Nagano et al. (2006) study to calculate the exposure-response
relationship for cancer incidence, which focused primarily on mammary gland cancer
as the most sensitive endpoint
However, it was accepted that systemic EDC exposure in humans may manifest itself
as alternative cancer endpoints. Indeed the RAC paper on the exposure-response
function, notes, “Therefore, the choice of mammary tumours for this risk assessment
is based rather on genotoxic potential and the best dose-response rather than its
relevance to a specific human cancer”. It is worth noting that beyond breast cancer,
hemangiosarcomas and forestomach tumours in rats, in addition to lung, reproductive
and liver tumours in the mice model have been reported in the relevant scientific
literature. Therefore, to err on the side of caution, a general approach utilizing collated
cancer mortality statistics has been used in this analysis (breast cancer is associated
with a relatively low mortality, compared to other forms of cancer). It is also the case
that breast cancer morbidity and mortality data tend to focus on females, while the
exposed worker population in Épernon is predominantly male
The excess risk estimates for workers exposed to EDC can be calculated as follow: RAC
ERR = RAC ERF*Exposure. It means, for inhalation and dermal route, respectively
RAC ERR (inhalation) = 6.0×10-7 per µg/m3 x concentration [µg/m3]
RAC ERR (dermal) = 2.1×10-6 per µg/kg bw/day x concentration
[µg/kg bw/day]
These RAC ERFs are computed on a basis of 40 years. In order to calculate the number of
additional cancer cases per authorisation period (5 and 12 years) it was necessary to weigh
the function by the relevant period. The following table presents the above dose-response
functions (the ERF) in terms of assumed assessment period of 1 year.
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7.3.5 Economic valuation of additional fatal and non-fatal cancer cases among
Expanscience’s workforce
The aim of this section is to assess the economic benefits of avoiding the possible excess
cancer cases that would be associated with the use of EDC over additional periods of 5 and
12 years in the manufacturing of Piascledine® 300.
In addition to the human toll of cancer, its financial cost is also to be taken into account. The
economic valuation of the total health impacts takes into account two important welfare
components, namely the costs associated with Mortality and Morbidity:
• Mortality is the term used for the number of people who died within a population
It comprises the lost earnings after premature death.
• Morbidity refers to the state of being diseased or unhealthy within a population.
It comprises both the costs associated with individuals taking sickness leave for a
defined period of time (temporary absence), and the costs of individuals being
declared incapacitated or disabled because of cancer (permanent absence).
7.3.5.1 Reference values used to monetize chemicals-related Mortality and Morbidity
a) Reference values used to monetize chemicals-related Mortality
For fatal cancers, there are alternative ways of estimating a monetary value. In this SEA, we
have applied a value of a statistical life (VOSL). VOSL is the aggregation of individuals'
willingness to pay for fatal risk reduction and therefore the economic value to society to
reduce the statistical incidence of premature death in the population by one. This approach
offers the advantage to be directly applicable to value the number of additional cancer cases.
Other methods would have required much more detailed data/assumption on when the worker
might get cancer and how many years they would live with the cancer before premature
death.
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8 ANALYSIS OF IMPACTS – “NON-USE” SCENARIO: CLOSING OF THE
WHOLE RHEUMATOLOGY BUSINESS
Economic impacts of the closing of the Rheumatology business
This section estimates the economic impacts over the 2018-2029 period of the closing of the
Rheumatology business of Expanscience.
We have considered two dimensions of costs:
1) One-off costs correspond to non-recurring charges that will only occur once and are
therefore considered as extraordinary items. For example, one-off costs include the
following:
Severance costs associated with workforce reduction
Asset write-offs following the destruction of buildings or equipment
Local workforce training costs in the scenario of relocation
2) Operating costs are recurring costs related to business operations. These include production
costs but also all costs not directly associated with production such as wages, employee
benefits and pension contributions, transportation and travel, amortization and depreciation,
rent, maintenance, …
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Social impacts
8.2.1 Impact on Expanscience’s workforce
As mentioned in section 4.3, Expanscience has identified 332 employees who would be affected by
the closing of its Rheumatology activity (please refer to Table 3 in section 4.3 for more details on
impacted employees).
Based on an average severance package of 80 k€ / employee, the total financial burden for lay-offs
would represent ca. 27 M€ for Expanscience. This provision would represent a real threat for the
future of the Company.
8.2.2 Impact on suppliers
A closing scenario would impact all the players of the Rheumatology supply chain (suppliers and
subcontractors). Expanscience has identified 97 employees who would be indirectly affected by the
closing of its Rheumatology activity (please refer to Table 4 in section 4.4 for more details on
impacted suppliers).
As described in section 4.4, the three avocado oil suppliers of Expanscience have designed specific
patented production processes to comply with the Company’s expectations in terms of oil quality.
The avocado oils obtained through their specific processes cannot be sold to other clients even in
the pharmaceutical industry since these processes are patented by Expanscience.
A closing scenario of Expanscience Rheumatology business would therefore result in the
bankruptcy of its avocado oil suppliers (70 job losses outside E.U.).
8.2.3 Impact on distributors
The impact on distributors in France (large pharmaceutical wholesalers and pharmacies) and in the
rest of the world (large pharmaceutical wholesalers) would be low as their activities with
Expanscience represent less than 5% of their total turnover.
Still, we did not take into account in our analysis the potential legal risks linked to the inability for
Expanscience to fulfil its contractual obligations to supply the product to its distributors.
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Wider economic impacts
In this section, we will evaluate the wider economic impacts (i.e. impacts that have macro-
economic implications) to assess the full implications of the closing of Expanscience Rheumatology
business.
We have identified that the closing of these activities would result in serious tax revenues losses
for the E.U. and the French government.
Expanscience is paying 2 main types of taxes in the E.U. and most of its profits come from its
Rheumatology business. The discontinuation of Expanscience Rheumatology activities would
mechanically result in a loss of tax revenues for the E.U.
Based on the taxes paid by the Company in 2014, we have assumed these proportions would remain
constant over the 2014-2029 period for the operating income tax and the added value tax, but that
the pharmaceutical tax would not be paid anymore:
- Tax on operating income: % of Rheumatology EBIT
- Tax on added value: % of Rheumatology sales (weighed average of French
and international values)
We have estimated these annual losses in Figure 16 hereafter over the 2018-2029 period.
Figure 16 - Taxes paid by Expanscience for its Rheumatology business
The Net Present Value (NPV) of the losses in tax revenues for the period 2018 – 2029 amounts to:
- NPV of tax losses for E.U. = ca. M€
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In addition to the taxes directly paid by Expanscience, we should also consider all the taxes paid by
its suppliers and distributors. This amount is difficult to estimate and was therefore not quantified in
this SEA. The current estimates are therefore under-estimating the overall tax impact of the “Non-
Use” Scenario.
Conclusions of the “Non-Use” Scenario (i.e. the closing of the Rheumatology business)
Given the limited number of workers exposed to EDC in the “Apply for Use” Scenario, especially
when taken in combination with the low risk of contracting a cancer, the estimated economic
burden of the possible excess cancer cases (~12.6 k€) would be low. Indeed, the disruption of the
operations of Rheumatology will result in a significant reduction of the Company’s workforce (332
job losses) and of its suppliers’ (97 job losses; see Figure 17 hereafter).
Figure 17 – Comparison of impacts of a continued use of EDC during 12 years vs. the closing of
Expanscience Rheumatology business
Expanscience top management has also expressed serious concerns regarding the ability of
Expanscience to support such a heavy financial burden. Indeed, the closing of the Rheumatology
business could lead to a worst case scenario that would be the bankruptcy of the whole Company.
The social impacts would be significant for both Expanscience employees and third parties (sub-
contractors, suppliers, and the town of Épernon). We have estimated that the bankruptcy of
Expanscience would result in about 1,000 job losses (considering 893 employees for Expanscience
and at least 97 employees for its suppliers).
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9 ANALYSIS OF IMPACTS – “SHORT AUTHORISATION” VARIANT:
RELOCATION OF AVOCADO AND SOYBEAN UNSAPONIFIABLES
PRODUCTION OUTSIDE E.U.
Economic impacts
In this variant, we consider the relocation of the extraction step (using EDC) of the API
manufacturing process to a country outside the E.U. We have assumed a 5-year authorisation for
Expanscience to use EDC to make that variant scenario realistic. This period would allow
Expanscience to achieve the construction of the new site abroad and obtain approvals of our
regulatory amendment while maintaining production in Épernon, France. Sales would therefore not
be impacted by the relocation.
As for Scenario 1, we have considered two dimensions of costs:
- One-off costs
- Operating costs
9.1.1 One-off costs
The Company will have to support the following one-off costs:
- Destruction of the building where the extraction step is performed in Épernon, France:
This cost is estimated at 3 M€ and will be supported in 2023 when the extraction step would
be closed in Épernon, France
- Assets write-offs: Write-off of all assets related to the extraction step of the Épernon facility
(building, equipment and other assets) – These costs would also be supported in 2023 when
the extraction step would be closed in Épernon, France
– Net book value (as of end of 2022) = ca. 8 M€
- Severance costs: 21 employees concerned with an average severance package of 80k€ /
employees – These costs would be supported in 2023 when the extraction step would be
closed in Épernon, France – Total costs = 1.7 M€
- Training costs: development and training of local workforce by Expanscience staff in
Épernon – 100 k€ / year in 2021 and 2022 representing a total cost of 200 k€ for the
Company
These extraordinary items represent one-off charge of 12.9 M€ for the Company.
In addition to these one-off costs, Expanscience will also have to support a 26 M€ expense
corresponding the different investments in the new facility (i.e. purchase of land, buildings,
equipment). This investment would be amortized over 15 years and is therefore included in the
Depreciation and Amortization (D&A) forecasted in the next section (see Table 26).
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Conclusions of the “Short Authorisation” variant (i.e. the relocation of the Avocado and
Soybean unsaponifiables production outside E.U.)
In the “Short Authorisation” variant, the cumulated EBIT loss would be M€ over the 2018-2029
period.
The social impact for Expanscience employees and its suppliers would be limited to employees
working on the extraction step. Indeed, the relocation of the extraction step abroad would result in a
reduction of the Company’s workforce (21 job losses) and 9 job losses for its suppliers (see Figure
19 hereafter). In parallel, 40 new functions would be created to run the new facility abroad.
Figure 19 – Impacts of the “Short Authorisation” Variant
This variant scenario is not the preferred option of Expanscience top management. The
Company is committed to maintaining all its operations in Épernon, France when possible. In
this context, Expanscience has designed a global substitution plan to produce Piascledine®
300 through a new process with an alternative solvent (MIBK) and sell it in all the countries
where the product is currently sold by 2029 (please refer to section 5.7 of the AoA document
for more details).
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10 COMBINED ASSESSMENT OF IMPACTS
Comparison of impacts
The previous sections have highlighted the main costs and benefits of the «Non-Use» scenario (i.e.
the closing of the Rheumatology business) and the “Short Authorisation” variant (i.e. the relocation
of the API production in a country outside E.U). These impacts vs. a continued use of EDC are
summarized in Figure 20, and the impacts of the “short authorisation” variant are summarized in
Figure 21 hereafter.
Figure 20 – Comparison of impacts of the continued use of EDC vs. the “Non-Use” scenario
Figure 21 – Impacts of the “Short Authorisation” variant
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Uncertainty analysis
10.2.1 Health Impacts
This section describes the key sources of uncertainty that can be identified in the above analysis,
with a particular focus on those that might have an impact on the final outcome of the SEA.
RAC’s paper on the exposure-risk relationship, breast cancer was the most sensitive endpoint in the
rat study used to calculate the human exposure-risk estimate. However, as exposure is systemic, it is
possible that breast cancer would not be the endpoint observed in exposed individuals. Furthermore,
use of breast cancer as an endpoint will tend to lower the mortality risks as there is a high level of
survivorship. Whether or not breast cancer is a potential risk to men, is linked to the aforementioned
point. The applicant’s workforce primarily comprises male workers; to address this complexity, this
SEA adopts a more general approach, utilising overall cancer risk with overall mortality and
morbidity statistics. Clearly, this approach is more conservative than considering breast cancer
alone, as the latter has a high survival rate (ca. 75%), while other cancers will have a much lower
survival rate. The human health impact costs could thus be overly conservative.
10.2.2 Economic Impacts
Economic uncertainties are linked to the hypotheses taken in the “Non-Use” scenario and the “Short
Authorisation” variant.
In the “Non-Use” scenario, uncertainties come from the estimation of Rheumatology sales and more
specifically of Piascledine® 300 sales. We adopted a conservative approach by taking sales
projection below the current actual trend. As Piascledine® 300 currently accounts for nearly %
of Rheumatology sales and that Rheumatology generates % of Expanscience EBIT, we
estimated that the end of production of Piascledine® 300 would lead to the closing of the whole
Rheumatology unit and potentially to the bankruptcy of Expanscience. The capacity of
Expanscience to bear the impact of the closing of its Rheumatology business is indeed hard to
evaluate.
In the “Short Authorisation” variant, we may have underestimated the relocation costs. Indeed, the
Company has not yet selected the country where it would implement its new production site.
Consequently, the investment required to build a new production site abroad were based on
Expanscience past experience with the construction of its new building in Épernon, France.
Assumptions on operating costs were based on countries benchmarks. In this context, operating
costs constitute the main source of uncertainties as these costs could significantly vary depending
on the new country of production. In this variant we have also made the assumption that the
structure of taxes would remain unchanged in the new country, which will probably not be true.
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11 CONCLUSIONS
This Socio-Economic Analysis aims to quantify the relevant health, economic and social impacts of
the continued use of EDC after the sunset date of November 22nd, 2017 vs. the “Non-Use” and the
“Short Authorisation” variant scenarios (i.e. closing the whole Rheumatology business in France –
(“non-use”) and relocating of the extraction step involving EDC outside E.U. (“Short
Authorisation”)).
From the human health perspective, the excess cancer risk associated with the continued use of
EDC after the sunset date has been monetized on the basis of three main cost components: direct
costs of treating patients, productivity losses and hidden costs (health insurance premiums,
nonmedical expenses, informal care …). Given the limited number of workers exposed to EDC and
the safety measures put in place by Expanscience, the additional risks of contracting cancer
(“excess cancer risk in workers”) and the estimated economic burden of the potential additional
cancer cases associated with the continued use of EDC (of ~12.6 k€ over 12 years) clearly appear
very low when compared to the economic impact of M€ over the 2018-2029 that Expanscience
would experience in the «Non-Use» scenario. The “Short Authorisation” variant would have a total
economic impact (including profit losses and costs of excess cancer cases in France) of M€ over
the period 2018-2029. Please refer to the sections 9 and 10 of the CSR document for more data on
potential excess cancer cases.
The “Non-Use” scenario would have a significant social impact since it would imply suppressing
282 jobs at Expanscience and 27 at suppliers’ within E.U., and 120 jobs outside E.U. (50 at
Expanscience and 70 at suppliers’). In the “Short Authorisation” variant, 21 workers at
Expanscience would be laid off within the E.U and 9 at suppliers’. In the worst case scenario, the
closing of the Rheumatology business could lead to the bankruptcy of Expanscience, since
Rheumatology generates % of the Company’s EBIT. The social and economic consequences of
such a worst case scenario would be even more dramatic but have not been monetized in the current
document.
In conclusion, this application for authorisation has demonstrated that from the point of view of
Expanscience, a 12-year authorisation should be granted to enable the full deployment of the
alternative production process. It has been demonstrated that the socio-economic benefits of
continued used outweigh the potential costs of the risk of a continued use of EDC.
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APPENDIXES
APPENDIX A – Detailed process description
A.1. Process description: used as a process and extracting solvent in fine chemical processes
(i.e. pharmaceutical)
Expanscience is using EDC as a major extraction solvent in a liquid/liquid extraction unit
operation. The active substance (Active Pharmaceutical Ingredient) of our drug corresponds to a
blend of highly purified avocado and soybean oil unsaponifiable matters. These families of
molecules obtained through extraction are purified separately from the two independent sources of
oil: avocado oil on one hand and soybean oil on the other hand. To reach adequate purity of
unsaponifiables, a specific proprietary and highly selective extraction and purification process has
been designed. This process involves a key liquid/liquid extraction step using EDC.
The overall Active Pharmaceutical Ingredient (API) manufacturing process is described in figure
hereafter.
Different steps of the overall API manufacturing process
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The extraction process can be divided in 5 main steps (as described in the figure hereafter):
Saponification of the oil in a mixed vessel containing the oil, water, ethanol and a strong
base and dilution
First liquid/liquid extraction of the unsaponifiable compounds from the saponification
reaction mixture, using EDC in a counter-current agitated column
Washing of the solvent phase (EDC + unsaponifiable compounds) with water to remove
ethanol and soap traces (second liquid/liquid extraction)
Evaporation of the solvent in a falling film evaporator, and recycling
Deodorisation of the extract through water vapour stripping to remove remaining solvent
traces and other minor contaminants to obtain a pure unsaponifiable fraction
1
2
3
4
5
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The EDC evaporated during step 4 can be directly re-used in the extraction process. In addition, the
EDC collected after step 2, step 3 and 5 is purified in a specific process on our industrial site
(reactivation process) in order to be recycled and re-used in the extraction step (batch process
performed continuously 7/7). The ethanol engaged in the process is also collected (from the
aqueous phase), purified and recycled.
Schematic overview of the extraction process
NB: Avocado and soybean oil are processed separately; the blend of avocado and soybean oil
unsaponifiables is made when filling the capsules. The dotted pink line shows the limit within which
EDC is used.
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The detailed process is described in our Marketing Authorisation file granted by health authorities
(AMM in France). Initial raw materials (soybean and avocado oils) are from plant origin. Their
composition may vary depending on climatic conditions and geographic location of the culture.
The avocado and soybean oil unsaponifiables extracted as such separately, are transferred in an
independent part of the facility and integrated in capsules. No EDC is used in this second part of the
plant (see more pictures of the plant in Appendix B).
Historically, EDC has been used for avocado and soybean oil unsaponifiables extraction because of
its selectivity towards the targeted molecules, enabling to get active substance (Active
Pharmaceutical Ingredient) matching quality requirements in a robust and reproducible way (to
obtain the same quality and yield whatever the origin of the oils).
The targeted molecules (the oil unsaponifiables) are a blend of various molecules exhibiting a large
spectrum of polarity, ranging from non-polar such as hydrocarbons and furanic compounds, to
highly polar, like tocopherols or aliphatic alcohols. EDC enables to extract the whole spectrum of
molecules in one step with a very good selectivity. The clinical activity of our drug substance is not
linked to a given specific molecule but to the whole extract: its composition is fundamental for its
pharmaceutical activity.
A.2. Transport
EDC is shipped to the production facility as a bulk using 24 m3 tanker trucks. The containers and
tankers used for bulk EDC are compliant with the European Agreement of Road Transport of
Dangerous Goods (ADR standards). The tankers are certified by an approved third party inspection
body and comply with the French National Standards for transportation. Road Transport Operations
are carried out safely in compliance with all the transportation requirements. Under the approved
standards, the tank farm and tank container undergo periodic inspections.
Ground floor Upper floors
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A.3. Storage
EDC is stored in a specific zone of the manufacturing plant in above ground storage tanks of 30 m3
capacity. These tanks are under controlled atmosphere with nitrogen. The storage area is equipped
with secondary containment. As this area is classified “Ex-zone”, the facility is totally fenced-up
and surrounded by humps. All transfer lines are aerial while all roads and operating areas are paved
with either concrete or asphalt. The storage tanks are used through a thermal oxidizer unit to
prevent from any air emission. The tanker transfer area is also equipped with a basin to retain any
possible leaks from the discharge pipe. The retention capacities are designed to retain the total
capacity of a tanker truck.
The storage area is also fully equipped for enhanced security:
- Specific fire protection
- Leak detection and warning devices
- Emergency scrubbing systems for storage of toxic gases
- EDC tank is filed with nitrogen gas atmosphere “inerted” to minimize explosion risks
All liquid transfer operations follow detailed written procedures to minimize the risks of accidental
spillage. Storage tanks are venting to a thermal oxidizer system (incinerator) to prevent from air
pollution.
Wastewaters generated during the process (steps 1,2 and 3) are first collected, treated in a specific
unit (Proscon) to remove any traces of solvents and then directed to the on-site biological treatment
facility. After this biological treatment, wastewaters are discharged into a common wastewater
treatment plant. Before reaching the discharge point, wastewaters are continuously sampled,
monitored for pH, Chemical Oxygen Demand (COD), flow rate and temperature and subjected to
daily analysis.
Pictures of solvent storage tanks
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Pre-treatment facility for sulphate-rich wastewater
from the molecular distillation and plant extraction
unit
Wastes generated from EDC use are disposed and
handled by authorized waste disposal companies. All
wastes are incinerated at an agreed waste treatment
facility. A file of hazardous waste shipment and
disposal records is being held to certify that wastes
are properly handled. A summary of these records is
sent every year to the competent authorities
(DREAL) as required.
A.4. Recycling
EDC is entirely recycled on site by evaporation and distillation within a dedicated solvent recovery
plant. Expanscience has achieved a recovery yield of 99% during 2014. This high performance
recycling process allowed us to recover and reuse 1,650 tons of EDC versus a waste of only 13 tons
of lost EDC over 2014.
This performance is explained by two main technical aspects:
1) The very low solubility of EDC in water
2) The EDC / alcohol / water azeotrope chemical feature making it easy to separate EDC from
alcohol and water (ethanol is fully recycled at the end of the process)
Chemical plant and its solvent regeneration unit
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APPENDIX B – Other pictures of the existing facility
Aerial view of the site in Épernon, France
Transport of EDC in a confined and controlled environment – all equipment is under controlled
atmosphere (nitrogen)
Unit dedicated to the treatment of Volatile Organic Compound (VOC) emissions
Carbon filter unit Thermal oxidiser
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APPENDIX H
H.1 Methyl iso-butyl ketone (MIBK, CAS 108-10-1)
Classification of MIBK is shown in the figure below.
Source: http://echa.europa.eu/web/guest/home
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The chronic progressive nephropathy (CPN) is common in older rats, with a high background
incidence in controls. It was increased in incidence (at all exposure concentrations, with a clear
dose-response from the mid to the high dose) and severity (increased only at the highest exposure
concentration) by MIBK. Although an increase in incidence (but not severity) was observed already
at the lowest concentration tested in this chronic inhalation study, this concentration is considered
the NOAEC of this study for non-neoplastic effects (450 ppm, 1868 mg/m3).
A subchronic inhalation study by Phillips et al. (1987) exposed rats and mice to 50, 250 and 1000
ppm (6 h/d, 5 d/w, 90 days). Hyaline droplets in the kidney of male rats and increased liver weights
in mice were observed at ≥ 250 ppm (1038 mg/m3), and at the highest concentration there were
increased liver weights in both species. The renal effects in male rats are considered to be specific
to the male rat (see above). A further subchronic rat inhalation study by David et al. (1999) reported
transient reduced activity and increased relative liver and kidney weights in combination with
increased terminal body weights at ≥ 750 ppm, 3113 mg/m3).
Exposures of rats and mice to up to 1000 ppm (4150 mg/m3) for 6 h/day, 5 days/week for 14 weeks
did not affect testicular weights or the histology of male or female reproductive organs. A 2-
generation study was performed in rats with exposure concentrations of up to 2000 ppm (8300
mg/m3). A NOAEL of 1000 ppm (4150 mg/m3) was determined, based on parental toxicity in form
of reduced body weight gain and food consumption and increases in liver and kidney weights and
neonatal toxicity (anesthetic CNS effects observed during exposure on post-natal days 22 and 28).
No effects were observed on reproduction (Nemec et al., 2004). Developmental toxicity studies on
rats and mice with exposure concentrations of 300, 1000 and 3000 ppm on gestation days 6-15
caused maternal toxicity and fetotoxicity (reduced pup viability and weights, delayed ossification)
at the highest concentration (3000 ppm, 12450 mg/m3) in both species. No effects were observed at
1000 ppm, 4150 mg/m3 (Tyl et al., 1987).
Most of the available studies on genetic toxicity showed negative results, e.g. Ames-Tests,
mutagenicity tests in yeast, a chromosome aberration test in rat liver cells in vitro, an unscheduled
DNA synthesis assay in primary rat hepatocytes in vitro, a cell transformation assay with
BALB/3T3 cells, and a mouse bone marrow micronucleus test. Mouse lymphoma tests were
negative with metabolic activation; however, without metabolic activation equivocal results have
been obtained (significant effect without dose-response relationship). In a transformation assay with
mouse embryo cells, significantly increased frequency of morphological transformations were
observed at the highest exposure level in the absence of metabolic activation (Greim, 1996; OECD,
2009; WHO, 1990).
MIBK induced kidney tumours (renal tubule adenoma and carcinoma) in male rats and liver
tumours in male and female mice (Stout et al., 2008, identical to NTP TR 538, 2007), leading to
NTP’s conclusion that there was “some evidence” of carcinogenic activity of methyl isobutyl
ketone in male rats and in male and female B6C3F1 mice. The authors concluded that there was
“equivocal evidence” of carcinogenic activity of methyl isobutyl ketone in female F344/N rats,
based on the occurrence of two renal mesenchymal tumours in the 1800 ppm group. The increases
in tumour incidences in male rats may have resulted from the increased severity of CPN, either
through alpha-2-µ-globulin-dependent or -independent mechanisms. An alpha-2-µ-globulin
accumulation in the male, but not female rat kidney was reported by Borghoff et al. (2009),
indicating that the renal effects in male rats are species- and sex-specific. However, IARC (2012)
discussed that a dose-response relationship was not evaluable in this study by Borghoff et al.
(2009), and the incidence and severity of the observed chronic progressive nephropathy suggest the
involvement of alternative mechanisms. IARC (2012) concluded that the “alpha-2-µ-globulin-
induced nephropathy may contribute to the renal tumour response, but the critical component(s) of
the nephropathy most closely associated with the development of tumours has not been identified”
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and therefore the evidence for an alpha-2-µ-globulin-mediated mechanism is weak. According to
IARC (2012), the relevance of the tumour response in the rat kidney to humans cannot be excluded.
The liver tumours in mice were not associated with cytotoxicity (regenerative cell proliferation) and
there is only weak evidence for a nuclear receptor-mediated mechanism (IARC, 2012). The
histologic appearance of the hepatocellular proliferative lesions was consistent with those that
develop spontaneously in control mice. IARC stated that therefore the relevance of the tumour
response in the livers of mice to humans could not be excluded. Based on this evaluation, IARC
concluded in deviation from the authors of the NTP study, that there is “sufficient evidence” for
carcinogenicity in experimental animals, resulting in a 2B classification (“possibly carcinogenic to
humans”).
A new study by Borghoff et al. (Borghoff et al., 2014; Borghoff et al., 2015) investigated the mode
of action for renal tumours caused by MIBK. In this study, exposure conditions as used in the NTP
cancer study with rats were applied with inhalation exposure duration of 4 weeks and various
endpoints related to renal toxicity and an alpha-2-µ-globulin accumulation-mediated mechanism
were investigated. The authors found that CPN was increased after four weeks of exposure in male,
but not in female rats. Alpha 2-µ-globulin concentrations, hyaline droplet accumulation and
proliferation of cells of the renal cortex were increased with dose in male rats, but were not
observed in female animals. The authors consider this sufficient evidence to conclude that renal
tumours are caused by MIBK by an alpha-2-µ-globulin-dependent mechanism, unique to male rats.
The reference concentration (RfC) derived by the U.S.EPA for inhalation exposure is 3 mg/m3
(EPA, 2003b; 2015). This is based on the fetotoxic effects documented in the study by Tyl et al.
(1987) with a NOAEC of 1000 ppm (4150 mg/m3), adjusted for continuous exposure and applying
an extrapolation factor of 300 (3 for interspecies, 10 for intraspecies variances, and 10 for
deficiencies of the data base). As the assessment factor for data base deficiencies is not included in
the ECHA guidance R.8 methodology (ECHA, 2012a), an analogue guidance value would be 30
mg/m3 for the general population. For workers, this value can be converted to 168 mg/m3, under
consideration of 5 working days per week, a reduced intraspecies variance factor of 5 in workers
(instead of 10 for general population) and an additional factor of 2 (10 m3 respiratory volume/shift
vs. 20 m3/day) according to ECHA (2012a).
The German Ad-hoc Working Group for Indoor Air Guide Values derived a health hazard guide
value (RW II) of 1 mg/m3 and a precautionary value (RW II) of 0.1 mg/m3 (Ad-hoc-AG, 2013).
Both are based on the NTP study with renal effects in female rats with a benchmark-dose (BMDL10)
of 320 mg/m3, corrected for continuous exposure: 57 mg/m3. The RW II was derived applying a
total extrapolation factor of 50 (2.5 and 10 for inter- and intraspecies variances, respectively, and an
additional factor of 2 to account for a higher respiratory rate of children). The RW I is per definition
0.1 x RW II. The conversion of the RW II for workers would result in a DNEL of rounded 13
mg/m3 (320 mg/m3 on 6 h/d in rats correspond to 161 mg/m3 for workers with 10 m3 respiratory
volume per shift, extrapolation factors of 2.5 for remaining interspecies and 5 for intraspecies
differences).
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H.2.2 Discussion of suitability of reference values for comparative assessment
Inhalation exposure
Most occupational exposure limits are 20 ppm = 83 mg/m3 (ACGIH, 2014; AGS, 2012; DFG, 2014;
IFA, 2014; SEG, 1991), mainly based on the irritative and neurotoxic properties of the substance.
The basis for derivation of the DNELs for inhalation exposure in the registration dossier is not
apparent from the given information. The value of 83 mg/m3 for workers points to an adoption of
the OEL.
Other reference values were derived for the general public and are not directly applicable for this
assessment.
A NOAEC of 450 ppm (1868 mg/m3) is derived from the NTP study in this document, based on
renal effects in female rats and the slightly reduced body weights. According to ECHA guidance
R.8 (ECHA, 2012a), this experimental NOAEC (6 h/d) is converted into a human equivalent
workplace concentration
by correcting for 6 h exposure in the experimental study compared to an 8h shift
by correcting for physical activity (6.7 m3/ 10 m3)
of 939 mg/m3.
Using assessment factors of 2.5 for further interspecies differences and 5 for intraspecies variance
in workers, a DNEL of 75 mg/m3 results.
The same NOAEC of 450 ppm (1868 mg/m3) was derived from the same study in the registration
dossier based on the non-neoplastic lesions observed in the kidneys at higher dose levels.
Dermal exposure
The dermal DNEL presented in ECHA-CHEM cannot be used for comparative assessment without
a full understanding of its origin.
As with EDC, this exposure route is considered to be negligible compared to inhalation exposure,
due to the substance’s high volatility. Therefore, the dermal exposure route is not considered for
this comparative assessment.
Recently, IARC (2012) classified MIBK for carcinogenicity in Group 2B (“possibly carcinogenic to
humans”). In absence of evidence for genotoxic activity of the substance the carcinogenicity of
MIBK for humans is unclear and cannot be finally evaluated, but recent research on the mechanism
for the renal tumours observed in male rats indicates that these tumours are caused by a sex- and
species-specific mechanism.
H.2.3 Conclusion: Tentative DNELs for comparative assessment
A tentative DNEL for inhalation exposure of methyl isobutyl ketone is 75 mg/m3 for workers. This
value is similar to the DNEL reported in the registration dossier and most OEL.
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