Committee for Risk Assessment (RAC) Committee for Socio-economic Analysis (SEAC)

Transcription

1 Committee for Risk Assessment (RAC) Committee for Socio-economic Analysis (SEAC) Opinion on an Application for Authorisation for Use of diglyme as a process solvent in one step of the manufacturing of an Active Pharmaceutical Ingredient used in an anti-protozoal drug. ECHA/RAC/SEAC: Opinion N AFA-O /D Consolidated version Date: 15/06/2017 Annankatu 18, P.O. Box 400, FI Helsinki, Finland Tel Fax echa.europa.eu

2 Consolidated version of the Opinion of the Committee for Risk Assessment and Opinion of the Committee for Socio-economic Analysis on an Application for Authorisation Having regard to Regulation (EC) No 1907/2006 of the European Parliament and of the Council 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (the REACH Regulation), and in particular Chapter 2 of Title VII thereof, the Committee for Risk Assessment (RAC) and the Committee for Socio-economic Analysis (SEAC) have adopted their opinions in accordance with Article 64(4)(a) and (b) respectively of the REACH Regulation with regard to an application for authorisation for: Chemical name: diglyme EC No.: CAS No.: for the following use: Use of diglyme as a process solvent in one step of the manufacturing of an Active Pharmaceutical Ingredient used in an anti-protozoal drug. Intrinsic property referred to in Annex XIV: Article 57 (c) of the REACH Regulation applicant: ISOCHEM Reference number: Rapporteur, appointed by RAC: Lina DUNAUSKIENE Co-rapporteur, appointed by RAC: - Rapporteur, appointed by SEAC: Co-rapporteur, appointed by SEAC: Andreas LÜDEKE Jānis LOČS This document compiles the opinions adopted by RAC and SEAC. 1

3 PROCESS FOR ADOPTION OF THE OPINIONS On 22/02/2016 ISOCHEM submitted an application for authorisation including information as stipulated in Articles 62(4) and 62(5) of the REACH Regulation. On 02/05/2016 ECHA received the required fee in accordance with Fee Regulation (EC) No 340/2008. The broad information on uses of the application was made publicly available at on 27/04/2016. Interested parties were invited to submit comments and contributions by 22/06/2016. No comments were received from interested parties during the public consultation in accordance with Article 64(2). The draft opinions of RAC and SEAC take into account the responses of the applicant to the requests that the SEAC made according to Article 64(3) on additional information on possible alternative substances or technologies. Due to the need to ensure the efficient use of resources, and in order to synchronise the public consultation with the plenary meetings of the Committees the time limit set in Article 64(1) for the sending of the draft opinions to the applicant has been extended until end of March The draft opinions of RAC and SEAC were sent to the applicant on 23/03/2017. The applicant informed on 21/04/2017 that it wished to comment the draft opinions of RAC and SEAC according to Article 64(5) and sent his written argumentation to the Agency on 21/04/2017. ADOPTION OF THE OPINION OF RAC The draft opinion of RAC The draft opinion of RAC, which assesses the risk to human health arising from the use of the substance including the appropriateness and effectiveness of the risk management measures as described in the application and, if relevant, an assessment of the risks arising from possible alternatives was reached in accordance with Article 64(4)(a) of the REACH Regulation on 09/12/2016. The draft opinion of RAC was agreed by consensus. The opinion of RAC Based on the aforementioned draft opinion and taking into account written argumentation received from the applicant, the opinion of RAC was adopted by consensus on 09/06/

4 ADOPTION OF THE OPINION OF SEAC The draft opinion of SEAC The draft opinion of SEAC, which assesses the socio-economic factors and the availability, suitability and technical and economic feasibility of alternatives associated with the use of the substance as described in the application was reached in accordance with Article 64(4)(b) of the REACH Regulation on 15/03/2017. The draft opinion of SEAC was agreed by consensus. The opinion of SEAC Based on the aforementioned draft opinion and taking into account written argumentation received from the applicant, the opinion of SEAC was adopted by consensus on 15/06/

5 THE OPINION OF RAC The application included the necessary information specified in Article 62 of the REACH Regulation that is relevant to the Committee s remit. RAC has formulated its opinion on: the risks arising from the use applied for, the appropriateness and effectiveness of the risk management measures described, the assessment of the risks related to the alternatives as documented in the application, as well as other available information. RAC confirmed that it was possible to determine a DNEL for the reprotoxic properties of the substance in accordance with Annex I of the REACH Regulation. RAC confirmed that there appears not to be any suitable alternatives that further reduce the risk. RAC confirmed that the risk assessment in the application does demonstrate adequate control of risks from the use applied for, provided that the risk management measures and operational conditions as described in the application and in further information submitted by the applicant are adhered to. THE OPINION OF SEAC The application included the necessary information specified in Article 62 of the REACH Regulation that is relevant to the Committee s remit. SEAC has formulated its opinion on: the socio-economic factors and the availability, suitability and technical and economic feasibility of alternatives associated with the use of the substance as documented in the application, as well as other available information. SEAC took note of RAC s confirmation that it is possible to determine a DNEL for the reprotoxic properties of the substance in accordance with Annex I of the REACH Regulation. SEAC took note of RAC`s confirmation that the risk to human health from the use of the substance is demonstrated to be adequately controlled. SEAC confirmed that there appear not to be suitable alternatives in terms of their technical and economic feasibility for the applicant. SEAC considered that the applicant's assessment of: (a) the potential socioeconomic benefits of the use, (b) the potential adverse effects to human health of the use and (c) the comparison of the two is based on acceptable methodology for socio-economic analysis. Therefore, SEAC did not raise any reservations that would change the validity of the applicant s conclusion that overall benefits of the use outweigh the risk to human health, whilst taking account of any uncertainties in the assessment. 4

6 SUGGESTED CONDITIONS AND MONITORING ARRANGEMENTS Description for additional conditions and monitoring arrangements for the authorisation: 1. In order to further limit the potential for exposure, the applicant shall implement within 2 years appropriate risk management measures as follows: a) for the transfer of diglyme, i) a system must be implemented which minimises the potential for dermal and inhalation exposure; the system must prevent, to the extent possible, the possibility of contact with contaminated outer surfaces of dip-pipes used to drain containers and / or drums by, preferably, implementation of a technique not requiring removal of once-immersed pipes; ii) pump(s) designed to minimise emissions to air and exposure via dermal contact must also be utilised; iii) sources of further diglyme emissions (including during the addition of reducing agent) and potential dermal exposure need to be identified and addressed by sufficiently closed systems / tight connections; b) closed sampling must be installed; c) the areas where diglyme is not handled directly must be kept free from contamination by implementing adequate housekeeping / cleaning procedures and practices. 2. The applicant shall continue programmes of occupational exposure measurements (for inhalation exposure, and, if possible, for dermal exposure) for all the activities with potential for worker exposure, at least once per year. The results shall be used to review the applied RMMs and OCs. These monitoring programmes shall be based on relevant standard methodologies or protocols and be representative of the range of tasks undertaken in the WCSs and number of workers performing them. 3. The applicant must implement a regular measurement programme (for example wipe testing of contaminated surfaces) ensuring that general housekeeping and work practices are observed. These measurements must be based on relevant standard methodologies or protocols and the use of a method with detection limit and limit of quantification allowing meaningful exposure evaluation. The results of the monitoring must be included in any subsequent authorisation review report submitted. The results of the above monitoring, review of RMMs, as well as a report describing the improvements of the RMMs implemented must be available to the national enforcement authorities on request and be included in any subsequent authorisation review report submitted. REVIEW Taking into account the information provided in the application for authorisation prepared by the applicant, the duration of the review period for the use is recommended to be 7 years. 5

7 JUSTIFICATIONS The justifications for the opinion are as follows: 1. The substance was included in Annex XIV due to the following property/properties: Carcinogenic (Article 57(a)) Mutagenic (Article 57(b)) Toxic to reproduction (Article 57(c)) Persistent, bioaccumulative and toxic (Article 57(d)) Very persistent and very bioaccumulative (Article 57(e)) Other properties in accordance with Article 57(f) [please specify]: 2. Is the substance a threshold substance? YES NO Justification: Bis(2-methoxyethyl)ether (diglyme) has a harmonised classification as Repr. 1B, H360FD according to Classification, Labelling and Packaging Regulation, (EC) 1272/2008. Based on studies which show its reprotoxic potential, the Risk Assessment Committee (RAC) has concluded that bis(2-methoxyethyl) ether should be considered as a threshold substance with respect to risk characterisation (reference to the studies examined are included in the RAC document `RAC/33/2015/08 rev 1 Final`). 3. Hazard assessment. Are appropriate reference values used? Justification: RAC has established a DNEL for the reprotoxic effect following exposure to diglyme (RAC/33/2015/08 rev 1 Final). Based on experimental animal data (cited in the RAC document), a potential risk for reproductive and development effect of the substance, if present above a DNEL, was noted. In the absence of epidemiological studies on occupational exposure to diglyme that would be useful in identifying any quantitative risk for humans, the calculated DNEL is based on the most relevant, robust study in experimental animals (for inhalation route: inhalation rat, development and testicular effects, for the oral route: oral rabbit and mouse, developmental effect; dermal route: extrapolation from oral route). 6

8 The following DNELs were calculated by RAC and used by the applicant: Derived DNELs General population Workers Inhalation (mg/m 3 ) Oral (mg/kg ) Dermal (mg/kg ) Are all appropriate and relevant endpoints addressed in the application? The risk for reproductive effect was estimated by the applicant using the developed by RAC DNELs for all relevant routes of exposure and exposed populations. 4. Exposure assessment. To what extent is the exposure from the use described? Description: ISOCHEM is a toll-manufacturer for a pharmaceutical company, manufacturing an active ingredient for an anti-protozoal drug at one single site in Pithiviers, France. The manufacturing process consists of 3 reaction steps: (a) synthesis of a precursor P0- diglyme is not used in this step; (b) synthesis of intermediate P1 diglyme is used as a process solvent; (c) conversion of P1 to P2 - diglyme is not used in this step. According to the applicant the number of workers possibly involved in tasks with potential for direct exposure to diglyme is in total 40, comprising 5 teams of 8 workers. RAC notes that the information about some of the conditions of use and about the overall exposure assessment was amended considerably by the applicant in the answers to the RAC questions. The applicant in the answers to RAC questions and in particular in its comments on the RAC s draft opinion also provided information on further Risk Management Measures implemented since the application was submitted. This information has been taken into account in the opinion and is discussed in several parts of the text below. The main changes resulting from the applicant s comments on the draft opinion are specifically identified in text boxes at the ends of the various sections and sub-sections. The following contributing scenarios are presented in the application: Table 1: Contributing Scenarios presented in the Use Contributing ERC / PROC Name of the scenario scenario ECS 1 ERC4 Industrial use of processing aids in processes and products, not becoming part of articles WCS 1 PROC 8b Transfer of diglyme - charging of the reactor, transfer between reactors, transfer of recycled diglyme WCS 2 PROC 3 Use in closed process (synthesis or formulation) WCS 3 PROC 8a Cleaning and maintenance operations WCS 4 PROC 9 Sampling and transport to the laboratory WCS 5 PROC 15 Use as laboratory reagent 7

9 4-6 batches are manufactured per year, each involving use of 5.6 tonnes of diglyme (manufacture of a single batch takes 5 weeks, or 2 weeks if only the step involving diglyme is considered). The annual fresh solvent purchase is limited to ca. 2.5 tonnes, as diglyme is recycled on site by distillation under vacuum, in order to be re-used in the process. Workers exposure Taking into account also the additional information submitted on request of RAC, the tasks performed as described by the applicant are summarised in Table 2. Table 2: Summary of worker contributing scenarios Contributing scenario WCS 1 Transfer of diglyme - charging of the reactor, transfers between reactors, transfer of recycled diglyme Brief description I Charging of the substance from several 200 kg drums into the reactor is performed by an operator under Local Exhaust Ventilation (LEV) comprising a flexible ventilation hose, connected to a scrubber, but without any capturing hood (mechanical general ventilation is also implemented in the room). The operators perform the following tasks per drum: i. Opens the drum ii. Introduces a pipe into the drum the pipe is connected to the reactor through a pump, the type of which was not specified (also the LEV is adjusted next to the opening of the drum) iii. Closes the empty drum after the end of charging. II Transfers (apparently several per batch) of diglyme / reaction mixtures from reactor to reactor (including via a balloon), using the same flexible pipes and pump as for the loading after connection is established, lines are closed. III Diglyme transfer to drums after recycling by distillation ( unloading ). Operators tasks performing filling of drums are similar to the reactor loading: i. Opens the drum ii. Introduces a pipe into the drum the pipe is connected to the reactor through a pump (also the LEV is adjusted next to the opening of the drum) iii. Closes the full drum after the end of transfer. IV Addition of reaction reagent. Potential exposure sources: - Inhalation and dermal: During all the above processes. 8

10 In its comments to the draft opinion the applicant informed that changes have been gradually implemented on site after submission of the application, such as i) storage of recycled diglyme in 1000L containers instead of 200L-drums, with subsequent loading of recycled diglyme from these containers; ii) different type of connections during loading/unloading; iii) organisational measures towards spreading the use of fresh diglyme (which is loaded from drums, the potential for exposure being higher) so that no more than one drum is used per batch (the remaining quantity comes from the containers with the recycled diglyme): for one batch, in one day 2 containers are loaded into a reactor, another day 1 container and 1 drum are loaded into another reactor. The tasks under WCS1 may be described as following (tasks I, II, and III will occur on separate days): I. Loading of diglyme from 1000l container to reactors: - The worker connects the pipe valve with the container valve to start the loading of diglyme. - When the container is empty, the pipe is purged with nitrogen, valves are closed and the pipe is removed to be installed in another container, if needed, or it is stopped with a stopper. Duration of the connection/disconnection tasks: 2 min per container. II. Loading of fresh diglyme from 200l drum to reactors - Capturing system (LEV) is fixed to the drum, dip pipe is introduced into the drum and loading of the drum is started by opening the valve for the auto-suction pump. The dip pipe and the capturing system are removed and the drum is closed after the loading is finished. Duration of the connection, loading, and disconnection tasks: 12 min, with exposure potential lasting less than 2 minutes. III. Unloading of recycled diglyme to the containers - The worker fixes the capturing system (LEV) on the container, then the pipe is connected to the valve. - Once the container is full, the pipe is purged with nitrogen and the valve is closed. - The pipe and the capturing system are removed to be installed on the next container, if needed, or stopped with a stopper which is a requirement in the pharmaceutical industry to avoid cross contamination. Duration of the connection/disconnection task: 2 min The worker removes the gloves and disposes of them immediately after each potential contact with diglyme in the tasks described above. Potential exposure sources: - Inhalation: emissions during the loading and unloading procedures. - Dermal: mainly contamination of outer surfaces of pipe during the loading and unloading procedures. 9

11 WCS 2 Use in closed process (synthesis or formulation, including closed transfers) Manufacturing process and distillation closed reactors, connected to other equipment by hard piping. All reactors are equipped with LEV (type not specified). Potential exposure sources: - Inhalation and dermal: no specific sources identified by the applicant under normal process conditions. Potential exposure due to fugitive emissions, during monitoring of the process (process conditions, valves, pipes, material flows, agitators etc.), and during conducting tasks for other stages of the process occurring in the same room. According to the applicant, any emissions in WCS2 are more likely to originate from the distillation step. Similarly to the rest of the synthesis, distillation is performed in a closed system, but in contrast with the actual synthesis step it is conducted at atmospheric pressure and high temperature. In its comments to the draft opinion the applicant clarified that WCS 2 also includes these transfers in closed system: - transfer of extraction water and distillation residue to waste tanks through hard pipe and a pump; - and then also transfer via hard pipe to an incinerator on-site. WCS 3 Cleaning and maintenance operations (PROC 8a) Commencing any maintenance, the reactors and all other used equipment (pump, flexible and rigid pipe) are decontaminated using a solvent (water or methanol). An operator introduces a spray ball via a dedicated hole on the top of the empty reactor. The operator also introduces the appropriate solvent in the closed reactor. The spray ball pumps the solvent from the bottom of the reactor in a closed loop. During the decontamination of reactor and equipment the reactor is closed. At the end the cleaning solvent is transferred to a waste tank via pipes for subsequent incineration and the spray ball is dismantled from the reactor. Maintenance of reactors and equipment is performed after the completed decontamination process. Potential exposure sources: - Inhalation and dermal: during introducing the spray ball, the cleaning of reactor, and maintenance of equipment after system flashing/decontamination. WCS 4 Sampling and transport to the laboratory (PROC 9) Sampling of diglyme drums and reactor - before sampling a flexible ventilation hose (connected to a scrubber) is positioned close to the sampling valve; then the operator opens the valve and pours the sample into the sampling jar. 1 Potential exposure sources: - Inhalation and dermal: during the sampling. WCS 5 Use as laboratory reagent (PROC 15) Sample preparation for Quality Control (QC) and analyses performed in fume cupboard (duration less than 5 min). Waste is collected in closed containers and is transferred to the waste tank before incineration. Potential exposure sources: - Inhalation and dermal: during the sample preparation, injection in the analysis device. 1 In the original CSR tehnical RMMs were reported however answering on RAC questions the information was corrected. 10

12 RMMs applied The RMMs implemented along with the effectiveness that has been taken into consideration in the exposure assessment (in particular modelling) are summarised in Table 3. Technical and organisational RMMs, as well as PPE are implemented in the plant and the general description is included in the CSR (Chemical Safety Report), which was updated upon request from RAC for providing further information. - Protection for the inhalation route The ventilation comprises general mechanical ventilation in the rooms where reactors are located, LEVs for WCSs 1-4 (for transfer and sampling tasks) consisting of a flexible hose without capturing hood, positioned manually next to the drums / sampling valve connected to water scrubbers, and fume cupboards in the laboratory (WCS5). General ventilation extractors are checked every 4 years. The filters of the incoming air to the product isolation room are replaced every 3 months (those filters only prevent from outside dust contamination). Air respirator protection (Respiratory Protection Equipment - RPE) comprising a full-face respirator with screw-on filter cartridge ABEK2HGP3 in aluminium housing is required for workers performing tasks in WCS1, WCS3 and WCS4. The masks are checked by an external company once a year. The cartridges for the masks are changed every 6 months, or if necessary more often. - Dermal protection Solvent-resistant nitrile rubber gloves (EN 374) are used for all WCSs where dermal contact is expected. The thickness or break-through time of the gloves for diglyme were not provided by the applicant as such information was not available from the producer. Also additional PPE are required - chemical protective suits (WCS1-4), safety shoes (WCS2, WCS3), and safety googles (WCS5). The proper use, storage, and availability of PPE (including RPE and gloves) is regularly checked by the applicant. Furthermore, a behaviour safety programme for proper use of PPE is implemented by the applicant in the plant. In its comments to the draft opinion the applicant clarified that due to the changes implemented on site the workers are now required to remove and dispose of gloves after each handling of equipment which could possibly be contaminated by diglyme. The workers are required to wash hands immediately after removing gloves. The applicant also informed that after confirmation that the technical improvements (use of 1000L containers, semi-automatic sampler see discussion below - etc.) of the conditions of use of diglyme will lead to reduction of the exposure, the applicant will re-evaluate this newly implemented RMM and might consider more reasonable and environmentally friendly use of PPE (gloves). 11

13 - Further organisational RMMs A training system has been established for promoting the safe use of diglyme, including: a) specific training program for working with CMR substances, b) specific Standard Operating Procedure (SOP), relevant to applied for use. Finally, the applicant explained that during loading of diglyme there is only one operator in the working area and warning signs are placed in order to inform and to protect other workers. 12

14 Table 3: Operational Conditions and Risk Management Measures Contributing scenario Duration and frequency of exposure Concentration of substance Ventilation used + effectiveness described by the applicant RPE used+ effectiveness Skin protection + effectiveness 1 Other RMMs WCS 1 Transfer of diglyme - charging of the reactor, transfers between reactors, transfer of recycled diglyme 3-4 h < 4h* 100%* General ventilation, flow rate 7,300 m 3 /h, 5-10 ACH (air changes per hour)* LEV (Inhal) comprising flexible ventilation hose without capturing hood, manually positioned next to the drum s opening, flow rate 4000 m 3 /h, effectiveness 90%* 2 LEV assumed by applicant also to apply to dermal exposure, effectiveness 95%* Full face cartridge respirator(apf 10), effectiveness 90%* Nitrile rubber gloves SOL-KNIT , effectiveness 95%* Technical RMMs: LEV flexible ventilation hose connected to scrubber; Organisational RMMs: training for workers Other PPE: protective (Nomex ) safety shoes suit WCS 2 Use in closed process, (synthesis or formulation, including closed transfers) <8 h* In its comments to the draft opinion the applicant explained that the flexible ventilation hose was replaced by a tightly connected capturing system. 100%* General ventilation, 5-10 ACH* LEV (Inhal), type not specified, effectiveness 90%* No Nitrile rubber gloves SOL-KNIT , effectiveness 95%* - LEV in the capturing system connected to scrubber; - For loading/unloading from/to containers: nitrogen purging to dry the piping system after use. Technical RMMs: closed system hard piping in closed system connects reactors with additional equipment (not specified) and the waste tank 1 The break-through time and thickness for gloves is not be provided by the producer. 2 See picture in Annex I. 13

15 Organisational RMMs: training for worker WCS 3 Cleaning and maintenance operations WCS 4 Sampling and transport to the laboratory <1 h <1 h* < 2min. per sample, samples per year, on days of operation 5 min at max** <15 min* >25%* General ventilation, 5-10 ACH*, LEV (Inhal), type not specified, effectiveness 90%* LEV assumed by applicant also to apply to dermal exposure, effectiveness 90% 100%* General ventilation, 5-10 ACH*, LEV (Inhal) comprising flexible ventilation hose without capturing hood, manually positioned next to the sampling point, effectiveness 90%* LEV assumed by applicant also to apply to dermal exposure, effectiveness 90% Full face cartridge respirator(apf 10), effectiveness 90%* Full face cartridge respirator(apf 10), effectiveness 90%* Nitrile rubber gloves, effectiveness 95%* Nitrile rubber gloves, effectiveness 95%* Other PPE: protective (Nomex ) safety shoes Technical RMMs: closed system Organisational RMMs: training for workers Other PPE: protective (Nomex ) safety shoes suit suit Technical RMMs: LEV flexible ventilation hose connected to scrubber Organisational RMMs: training for workers Other PPE: protective (Nomex ) suit WCS 5 Use as laboratory reagent < 5 min. sample preparation < 15 min* 100%* General ventilation, 5-10 ACH*, Fume hood, efficiency 90%* No Protective gloves Touch N Tuff EN374 gloves, effectiveness 95%** 80%*** Organisational RMMs: training for workers Other PPE: safety goggles * Values used in ECETOC TRA 3.0. model ** Value used in ECETOC TRA 3.0 and RISKOFDERM model. ***Value indicated in Succinct summary of representative risk management measures (RMMs) and operation conditions (OCs). 14

16 Exposure estimation methodology: Inhalation exposure: For the inhalation exposure assessment, the applicant has used three methods: ECETOC TRA 3.0 modelling (in the original CSR), as well as ART 1.5 modelling and some limited static air monitoring (data provided during the opinion development in response to RAC s requests for clarification). The measurements were conducted in 2016 with a portable VOC (Volatile Organic Compounds) monitor (type MiniRAE 3000) with a photoionisation detector. The measurements have been done (a) in March 2016 for WCS 1 (loading of reactor with diglyme from 200 L drums- 6 to 9 min per drum, measured for 4 drums, removal of pump 4 minutes, loading of the reducing agent into the reactor containing diglyme - 43 minutes) and WCS 4 (sampling 9 minutes); (b) in October 2016 for WCS 2 (only for one task chloroform distillation process). The applicant submitted information on measurements, including measurement dates, the description of tasks performed by workers during the measurements, sampling duration, and the limit of detection (LoD) for the MiniRAE 3000 device 0.1 ppm (0.56 mg/m 3 ). The applicant stated that the measurements were performed in order to check the efficacy of the local aspiration (flexible hoses) not for worker exposure purposes. Therefore, the measurement device was placed close to the openings (drum, reactor) on the side further from the LEV opening, which may represent worst case exposure (see figure in Annex I of this opinion). For WCS1, the applicant claimed to have used the 90 th percentile of exposure values (8- hours average TWA) for the RCR calculation for workers. However, as discussed below, in practice the applicant first converted the measured average exposure for each sub-task (e.g. loading from first drum, loading from second drum, loading of the reducing agent, etc.) to 8h-TWA based on the sub-task s duration, and then calculated the 90 th percentile of the set of 8h-TWA values therefore not taking into account that these tasks take place on the same day, and the exposures should be considered jointly. For WCS 2, measurements were presented only as supporting information, as only one task was included in the monitoring campaign (distillation). Dermal exposure: Estimation of dermal exposure by the applicant was based on the ECETOC TRA 3.0 modelling. RISKOFDERM data were also provided as supportive information upon RAC s request. Discussion of the exposure information Inhalation The applicant indicates the exposure to diglyme is possible during the following tasks: (a) transfer of the substance from drums to reactor and from reactor to drums (WCS1), (b) cleaning and maintenance tasks (WCS3), (c) sampling of mixture and transfer of that to laboratory (WCS4) and (d) analysis of samples (WCS5). The synthesis process of the active pharmaceutical ingredient as such, occurring in individual reactors, is performed in closed system (WCS2) and is assumed by the applicant 15

17 not to lead to inhalation exposure under normal operational conditions (transfers between reactors are covered by WCS1). The applicant has also noted that during the reaction process the reactor is under vacuum. RAC considers that exposure is possible due to presence of fugitive emissions. In any case, as described above WCS2 is also included in the applicant s quantitative exposure assessment. MiniRAE 3000 device used to perform measurements is designed to directly measure volatile organic compounds (VOC) via a photoionization sensor. I.e. it does not measure specifically diglyme 1. The concentration of VOCs was measured during defined time periods (see below); concentrations are measured by the device every 15 seconds: (a) WCS 1: - loading of reactor with diglyme from 200 L drums- 6 to 9 min per drum 2, in total 25 min in sequent 4 measurements (i.e. emptying of 4 drums) in sequence in one day; - removal of pump 4 minutes 1 measurement, - loading of reactor with the reduction agent (diglyme is already in the reactor) - 42 minutes 1 measurement, (b) WCS 2: - only for one task - distillation of chloroform 71 and 73 minutes, 2 measurements in sequence in one day, (c) WCS 4: - sampling 9 minutes, 1 measurement. As mentioned above, measured data are used for exposure estimation for WCS 1 and WCS 4. The measuring device is automatic and for each minute gives as an output values of average, maximum, minimum, and real (i.e. last 15 sec measured) concentrations. Also 8h-TWA is calculated by the device automatically for each measurement. The applicant used for the assessment average values for the duration of measurement. These values were converted to 8h-TWA and finally the values were also corrected, where relevant, to take into account the assumed effectiveness of RPE (90%). RAC considers a different, to some extent, approach in terms of (a) using the maximum value from among the 1min-averages reported during the sampling period (the applicant used the average of those), (b) for WCS1, correcting the 8h-TWA conversion methodology used by the applicant to account for the exposure resulting from subsequent transfers and (c) taking into account also the exposure during removal of the pump in the calculations. On the first point (a), a more conservative statistical value was selected despite the fact that the static measurement was taken closer to the source than the operator would be, to account for lack of representativeness (single day measurement, not covering all transfers performed) and for the fact that the subsequent conversion to 8h-TWA assumes zero exposure during the remaining duration of the task. RAC s approach may have led to a potential overestimation of the exposure during loading of the reducing agent to the diglyme-containing reactor, as during that task high exposure concentrations were measured soon after the beginning of loading (1-min averages up to 47 mg/m 3 for 2-3 min) whereas most of the 1-min average values during the 42-minutes task were close to the 1 The actual range and sensitivity per VOC may depend on the lamp used (the photoionization sensor comes with a standard 10.6 ev and optional 9.8 ev or 11.7 ev lamps) 2 After 6 to 9 min empty drums are closed and new drums are opened. 16

18 limit of detection). On the second point (b), RAC noted that for WCS1 the applicant converted to 8h-TWA each of the 5 task-specific exposures (loading and adding the redaction agent) and then calculated the 90 th percentile of those separate 8h-TWAs. In this way, the applicant did not take into account that those tasks occur at the same day, and therefore exposures / TWAs should be added instead. For WCS1, the device is located directly on drum, next to the opening, on the side further from the LEV in the other side of the LEV. Based on that, RAC considers that it is likely that only diglyme s concentration, not of other VOCs, was measured. Therefore, taking also into account the adjustments mentioned above, RAC agrees with applicant s approach to use the measured concentrations for further risk assessment, as reasonable worst case. However, RAC has questioned the number of transfers covered by the measurement campaign (4 drums of 200kg), as this appears not to be consistent with the amount needed per batch (5.6 t, which rather equals 28 drums of 200kg). The applicant explained that i) one batch of API synthesis requires two batches of the intermediate P1 therefore the daily loading volume is half of the batch-volume, i.e. 2.8t; and ii) for the intermediate batch the loading is again split into two days: in one day 6-7 drums (1.4 t) are loaded in reactor, in next day 6-7 drums (1.4 t) are mixed with reducing agent in the second reactor and the mixture is transferred to the first reactor. No measurements have been performed for the unloading (of used diglyme) back to the drums, but according to the applicant similar exposure can be assumed, as the process followed is very similar to that during loading. However, RAC understands that unloading (at least of the 2.8t of each intermediate batch) can be performed in one single day, therefore the relevant exposure estimation was adjusted by RAC. Still, there is some uncertainty in this respect. RAC also notes that unloading back to the drums may be associated with higher exposure than loading from drums, due to the naturally higher expected turbulence of the liquid in the drum. It needs to be noted that the measured value, re-calculated by RAC (0.60 mg/m 3 for loading and 0.35 mg/m 3 for unloading 3 ) is more than one order of magnitude higher that the value considered by the applicant (0.018 mg/m 3 ), and then the modelling result (0.025 mg/m 3 ) which assumes 90% LEV effectiveness and PROC 8b. Although for WCS1 the drum-emptying operation was at least repeated some times and separate measurements were taken, for WCS 4 only one measurement is available. RAC would be more confident if more measurements were available. However, as the measurement was done directly next to the sampling point, this value was used by RAC for risk assessment as indicative case, by applying again the relevant adjustment as mentioned above (modelled values also are available in Table 4). The value taken by RAC for risk characterisation is measured, re-calculated value mg/m 3 (used approach described above), which is higher that the value used by the applicant mg/m 3 (modelled values are mg/m 3 in initial CSR and mg/m 3 in additional submitted answers). For WCS2 measured data are not used by the applicant, taking into consideration the following points: (a) only one task (distillation) was covered by the measurement campaign, (b) synthesis process is performed in a closed system, while in the same room two other reactors are located and other VOCs are used. Consequently, even if the measuring device was calibrated for diglyme, it is not impossible that quantification may have been distorted 3 For the loading scenario, RAC has considered 7 loadings + addition of reduction agent + removal of the pump. For the unloading scenario, RAC has considered 14 unloadings + removal of the pump.. 17

19 by the distillation solvent itself or other VOC used in the room. 4 In the initial CSR, the applicant used ECETOC TRA for exposure estimation (including also for WCS 2). However, in the context of answering RAC s requests for clarifications, the applicant performed further modelling using the higher tier ART model, as he considered that ECETOC TRA estimated values were not realistic. The applicant indicated that ART takes better consideration of the range of RMMs implemented in the site including that synthesis process is performed in a closed system. RAC notes that as the applicant did not provide sufficient information on the LEV used for WCS2, its assumed effectiveness (twice 80%, i.e. overall 96%) is considered as not substantiated. RAC is of the opinion that measurements would have provided a more reliable means of assessing the exposure for WCS2. However, RAC accepts the approach of using ARTmodelled exposure concentrations for risk characterisation for WCS2. RAC also notes that significant amounts of chloroform may also have been measured by the device 5 ; as well as that most measurement points during distillation were close to the detection limit of the device (0.56 mg/m 3 ). The applicant has also noted that the specific step of WCS2 during which the measurement was made (the distillation) is, as the rest of the synthesis, in closed system but that the distillation is conducted at atmospheric pressure and high temperature. Therefore this specific step was defined as the highest exposure scenario within the context of WCS2. Furthermore, a different measurement device and methodology would be needed to properly determine the exposure of workers. It must be noted that although RAC accepts the approach of using ART estimation, it still sought from the applicant justification for some of the input parameters used in ART. For the localised controls with 80% assumed effectiveness (vapour recovery system), which were counted twice in the model (primary plus secondary), the applicant did not provide a justification (only primary control applied therefore potentially underestimated exposure by a factor of 5). RAC still notes that the applicant assumed a ventilation rate of 3 ACH (potentially overestimated exposure in this respect, as actual rate reported by the applicant is 5-10 ACH based on ventilation rate and room volume). For WCS 3 (cleaning and maintenance) and WCS 5 (use as a laboratory reagent) ECETOC TRA modelled exposure concentrations are used by the applicant. RAC accepts the use of ECETOC TRA for inhalation exposure assessment (WCS 3 and WCS 5). RAC notes that, given the specific design of the LEV used for WCS3, its assumed effectiveness (90%) is considered as not sufficiently substantiated. Nevertheless, it is taken forward for risk characterisation. Exposure estimates used by the applicant for risk characterisation are presented in Table 4. Exposure concentrations chosen by RAC for inhalation and dermal exposure as the more appropriate are provided in Table 5. In its comments on draft opinion the applicant stated that in February 2017 an external company was hired and conducted personal and static sampling during 8h at different phases of the P1 intermediate production. According to the applicant the results for all the samples were below the detection limit. However, at RAC s request for clarification it was admitted that the analysis method employed by the service provider had a high detection 4 Explanation from the applicant during the trialogue meeting. 5 The reaction mixture is extracted with chloroform and the separated organic phase contains mainly diglyme and chloroform. Chloroform is distilled first, before the remaining organic phase (diglyme) is transferred to another reactor in the same room. where it will be distilled under vacuum for recycling purposes. The measurements were only performed for the chloroform distillation phase. 18

20 limit (10 mg/m 3 ), which was linked to the duration of sampling (8h), therefore limiting the relevance to the assessment of the actual exposure. The applicant also informed RAC about their plan to organise a new comprehensive occupational exposure measurement campaign to evaluate diglyme exposures during the next production in October 2017 and to perform related risk assessment afterwards. RAC acknowledged the applicants efforts to re-evaluate inhalation exposures, however due to the high LOD of the method used (much higher than measurements previously reported) the new data is not useful for the assessment and therefore it was decided to use the previously provided data. At the same time, RAC acknowledges that technical improvements introduced after the submission of the application (reduction of number of diglyme transfers, tighter connections for loading and unloading and use of tighter LEV) and considers that previously provided measurements for WCS1 might overestimate current inhalation exposures. It must though also be noted that the previous measurement data had indicated that for WCS1 considerable part of the inhalation exposure is related to tasks other than transfers of diglyme as such, not expected to be affected by the introduced improvements, such as the addition of the reducing agent to the reactor (displacement of diglyme vapours) and the removal of the pump. Dermal: For dermal exposure, in the initial CSR the applicant used ECECTOC TRA v 3 modelled exposure estimates for all WCSs. Evaluating the used input parameters, RAC questioned applicant s approach to consider LEV for dermal exposure for WCS1, WCS3, WCS4 and WCS5, as well as the gloves effectiveness 6 assumed for WCS 5. The applicant submitted the following justifications for considering the effect of LEV in dermal exposure in ECETOC TRA: i. WCS 1: (a) as LEV is used, that fully justifies LEV consideration for dermal exposure, (b) TRA overestimates the exposure considering implemented RMMs gloves (conform EN374, assumed 95% effectiveness), chemical protective suit, air respirator), (c) calculations without consideration of LEV for dermal exposure (95% protection) would lead to 20 times higher exposure concentrations, which cannot be realistic based on implemented OCs and RMMs. ii. WCS 3: (a) reactor is closed, (b) operators are not in contact with cleaning solvent or solvent waste, (c) operators are wearing PPE, (c) calculations without consideration of LEV for dermal exposure (90% protection) would lead to 10 times higher exposure concentrations, which cannot be realistic based on implemented OCs and RMMs. iii. WCS 4: (c) calculations without consideration of LEV for dermal exposure (90% protection) would lead to comparably high dermal exposure values For WCS 5, the correction for the effect of LEV on dermal exposure was not applied in ECETOC TRA in the updated CSR submitted after the trialogue. RAC asked the applicant to also consider the possibility to use different models, of higher Tiers e.g., RISKOFDERM, for sensitivity analysis. 6 The effectivness in the Succinct summary of representative risk management measures (RMMs) and operational conditions (OCs) is 80%, in model used 95%. 19

21 The applicant submitted also RISKOFDERM estimates, but expressed the view that these are reliable only for WCS4, with the below justification: i. RISKOFDERM gives unrealistic exposure values for WCS 1 (0.091 mg/kg for each single drum unloading), which cannot be considered realistic given the RMMS and OCs implemented on site; ii. RISKOFDERM does not contain an appropriate module for estimation of dermal exposure during cleaning operations (WCS 3); For WCS 4 RISKOFDERM 2.0 modelled value is used by the applicant (90 th percentile value). RAC does not agree with the above justifications and considers that for the tasks where dermal exposure is expected to be due mainly to splashes or contact with contaminated surfaces, such as those covered by WCS 1 and 4, LEV is not expected to have any significant effect on dermal exposure. Use of LEV effectiveness as a proxy for other measures is not justifiable. The applicant claims that the specific models are known not be sufficiently reliable for generally well controlled industrial activities. Given especially the design of the transfer processes (considerable potential for contact with contaminated surfaces or splashes) RAC has no good grounds to assume significant overestimation of the models for WCS1, which describes manual process, with repeated potential for exposure due to handling of the tools contaminated with diglyme and heavy reliance on PPE. RAC also notes the absence of information provided about the thickness and break-through time for diglyme for the used glove material 7. RAC could accept effectiveness higher than this assumed for the use of gloves (e.g. from 95% to 98%, i.e. a reduction of exposure by a factor of 2 or so) if the applicant had implemented Standard Operating Procedures for immediate change of the gloves in case of noticed contamination / contact with contaminated surface, accompanied by respective training and supervision. In response to RAC questions the applicant stated that workers are trained how to rinse, remove and replace their gloves. Still, an additional reduction by a factor of 10 (90%) or 20 (95%) as proposed by the applicant is considered as not justified by RAC. Concerning WCS3, taking into account that the reactors are flushed via a spray ball prior to maintenance, RAC accepts that the dermal exposure estimated by the models may have been considerably overestimated. RAC notes that in ECETOC TRA for this WCS the applicant has used PROC 8a, whereas other PROC, for example PROC 8b or other PROC reflecting limited, intermittent exposure possibility, better reflecting the work conditions, would be more appropriate. Therefore, the exposure for WCS3 is likely to have been considerably overestimated. In its comments on the draft opinion the applicant submitted new RISKOFDERM dermal exposure estimates for WCS1 and WCS3. For WCS1, these have taken into account the newly implemented RMMs. Input parameters were provided and were sufficiently justified 8. 7 The applicant stated that the information was not available by the producer of the gloves. 8 There is some uncertainty about the appropriateness of the use rate parameter (1L/min selected by the applicant, which is the estimated amount of diglyme on the outer surface of the dip pipe after loading the reactor; the actual transfer rate from the drum is 20L/min; use of the latter value gives an exposure 16 times higher). On the other hand, the applicant has assumed in the modelling scenario a duration of 12min for tasks with potential exposure, whereas based on the new description of the task and assuming that the dip pipe is not contaminated prior to immersion in the drum and that gloves are removed after disconnection this time may be up to 10 times lower (accordingly the output of the model would then be up to 10 times lower). 20

22 In terms of dermal exposure for WCS1, the applicant considered that the most conservative way to estimate dermal exposure for this WCS is to consider potential exposures while loading diglyme from 1 container and 1 drum to reactor to solubilize reducing agent due to the handling of the contaminated dip pipe. The applicant claimed that there is no direct contact of the operator with the diglyme in WCS3, however in his estimations using RISKOFDERM decided to adopt a conservative approach that a contact with the trace of diglyme may be possible during the introduction and/or the removing of the spray ball. It should be noted that in his estimations the applicant assumed 95% effectiveness for dermal protection due to implemented new Standard Operating Procedures for immediate change of the gloves after each contact with surfaces that could be possibly contaminated with diglyme. Taking into account all the engineering improvements already introduced by the applicant and the significant change in the maintenance of the gloves used by the workers, RAC considered the newly provided exposure estimates of dermal exposure for WCS 1 and WCS 3 as acceptable and used those values in further risk characterisation. However, RAC notes that estimation of dermal exposure via modelling is associated with a moderate to high level of uncertainty (the actual dermal exposure may be considerably lower or higher than predicted by the model, with individual work practices being an important factor). Exposure estimates of the applicant, presented in the CSR and those provided following RAC s requests, are presented in Table 4 Exposure estimates chosen by RAC (taking into account adjustments of methodology used for calculations) for inhalation and dermal exposure are provided in Table 5. Considering the uncertainties described above, two sets of values are presented for dermal exposure (with and without an additional LEV effectiveness of 90% in addition to the 95% effectiveness assumed for the gloves). 21

23 Table 4: Exposure estimates -inhalation (8h-TWA) and dermal routes reported by the applicant (values used eventually by applicant for risk characterisation appear in bold) Contribut -ing scenario WCS 1 (PROC8b) WCS 2 (PROC3) 12 Route of exposure Exposure values 9 used for risk characteri sation in original CSR Inhalation mg/m 3 Dermal mg/kg Inhalation mg/m 3 Dermal mg/kg Method ECETOC TRA ECETOC TRA* ECETOC TRA ECETOC TRA Additional exposure values 10 reported in context of responses to RAC requests mg/m mg/m mg/kg per drum (X 7 drums loaded per day = mg/kg ) mg/kg mg/m mg/m 3 - Method ECETOC TRA 10 Meas ured RISKO FDER M 11 ECETO C TRA** Measu red 13 ART Additional exposure values reported by the applicant in its comments on the draft opinion mg/kg for the complete task Method RISKOFDERM 9 Values adjusted for used PPE. 10 Input parameters altered by the applicant: duration 8h 4h; LEV effectiveness: 95% 90% 11 For one loading only in practice more loadings are performed in a day, so as the applicant also stated that this value needs to be multiplied accordingly by the number of loading tasks. 12 In the original description synthesis was described by PROCs 1, 3, and 4 (exposure estimates mg/m 3, mg/m 3, and mg/m 3 respectively). In responding to a RAC request, the applicant removed PROCs 1 and 4 with the explanation that the actual synthesis process in which diglyme is used is a batch process in a closed system. 13 For WCS2 the applicant reported a measured value of mg/m 3. However, after applying similar corrections as applied for the measurements on WCS1 above, RAC recalculated the exposure corresponding to the reported raw data to a higher value: 0.75 mg/m 3 (if we assume zero exposure the rest ~ 5.5. h) or 1.2 mg/m 3 (assuming 8 hours exposure at that level). Nevertheless, as discussed above, those measurements were not used by RAC further for risk characterisation. 22

24 WCS 3 (PROC8a) WCS 4 (PROC9) WCS 5 (PROC15) Inhalation mg/m 3 Dermal mg/kg Inhalation mg/m 3 Dermal mg/kg Inhalation mg/m 3 Dermal mg/kg ECETOC TRA ECETO C TRA* ECETO C TRA ECETO C TRA* ECETO C TRA ECETO C TRA mg/m mg/kg mg/m mg/m mg/kg mg/kg - - ECETOC TRA 14 ECETOC TRA** ECETOC TRA 15 Measur ed RISKOF DERM ECETOC TRA** mg/kg RISKOFDE RM * LEV is used for dermal exposure (90% effectiveness in all WCSs except in WCS1-95%) ** LEV for dermal exposure is not used Table 5: Exposure estimates -inhalation and dermal routes used by RAC Contribu ting scenario WCS 1 (PROC8b) WCS 2 (PROC3) Route of exposure LEV effectiveness Dermal without LEV effectiveness Exposure values 16 used for RCR calculations Method Exposure values used by RAC for RCR calculations after taking into account applicant s comments on draft opinion Method Inhalation 0.60 mg/m 3 Measured* 0.60 mg/m 3 Measured* Dermal with ECETOC TRA mg/kg 0.69 mg/kg Inhalation mg/m 3 Dermal mg/kg ECETOC TRA mg/kg ART mg/m 3 ART ECETOC TRA mg/kg RISKOFDERM ECETOC TRA 14 Input parameters altered by the applicant: concentration 100% 25%; duration 4h 1h; RPE effectiveness: 0% 90% 15 Input parameters altered by the applicant: duration 1h 15min; RPE effectiveness: 0% 90% 16 Values adjusted for used PPE. 23

25 WCS 3 (PROC8a) Inhalation mg/m 3 Dermal with LEV mg/kg effectiveness ECETOC TRA mg/m 3 ECETOC TRA ECETOC TRA Dermal without LEV effectiveness 0.69 mg/kg ECETOC TRA mg/kg RISKOFDERM WCS 4 (PROC9) WCS 5 (PROC15) Inhalation 0.01 mg/m 3 Measured 0.01 mg/m 3 Measured Dermal mg/kg RISKOFDERM mg/kg RISKOFDERM Inhalation ECETOC TRA mg/m 3 ECETOC TRA mg/m 3 Dermal mg/kg ECETOC TRA mg/kg ECETOC TRA * As explained above, this value is different from the measured value calculated by the applicant, due to including in the calculations also a further sub-task occurring at the same WCS (removal of pump), using different statistical values from the sets of 1-min measurement points per task (maximums instead of averages), and applying a correction regarding the 8h-TWA conversion methodology. Combined exposure: In the initially submitted CSR combined exposure was not considered. Based on additional information submitted on RAC request, while normally all tasks are performed by different operators (one operator per task), there is possibility that tasks included in different WCSs may be performed by the same operator. The following working contributing scenarios could be performed by the same worker during one shift: WCS1+WCS2+WCS4 The applicant calculated the combined exposure for workers considering both exposure routes inhalation and dermal. Uncertainties related to the exposure assessment: The level of uncertainty in workers inhalation exposure is noted, caused by: i) a small monitoring dataset (no history of monitoring), covering only some of the tasks and for those tasks comprising only single-day measurement; ii) use of a static direct-reading equipment instead of a personal sampling device, and only for the limited duration of sub-tasks; iii) use of a VOC-measuring device instead of a method dedicated to detection of diglyme; iv) some very high detected concentrations during adding of reaction agents and removal of pump in WCS1, the explanation of potential origin of which has been requested from to the applicants; the applicant stated that high values are expected during normal turbulence when introducing or removing material into or from the system; v) unjustified consideration of localised control twice (WCS2-inhalation via ART) and lack of sufficient substantiation for assumed LEV effectiveness for WCS3 (inhalation via ECETOC TRA); vi) the process description for WCS1 (unloading not presented in details). Use of Tier 1 modelling tool for the exposure assessment adds to the uncertainties. 24

26 It should be noted that the applicant informed RAC that a measurement campaign is planned to be implemented for workers exposure assessment during entire shift; this information will however have no influence on the current evaluation by RAC, as the data is not available during the opinion-making. In terms of dermal exposure, the main sources of uncertainty are: i) the absence of information on the diglyme-specific break-through time for the used glove material; ii) no sufficient clarity on the exact procedures used on site in case of glove contamination and the details of the training on the use of gloves; and iii) to some extent possible overestimations of dermal exposure by the predictions of the existing models; in particular for WCS3, overestimation is likely considering that the PROCs available may not well reflect the tasks and exposure situations. It is emphasized that the above uncertainties are confounded by the implementation of a rather low level of RMMs for WCS1 on site. This is discussed in section 5 below. In addition, the applicant did not provide information on the type of LEV used in WCS 2 and 3. While RAC has tried to take into account the above uncertainties to some extent, by choosing what could be considered as expected exposure values in the reasonable worst case the factors mentioned still play a significant role. Overall, RAC considers the level of uncertainties related to the exposure estimation to be moderate to high. Uncertainties related to the level of inhalation exposure remain after the evaluation of the applicants comments on the draft opinion, as the new measurement campaign performed followed a not appropriate methodology (too high LOD) It needs to be mentioned, that following the implementation of the changes to the transfer system, with tight-fitting LEV, it is likely that the actual exposure is lower than the one described in the application and considered for risk characterisation. In its comments to draft opinion the applicant reassured RAC about his plans to perform occupational exposure measurement campaign to evaluate diglyme exposures during the next production in October 2017 and to perform related risk assessment afterwards. The uncertainty related to the exposure via inhalation would be reduced if a method with sufficiently low LoD was used, allowing the meaningful analysis of exposure. In terms of dermal exposure, RAC notes that for WCS1 the applicant has recently implemented RMMs which have essentially reduced the duration of the tasks with potential for dermal exposure. These include the reduction of the number drums to be loaded per day, new Standard Operating Procedures for immediate change of the gloves after each contact with surfaces that could be possibly contaminated with diglyme, and associated hand washing. However RAC notes that otherwise the dip pipe still needs to enter the drum and therefore contamination of its outer surface and potential exposure during handling this is still a fact. The modelling estimate provided by the applicant on dermal exposure, although accepted by RAC for this assessment, is considered by RAC to be associated with moderate to high uncertainty, due to the input parameters used as well as inherent limitations of dermal modelling. RAC is of the opinion that uncertainties related to the dermal exposure could be reduced 25

27 by further improving the level of RMMs for the relevant tasks and by the applicant providing measurements that could help in evaluation of general housekeeping and work practices at the applicant s site (for example wipe testing of contaminated surfaces). Environmental releases / Indirect exposure to humans via the environment RMMs applied: The reactors, the LEVs, and the waste tank are all collected to separate water-scrubbers. The waste tank collects all wastes from the processes, which are then incinerated on-site 17. This includes wastewater from the extraction step, the distillation residue, the reactor cleaning methanol, the samples after lab analysis, and the wastewater from the scrubbers. Recycling minimises the amount of diglyme ending up in the above waste stream. Solid wastes and ventilation filters (filters for the incoming air) are sent for incineration offsite. In terms of limiting fugitive emissions, synthesis occurs in a closed system; reactors are stainless steel or glass line; hard transfer pipes are stainless steel or coated with PTFE; flexibles are coated with PTFE; the gaskets for the connections are in PTFE; and during the reaction process the reactor is under vacuum. No filters are used for the general ventilations. Release and exposure estimation methodology: In the CSR, releases to air were estimated by the applicant by using a release factor of (0.01%) based on the Technical Guidance Document s (2003, Appendix I, Table A1.1.) release factors. No releases to water or soil were assumed. In responding to RAC s requests the applicant also provided measurements of diglyme 18 from one of the scrubbers used (the one connected to the waste tank). In terms of fugitive emissions, the applicant mentioned that they have been evaluated with a method approved by the French authorities. No representative measurements on the general ventilation extractors have been feasible to do. PEC regional was estimated using the model EUSES. PEC local was not taken into account in the initial assessment. However the derived by EUSES values for the local scenario were available in the CHESAR file provided by the applicant on RAC s request; and they were used by RAC. Discussion on exposure of humans via the environment: Based on the above methodology and assuming a total use of 35 tonnes per year the applicant estimated an air release of 3.5 kg per year. 17 The temperature of the incinerator is >1000 o C and retention time of the waste in the oven is 3.1 to 3.3 sec (minimum required: 2 sec). Incineration parameters are monitored (temperature, COT, dust, dioxins, HCl, SO2 etc.), registered, and communicated to the French authorities. In case of the regulatory values are exceeded, the computer will stop the incineration process automatically. 18 Three measurements were done in periods where there was diglyme in the waste tank, in 2014, 2015, and The samples were taken on activated charcoal tubes, using an autonomous pump. The sampling time is 30 minutes. The samples were sent to the laboratory by refrigerated transport. Diglyme determination was performed according to NIOSH

28 RAC questioned the used approach, because of the use of a generic release factor (0.0001) from the superseded ESR/NONS TGD that was not specifically linked to operating conditions and risk management measures. In the response the applicant referred to the measurements from the scrubber. The highest of the 3 measurements from the scrubber connected to the waste tank (according to the applicant all below the quantification limit, but, at least some, above the detection limit limit also depends on the actual air flow) corresponds to a release amount of <0.576 g per day. Taking into account the days where diglyme-related operations occur per year, this is translated to an amount much less than 0.5 kg per year. The applicant s calculation using the most recent measurement leads to a value of 4 g per year from this scrubber, which though appears to be an underestimate. The summary of the applicant s release and exposure estimates for humans via the environment is provided in Tables 6 and 7 below. Table 6: Summary of environmental emissions Release route Release rate Release estimation method and details Water 0 kg/year No releases from the site Air 3.5 kg/year Diglyme amount: 0.01% (0.0001) Based on TGD release factor (TGD, 2003) Soil 0 kg/year No releases from the site Table 7: Summary of indirect exposure to humans via the environment Protection target * Predicted Environmental Concentration Exposure estimate and details (i.e. methodology and relevant spatial scale) Man via Environment - Inhalation Local PEC*: 2.67*10-6 mg/m 3 ** Man via Environment - Oral Local PEC: 1.81*10-5 mg/kg*d ** Man via Environment - Inhalation Regional PEC: 1.05*10-10 mg/m 3 Man via Environment - Oral Regional PEC: 3.37*10-9 mg/kg*d ** Value not reported in the CSR by the applicant, but retrieved in the CHESAR file which was made available on RAC s request RAC notes that the available emission measurements represent only one of the scrubbers, whereas no measurements are available from the scrubbers connected to the LEVs and the reactor, nor from the incinerator. Furthermore, possible fugitive emissions have not been quantitatively estimated. The above factors introduce some uncertainty about the possible releases to the environment. On the other hand, it is also noted that i) the measurements from the scrubber indicated a probable proper functioning and accordingly high effectiveness / low release from the scrubbers on-site; ii) the incinerator s temperature (significantly above diglyme s self- 27

29 ignition temperature of 190 o C), retention time and monitoring regime suggests high effectiveness; iii) the emission factor used by the applicant was applied to an assumed total volume of 35 tonnes per year (whereas the fresh solvent added annually is up to 3 tonnes per year); and iv) the mass balance provided by the applicant indicates that indeed the majority of the diglyme lost in the process (on average 2.5 tonnes per year max 3 tonnes per year) is collected in the waste tank (measured to be roughly 2.3 tonnes), which is then incinerated. Therefore the actual releases to the environment may indeed not be higher than estimated in the application. RAC also notes that the assessment of indirect inhalation exposure to humans via the environment using default assumptions of EUSES is conservative, particularly at the local scale, and could lead to an overestimation of risk. Taking the uncertainties mentioned above into account and considering the RMM in place to prevent releases to air, RAC considers that the indirect exposure via the environment calculated by the applicant is acceptable for risk characterisation especially considering that the RCRs calculated below for humans via the environment (section 5) are far below Therefore, the values of exposures of the general population via the inhalation and oral route estimated by the applicant were used by RAC to estimate the risks to the general population at local and regional scale. Uncertainties related to the environmental releases exposure / assessment of exposure to humans via the environment: There is some uncertainty regarding the selection of the release factors that were adopted from the TGD (2003), Appendix I. The TGD (2003) is not the most recent guidance document on the selection of release factors. However, considering the RMMs in place to prevent releases to the air and sensitivity analysis, RAC considers that the uncertainty is low, and emission factors proposed are acceptable for risk characterisation. Conclusion RAC considers that: Taking into account all submitted information, the tasks represented by WCSs and the ECS have been sufficiently described. The methodology used to estimate exposure values for workers contains moderate to high uncertainty. A limited number of measurements were performed using methodology not designed for the assessment of workers exposure. Where modelling was used, the justification provided for some of the input parameters was not sufficient. Use of a Tier 1 model is also linked to uncertainties. 19 Although the applicant did not follow RAC s request to also estimate the releases to air using the default ERC release factors (provided in ECHA s Guidance) refined based on the assumed effectiveness of the RMMs in place, RAC assessed that such an approach would have led to a release estimation of roughly kg per year, depending whether default or maximum achievable effectiveness of the implemented RMMs are assumed. The RCR will still be below 1 if this magnitude of releases is taken in the assessment. 28

30 Taking the uncertainties above into account, RAC considers that the estimated values, as adjusted by RAC, can be used as reasonable worst case and the basis for further risk characterisation with caution. Workers exposure estimation would be strengthened by monitoring worker exposure using relevant methodology. While the methodology used for the exposure estimation of the general population is also linked to some uncertainty, this is relatively minor and the estimated exposure values for humans via the environment can be used for risk characterisation. Taking applicants comments and newly provided information into account, RAC considers that the methodology used to estimate exposure values for workers still contains moderate to high uncertainty. RAC still notes that limited number of measurements were performed using methodologies either not designed for the assessment of workers exposure or using sampling methods with too high LOD due to which the results are considered unusable for exposure estimations. Modelling estimates for dermal exposure provided by the applicant in particular for WCS1 are associated with moderate to high uncertainty due to the inherent limitations of the model and some the input parameters selected by the applicant. RAC still considers that taking the uncertainties above into account, the estimated values, as adjusted by RAC, can be considered to represent reasonable worst case and used as the basis for further risk characterisation with caution. Workers exposure estimation would be strengthened by monitoring of exposure (for inhalation and where possible dermal exposure) using appropriate methodologies. 5. If considered a threshold substance, has adequate control been demonstrated? YES NO NOT RELEVANT, NON THRESHOLD SUBSTANCE Justification: For risk characterisation the applicant used the developed by RAC reference DNELs for the reproductive toxicity of diglyme. Workers Evaluation of the Risk Management Measures The risk management measures and operational conditions were very generally described in the initially submitted CSR; additional clarifications were provided in the answers to the RAC questions. The technical, organisational, and PPE - RMMs implemented by the applicant are described in Section 4. The multiple diglyme transfers via flexible pipes without leak-tight connection appear to be the main sources of exposure through inhalation, as well as dermal route (WCS 1). The main sources of inhalation exposure include the opening of the drum via which the pipe is inserted, the pump, and potentially also the point of connection at the reactors (no clear information about the type of connection). Main sources of dermal exposure include contacts 29

31 with contaminated outer surface of the hose (which was in the drum) and potential dripping or splashes. RAC is of the opinion that additional technical measures can be implemented, in particular for the tasks related to transfers of substance. A system limiting the potential for manual interventions related to transfers, in conjunction with the use of leak-tight connections (e.g. dry coupling) or implementation of other measures, placed higher in the hierarchy of control, that would reduce the potential for exposure, also from contact with contaminated surfaces, reducing also the need to rely on PPE, should be considered where possible. Considering the PPE themselves, the information provided regarding the used gloves, applicable procedures, relevant training and supervision is not considered as sufficient for the evaluation of their effectiveness. The information provided by the applicant indicates that a movable LEV is used extensively, with assumed high effectiveness (90%). However, the photographs provided show use of a corrugated flexible pipe, with no capturing device attached (such as hood), not enclosing the source of the emissions (see the photo in Annex I), limiting the effectiveness of the device. Therefore, considering the provided information (pictures in CSR), RAC is also of the opinion that a design of the LEV more appropriate for the tasks covered by WCS 1 (and WCS 4) must be considered. The applicant informed in the trialogue that the delivery of fresh diglyme in bulk (1000 L) containers instead of 200 L drums will be discussed with the substance supplier. In the last answers to RAC in November 2016 the applicant informed that a new diglyme container system for the storage of recycled diglyme is implemented; implementation of such measures would be expected to reduce exposure in WCS 1, especially during the loading of the reactors 20. In the future, the applicant also considers to reduce further the number of handlings and time involved in the loading of the reactor. While implementation of this method is a step towards reduction of the exposure related to handling, the applicant also needs to consider proper control of other potential high exposure sources during transfer tasks, such as unloading of recycled diglyme back to the storage containers, loading of reagents to diglyme-containing reactors, the need to disconnect, transport, and connect the same flexible pipe for various transfers, including between the reactors, as well as emissions from the pump. In this context, the type of the devices (e.g. couplings, bayonets, pumps, LEV) needs to be appropriate for reduction of emissions to the workplace and of the potential for dermal exposure. Apart from the above transfer tasks, the following tasks are indicated as possible sources of exposure to diglyme by the applicant: (a) cleaning and maintenance tasks (WCS3), (b) sampling of mixture and transfer of that to laboratory (WCS4) and (c) analysis of samples (WCS5). The RMMs already introduced by the applicant for exposure control for WCS 3, including flushing of reactors and the connected equipment with the solvent prior to maintenance, as well as a closed system during the flushing via a spray ball, may be considered to be appropriate. However, an assessment of the effectiveness of the diglyme removal capability of the methodology used may be needed especially in the context of the potential for 20 The applicant discusses that by using these containers it will be easier to channel the vent and the container opening time will be very short (only for unloading of recycled diglyme back to the container; no opening of the container for loading of diglyme to the reactor, as the pipe could be connected to a valve at the bottom of the container). Use of bulk containers would also minimise the numbers of samples to take (one for L container vs 5*200 L drums). 30

32 dermal exposure. For the sampling task (WCS 4), no technical RMMs are introduced. Again here in particular the LEV design is considered as not appropriate. The synthesis process of the active pharmaceutical ingredient (WCS 2) as such (not including transfers between reactors) is performed in a closed system. Specific SOP instructions are available on site describing the work procedure with CMR substances. In terms of RMM implemented for environmental releases, these are mainly controlled by the use of scrubbers connected to point sources of possible air emissions (reactors, LEVs, waste tank) and the on-site incineration of collected waste streams. The level of fugitive emissions could be reduced considerably, in particular if the various transfer processes occurred under a higher level of enclosure. In its comments to draft opinion the applicant noted that process changes have been implemented that i) reduced the number of manipulations of drums (from manipulation of 6 to 7 drums per shift to just one), due to the possibility to use 1000L containers with recycled diglyme since March 2016; ii) allowed tighter connections during loading/unloading followed, in case of the container, by nitrogen purging; and iii) allowed a tighter connection of the LEV system and specific piping system with auto-suction pumps were introduced in order to limit manual interventions. The procedure of replacing (removing and disposing of) gloves after each activity with potential for dermal contact and subsequent handwashing also contribute to the lower potential for dermal exposure. RAC also notes that the applicant is planning to install the semi-automatic sampling system (WCS 4) where the bottle will be screwed to the system for a filling, minimising potential of dermal exposure. According to the applicant such a sampling system will be in operation and will be used during the next production batch starting in October The applicant is also planning to continue monitoring programs, results of which would be used to analyse improvements of OCs/ RMMs and is planning to perform such monitoring at least once per year. The applicant also informed RAC about its efforts to find a reliable methodology for the evaluation of dermal exposures. For WCS1, RAC notes that the main source of dermal exposure (outer surface of pipe entering the fresh diglyme drum) remains, but the implemented changes have reduced significantly the daily duration of potential dermal exposure. In order to improve once again this step of drum loading, the applicant informed that it is investigating the use a dip-tube pre-installed in the drum system which will not have to be removed from the drum after the transfer of diglyme. Such an RMM will clearly reduce the potential for dermal exposure during connection/disconnection of the pipe. The applicant must also consider RMMs which could address any further sources of potential dermal exposure, which might for example include handling of the pump after loading/unloading and connections/disconnections at the reactors ends. Risk characterisation As described in Section 4, exposure estimation based on the modelled data was used for assessing exposure via inhalation route for WCS 2 (ART), WCS 3 (ECETOC TRA) and WCS 5 31

33 (ECETOC TRA) and via dermal route for all WCS (ECETOC TRA, WCS 4 RISKOFDERM). For WCS 1 and 4 inhalation route - measured values were used. The estimated exposure values were used for risk assessment. In Table 8 the RCRs are presented for each WCS and in Table 9 the combined RCRs are provided based on the exposure values taken from Table 5 (values chosen by RAC). Table 8: Risk characterisation ratios (RCR) for workers Contributing scenario Route of exposure Exposure (based on Table 5) RCR Combined routes RCR Exposure adjusted after applicants comments on draft opinion (based on Table 5) RCR adjusted after applicant s comment s on draft opinion Combined routes RCR adjusted after applicants comments on draft opinion WCS 1 (PROC8b) Inhalation 0.60 mg/m mg/m Dermal mg/kg mg/kg WCS 2 (PROC3) Inhalation mg/m mg/m Dermal mg/kg mg/kg WCS 3 (PROC8a) Inhalation mg/m mg/m Dermal mg/kg mg/kg WCS 4 (PROC9) Inhalation 0.01 mg/m mg/m Dermal mg/kg mg/kg WCS 5 (PROC15) Inhalation mg/m mg/m Dermal mg/kg mg/kg

34 Table 9: Combined risk characterisation ratios (RCR) Contributing scenario RCR inhalation route RCR dermal route RCR combined for routes RCR dermal route adjusted after applicants comments on draft opinion Total duration > 8 h* WCS 1 WCS WCS 4 Total duration 8 h ** WCS WCS WCS 4 RCR combined for routes adjusted after applicants comments on draft opinion *The exposure concentrations are calculated assuming for WCS1 < 4 h, WCS2 <8 h, WCS 4 <15 min., i.e. the approach used by the applicant. ** As the combined tasks does not last more than 8h, in these recalculations the exposure estimation for WCS2 assumes only 4h duration instead. Based on RAC reference DNELs for workers and the estimated exposure (see Section 4), the RCR for combined WCSs and routes of exposure was calculated to be 0.7, taking into account the effect of LEV on dermal exposure, as assumed by the applicant. However, RAC considers that dermal exposure estimates without LEV-effectiveness should be considered - therefore the RCR is For WCS3, the respective value is 2.9, which is however likely to be a considerable overestimate, as discussed above. It should be noted that based on RAC reference DNELs for workers and the estimated exposures adjusted after applicant s comments on the draft opinion (see Section 4), the RCR for 8 hours exposure, for combined WCSs and routes of exposure was now calculated to be Indirectly exposed workers Not assessed by the applicant. In particular for the duration of WCS1, it was mentioned that there are clear signs in the workshop indicating that the loading process is ongoing and during that time no other worker than the loading operator should enter the area. Man via the Environment exposure The applicant has taken into account exposure for general population considering both inhalation and oral exposure and used them for risk characterisation. 21 In the paper of RAC setting reference DNELs for diglyme (RAC/33/2015/08 rev 1 Final) the inhalation DNEL for workers is 1.68 mg/m 3 for testicular toxicity based on DuPont (1989) and 2.61 mg/m 3 for developmental toxicity based on DuPont (1988a). Thus, the DNEL for developmental toxicity is a factor of 1.55 higher than the DNEL for testicular toxicity. Since RAC based the DNELs for all routes on the inhalation study, the factor is applicable also to the dermal DNEL. Thus, applying the factor of 1.55 to an RCR of 3.4 for testicular toxicity gives an RCR of 2.2 for developmental effects. 33

35 The main exposure from the use of diglyme can be expected via ambient air. The emissions for soil and water are not considered because of the emission control measures implemented in the site (see Section 4). The calculated RCR are presented in Table 10. Table 10: Risk characterisation ratio (RCR) for MvE local Local PEC RCR Regional PEC RCR Inhalation 2.67*10-6 mg/m 3 7.9* *10-10 mg/m 3 3.5*10-10 Oral 1.81*10-5 mg/kg*d 2.0* *10-9 mg/kg*d 3.7*10-8 Combined route RCR 2.1* *10-8 Uncertainties and exposure control concerns Considering the exposure values estimated for WCS 1, the diglyme transfers and associated tasks (e.g. pump-handling) can be concluded to be one of the main possible sources of exposure through the inhalation, but also the dermal, route. As discussed above, the use conditions implemented for WCS1 are not appropriate in limiting the risk. Inhalation and dermal protection during transfer operations is based mainly on PPE plus an LEV system of questionable design. Improvements must be implemented taking better account of the principles of hierarchy of control, including e.g. dedicated storage facilities for diglyme, and the use fixed piping with tight connections and/or drycoupling. The design of the LEV system (at least for WCS 1 and WCS 4) also needs to be improved, to provide adequate protection from exposure resulting from remaining, after the implementation of the above improvements, exposure sources. Taking into account the new information provided in the applicant s comments on the draft opinion, for WCS1 the RMMs implemented better follow the principles of hierarchy of controls, especially terms of reducing the potential for inhalation exposure, but to certain extent also for dermal exposure. For WCS1 some improvements must still be implemented in this context to reduce the reliance on the use of gloves and work practices. Considering inhalation exposure, these relate to reducing exposure during tasks such as removal of the pump and to the displacement of diglyme vapours from the reactor during addition of the reducing agent to it. It should also be ensured that nitrogen used for purging is directed to the exhaust ventilation and scrubber. Considering dermal exposure, further RMMs must focus on i) eliminating the need to introduce a pipe into the drum containing the fresh diglyme in its comment on the draft opinion the applicant committed to investigate measures towards this aim and ii) identifying and addressing any further sources of dermal exposure. Appropriate monitoring programmes must also be performed for inhalation and where possible for dermal exposure, to validate the implemented changes. 34

36 Conclusion RAC concludes that: The highest (combined) RCR for relevant tasks of workers is 3.4. This is driven mainly by the dermal exposure estimates and while these are affected by the limitations of modelling, possibly being an overestimate, the final value reflects the result of the assessment for a process with deficiencies in terms of risk control measures (see last bullet point). However, the inhalation exposure estimates are characterised by moderate uncertainties too. The RCR calculated for local and regional scale for combined routes (inhalation and oral) are 2*10-4 and 4*10-8 respectively, based on which the risk is considered as adequately controlled for the general population. The identified uncertainties are associated with the measurement method followed for inhalation exposure and the assessment of dermal exposure, but are clearly confounded by the implementation of a rather low level of RMMs for WCS1 on site. Some deficiencies have been identified regarding the adequacy and appropriateness of the OCs / RMMs implemented to control the exposure, namely in terms of the implementation of the principles of hierarchy of control (e.g. transfer system requiring multiple manual interventions, with high reliance on PPE), as well as design of the LEV used for the transfer tasks. RAC concludes that adequate control has not been demonstrated for workers exposures. The level of certainty related to the level of workers exposure would be increased by a more robust assessment methodology based on appropriate measurement programmes. RAC concludes that adequate control has been demonstrated for the general population exposed via the environment. RAC concludes that the implemented OCs and RMMs are not appropriate and effective in limiting the risk, in particular for workers. Taking into account the applicant s comments on the draft opinion, RAC concludes that: The highest (combined) RCR for relevant tasks of workers is Dermal exposure is a significant contributing component. The RCR calculated for local and regional scale for combined routes (inhalation and oral) are 2*10-4 and 4*10-8 respectively, based on which the risk is considered as adequately controlled for the general population. The identified uncertainties are associated with the measurement method followed for inhalation exposure and the modelling assessment of dermal exposure. RAC concludes that adequate control has been demonstrated for workers exposures. However, the level of certainty related to the level of workers exposure would be increased by use of a robust assessment methodology based on appropriate measurement programmes and implementation of further measures to reduce potential for exposure. RAC concludes that adequate control has been demonstrated for the general population exposed via the environment. 35

37 RAC concludes that the implemented OCs and RMMs are appropriate and effective in limiting the risks, however notes that the applicant should i) continue monitoring exposures using appropriate methodologies, in order to assess newly implemented technical improvements; and ii) implement further RMMs as needed in order to minimise exposure and reduce the remaining uncertainties related to the exposure estimation. 6. If adequate control is not demonstrated, are the operational conditions and risk management measures described in the application appropriate and effective in limiting the risk? YES NO NOT RELEVANT The adequate control has been demonstrated. 7. Justification of the suitability and availability of alternatives 7.1 To what extent is the technical and economic feasibility of alternatives described and compared with the Annex XIV substance? Description: Summary of the analysis of alternatives undertaken by the applicant The applicant uses between 22 and 35 tonnes of diglyme per year as a process solvent in the manufacturing of an active pharmaceutical ingredient (API) with a confidential name, here called P2. P2 is exclusively toll manufactured by the applicant for one client, which uses it as an active ingredient in an anti-protozoal drug used to treat vaginitis of various origins. The manufacturing process of P2 consists of three key steps: manufacture of the precursor P0, manufacture of the intermediate product P1, and manufacture of the API referred to as P2. Diglyme is used in the second step of this process, to solubilise chemicals used for manufacturing of the intermediate product referred to as P1. The applicant notes that they are mandated by their client as a toll manufacturer of P2 and that they have limited to no authority to make changes to the production process without consent of the client. According to the applicant, investments in R&D cannot be made without the full cooperation of the client. SEAC finds it credible that the applicant, as a toll manufacturer, has limited authority to adapt the production process. According to the applicant there are essentially two approaches to substituting the diglyme: finding a different synthesis route or substituting diglyme with another solvent. A different synthesis route would require a complete process change while the change-over to another solvent would require substitution of several other chemicals as well. The applicant has limited information on alternative synthesis routes but considers nucleophilic substitution as the most promising alternative route for the synthesis of P1. 36

38 According to information provided by the applicant, P2 is manufactured only by two suppliers: the applicant and a second supplier outside the EEA. As the synthesis route of the non-eea manufacturer is confidential business information, it is unknown to both the applicant and SEAC. The applicant assumes that the synthesis process could be different, but does not know whether it is partially or entirely different. As both suppliers manufacture P2 exclusively for the client, scientific literature on the specific subject is scarce. A literature search by SEAC found four records relevant for the case at hand. The evidence found is consistent with the information provided by the applicant. In relation to assessing alternative solvents, the applicant has set the following criteria: - Compatibility with all the chemicals involved through the process; - Solubilisation of the P0, the reducing agent and the Lewis Acid; - Efficiency of the reaction compared to using diglyme as solvent (yield=78%); - Ability to recover the solvent from the process and re-use it; - No change in P2 impurity profile (to avoid the need for further purification steps and stability tests); - Compliance with the rules on solvent residues for pharmaceutical products. The applicant presented yield (efficiency of the reaction) mainly as a technical feasibility criterion in the application. SEAC views product yield as an economic feasibility criterion and notes that the applicant, at the same time, also used the costs due to changes in yield to justify the unsuitability of alternatives. These costs are outlined in the economic feasibility section later on. According to the applicant, the only known family of solvents potentially compatible with the above criteria are the aliphatic ethers. The application did not contain comprehensive justifications for the exclusion of other solvent families. On SEAC s request, the applicant clarified its justification for the exclusion of 8 solvent families by qualifying the compatibility (no interfering reaction) with the chemicals involved in the synthesis and provided literature data supporting its conclusion. In SEAC s view, the exclusion of the other solvent families is justified. Within the application, the identified potential alternative aliphatic ethers are Tetraglyme, MeTHF (2-Methyltetrahydrofurane), THF (Tetrahydrofurane), Dioxane, MTBE (Methyl tertbutyl ether) and IPE (Isopropyl ether), Proglyme and Butyl diglyme. In a first step they were investigated for their key properties and consequently Dioxane, Proglyme, Butyl diglyme, MTBE and IPE were dismissed because of the poor chance of success due to their solubilising power. Based on the results of the investigation, the selected alternatives were tested alone or in combinations. The criteria used for selecting the shortlisted alternatives can be considered as clearly defined. While the application itself was concise, the applicant did clarify the shortlisting process on SEAC s request. Technical feasibility The applicant analysed four commercially available shortlisted alternatives. To test each of the alternatives as substitutes for diglyme in the P2 manufacturing process, the applicant applied the P1 process conditions and the post-treatment to complete P2 manufacturing. 37

39 Overall, SEAC notes that the experiments done by the applicant are poorly described in the application (and additional information had to be requested by SEAC). Variations in synthesis parameters were limited to the quantity of reagents and time of reaction, with only a limited amount of experiments performed and data obtained. The results of the tests are outlined below. Alternative 1: THF During the manufacturing of P1 in the first step of the process, the reduction of P0 was incomplete. As THF did not solubilise the reducing agent and therefore did not permit the reaction (yield 0%), the applicant concluded that THF cannot be seen as a technically feasible alternative. As the reducing agent was not dissolved in THF, SEAC requested the applicant to provide additional information on alternative reducing agents to be used in the process. The additional information provided and the analysis of the alternative reducing agents are described below. Alternative 2: Tetraglyme An excess of 20% of tetraglyme was necessary to solubilise the Lewis acid. Although the reduction of P0 was complete, the yield was only 12% and the product manufactured deviated from the P2 specifications in terms of colour, aspect and purity measured by HPLC. To improve the yield, the applicant decided to experiment with a process where the reducing agent is solubilised in tetraglyme and the rest of the chemicals in other potential alternative solvents (MeTHF and THF Alternatives 3 and 4). Alternative 3: Tetraglyme + THF Tetraglyme was used to solubilise the reducing agent and THF to solubilise P0 and the Lewis acid. After 3 hours (the time required for the reaction with diglyme), the reaction was not complete and after 21 hours, the applicant decided to introduce water for hydrolysis. The applicant concluded that tetraglyme combined with THF can be used instead of diglyme for the reaction. This was the only alternative which may meet the specifications (colour, aspect, purity) of the intermediate product. It should be noted that Austria has submitted a CLH proposal for the classification of tetraglyme as Repr. 1B. Furthermore, THF is a carcinogen 2. Therefore, this combination of solvents might not be an appropriate long term alternative. Alternative 4: Tetraglyme + MeTHF As a fourth alternative combination of solvents, tetraglyme was used to solubilise the reducing agent and MeTHF to solubilise P0 and the Lewis acid. The advantage of MeTHF compared to THF is its lower density which may favour the separation of aqueous/organic phases. After 18 hours of the synthesis, even if P0 was not totally reduced, the synthesis followed. The synthesised product deviated from the P2 specifications in terms of colour, aspect and purity, which was due to the incomplete reduction of P0 after 18h of contact. The yield was 34% (with 23% losses during filtration due to solubility gradient). Applicant s conclusion on technical feasibility of alternative solvents The applicant concluded that tetraglyme combined with THF (Alternative 3) is the only alternative which may meet the specifications (colour, aspect, purity) of the intermediate product and can be used instead of diglyme for the reaction. 38

40 Alternative reducing agents In its analysis of alternatives the applicant focused mainly on replacing the solvent with another solvent, whilst keeping all other reagents the same. This resulted in difficulties due to the low solubility of the reducing agent in the alternative solvents. Within the application, LiAlH4 was considered by the applicant as a potential alternative reducing agent soluble in an alternative solvent, but it was dismissed due to safety reasons. In response to SEAC s questions, the applicant clarified that it had also conducted literature studies on different reducing agents within the process. The applicant stated that the alternative reducing agents are known at the research level but that, when available, they are not or extremely rarely used at industrial scale due to their very high prices. All identified alternative reducing agents were dismissed either because they are not available at industrial scale or because they would induce an unacceptable cost increase (further explained in the economic feasibility section), or because they are too hazardous. Alternative synthesis route SEAC notes that the use of a different synthesis route was only briefly mentioned as an option and thus not described in detail in the application. The applicant only stated that it considers nucleophilic substitution as the most promising route for the synthesis of P1. SEAC found four patents related to an alternative synthesis route for the production of P2, all of which rely on a synthesis via nucleophilic substitution. The applicant referred to this synthesis route in its application as its implementation would imply that there is no need for the reduction of carboxylic acids to an alcohol and therefore no need for using diglyme. As stated by the applicant, no concrete study into the technical and economic feasibility of an alternative synthesis route can be launched without the consent and investment of its client. SEAC recognises the limits of a toll manufacturer in modifying the synthesis and production process but regrets that more efforts have not been made in the assessment of alternative synthesis routes. Upon SEAC s request, the applicant elaborated further on the steps that would be required for implementing an alternative synthesis route, including chemical development, analytical development, process development, industrialization and regulatory issues. The costs needed for each of these steps are outlined in the economic feasibility section. According to the applicant, if it could find an alternative solvent or an alternative synthesis route that satisfies the industrial requirements and active pharmaceutical ingredient specifications, the transition process would require the following steps, which in total would require at least 11 years: R&D development (6-9 months); new processes following GMP have to be implemented (1 year); industrial validation batches have to be manufactured and qualified (1-1.5 year); stability study of P2 as such at applicant site (5 years); stability study of P2 in the formulation (medicine) conducted by the applicant s client (1 year); preparation of variation dossiers according to each country s requirements (1 year); evaluation of applications by authorities (1 year). In response to SEAC s request for clarification, the applicant provided further information confirming that stability tests over 5 years are specified as binding requirement for the production of P2 by the client. Based on this, the estimated 11 years for implementation of 39

41 an alternative synthesis route or alternative solvent seems realistic to SEAC. Conclusion on technical feasibility The information provided in the application was very brief, making it difficult for SEAC to follow the applicant s assessment of the technical feasibility of alternatives. The applicant provided clarifications to SEAC s information requests as well as during the trialogue. Based on the information provided, SEAC considers the applicant s conclusion on the technical feasibility assessment to be plausible, but notes that only limited variations in solvent quantities and process time were done in the applicant s tests, which limits the meaningfulness of the data obtained. SEAC concurs with the applicant that Alternative 3 is the only alternative solvent that meets the technical specifications of P2 manufacturing and thus is technically feasible. The main barrier to implement Alternative 3 is its hazards; in particular RAC concluded that the shortlisted alternative solvents would not appear to result in a risk reduction for human health. The applicant did not clearly conclude whether the alternative reducing agents or the alternative synthesis route would be technically feasible. However, SEAC notes that various regulatory and validation steps would be required before they could be implemented. According to the applicant, if it could find an alternative solvent or an alternative synthesis route that satisfies the industrial requirements and active pharmaceutical ingredient specifications, the transition process would require a minimum of 11 years. SEAC evaluated the arguments presented and the timelines and concludes that these seem realistic. Economic feasibility Alternative 1: THF The economic feasibility of Alternative 1 was not evaluated by the applicant because the reducing agent was not solubilised and the reduction of P0 was therefore not achieved. As not even the minimum requirement of a solvent for this process was achieved, the applicant concluded that the alternative cannot be considered technically feasible. Alternative 2: Tetraglyme The applicant did not consider Alternative 2 economically feasible as the yield was low (12%), the reaction required a higher volume of solvent compared to diglyme, and due to its very high boiling point tetraglyme cannot be recycled safely and economically. In response to SEAC s request for additional information, the applicant clarified that the low yield means that the cost of manufacturing the API, due to increased material costs and processing times, would become higher than its sales price, making the alternative economically infeasible. Alternative 3: Tetraglyme + THF According to the applicant, Alternative 3 is not economically feasible because of the reduced yield rate, a longer contact time (implying additional time is required for the production) and because tetraglyme and THF cannot be easily recycled by distillation (due to the formation of an azeotrope with water). In response to SEAC s request, the applicant confirmed that, due to the yield and non-recyclability of the solvents, the cost of manufacturing the API would become higher than its sales price, making the alternative economically infeasible. 40

42 Alternative 4: Tetraglyme + MeTHF Alternative 4 was not considered economically feasible by the applicant because of the reduced yield, a longer contact time (implying an additional time is required for the production), because the reduction of the precursor is not complete, and because tetraglyme and MeTHF cannot be recycled by distillation (due to the formation of an azeotrope with water). Similarly to Alternatives 2 and 3, the applicant also confirmed that the low yield of Alternative 4 and its non-recyclability means that the cost of manufacturing the API would become higher than its sales price making it economically infeasible. Alternative reducing agents In response to SEAC s questions, the applicant provided additional information on the economic feasibility of alternative reducing agents. Based on the two rounds of questions, SEAC collected the following information on the reducing agents considered: Availability at large scale Reagent cost compared to current reducing agent Quantity to be used compared to current reducing agent Cost of intermediate goods LiBH4 Raw material is more expensive and it requires also the use of Lewis Acid to reduce the acid function LiAlH4 Yes 4 times more similar Increase of more than 40% (not including increase of transformation cost due to special process) AlH3 Not commercial ly available LiAlH(OMe)3 or its analogue LiAlH(OtBu)3 (i- Bu)2AlH(DIB ALH) Only the analogue is available 4 times more 3,7 times more Capability to use Increase of 150% More soluble than the current reducing agent (if used in THF, part of risks remain). Not usable for safety reasons Used in THF (part of the risks would remain) Increase of 150% Depending on the final process. Yes 5 times more 6,7 times Increase of 250% Depending on more the final process. There is uncertainty regarding whether it is powerful enough. NaAlEt2H2 No N/A N/A N/A N/A 41

43 Taking into account the confidential information provided by the applicant on the current costs of intermediate goods and sales revenues, SEAC assessed the above increases in the cost of intermediate goods and agree that they would result in substantial profit losses. According to the applicant, the P2 cost structure cannot support such reagent costs. SEAC concurs with the applicant that, as these reducing agents are either not commercially available or would result in high costs, they cannot be considered suitable to the applicant. Alternative synthesis route Upon request, the applicant estimated the costs of implementing a new synthesis route: Process Cost estimate: Chemical development 50,000 Analytical development 150,000 Process development 250,000 Industrialization 200, ,000 Regulatory 20,000 Total: at least 670,000 The applicant did not provide any information about whether the operating costs would be different with the alternative synthesis route. Assuming that the manufacturing costs and annual sales revenues related to P2 would remain the same as with diglyme, SEAC finds that this alternative cannot be considered economically feasible for the applicant. Conclusion Overall, SEAC is of the view that more details (e.g. details of experiments done and analysis of scientific literature) should have been provided on the suitability of alternatives and the information provided in the analysis of alternatives should have been presented in a much clearer manner. Some of the assumptions underlying the original analysis were not outlined by the applicant, making it difficult to follow the applicant s justifications. Nevertheless, the applicant provided clarifications and additional information at SEAC s request and during the trialogue. Based on the tests conducted, SEAC concurs with the applicant that the only alternative solvent possibly meeting the specifications of the intermediate product (colour, aspect, purity) is the combination of tetraglyme and THF (Alternative 3). Nevertheless, SEAC notes that the amount of experiments performed and data obtained is limited and the applicant s assessment on technical feasibility cannot be considered fully elaborated. However, the potential reprotoxic classification of tetraglyme (Repr. 1B) and the economic infeasibility of this alternative (as the low yield would make the production unprofitable) led to the conclusion that this cannot be considered to be a suitable alternative. Since the applicant s assessment focused only on alternative solvents, SEAC requested additional information on the feasibility of changing to an alternative reducing agent. The replacement of the reducing agent was not considered suitable by the applicant mainly due to economic reasons. Moreover, many of the reducing agents considered were not commercially available. For the remaining alternative reducing agents, SEAC can concur with the applicant s conclusion (based on confidential estimates) that the operating profits would be significantly reduced by a switch-over to another reducing agent and that this can therefore not be considered a suitable alternative. 42

44 Based on the above, SEAC tends to concur with the applicant that neither of the described potential alternative solvents and alternative reducing agents would be both technically and economically feasible for the current manufacturing process. In relation to changing to an alternative synthesis route, the applicant stated that it considers nucleophilic substitution as the most promising route for the synthesis of P1. The applicant did not conclude whether or not the alternative synthesis route would be technically feasible. Moreover, the applicant emphasised that it cannot implement an alternative synthesis route without the consent of the client. No information was provided on the willingness of the client to implement a new synthesis route. SEAC recognises the limits of a toll manufacturer in modifying the synthesis and production process but regrets that more efforts have not been made in the assessment of alternative synthesis routes. Nevertheless, SEAC finds it credible that a minimum of 11 years would be required to implement a new synthesis route, due to the various steps needed (including the regulatory requirements for approval of changes to the process and the final product). In sum, SEAC can agree with the applicant s conclusion that there are no suitable alternatives available before the sunset date. No information was provided during the public consultation which would contradict this conclusion. Nevertheless, SEAC notes that the information provided by the applicant was not comprehensive and the applicant s assessment cannot be considered thorough. 7.2 Are the alternatives technically and economically feasible before the sunset date? YES NO Justification: According to the conclusion of the applicant, tetraglyme combined with THF (alternative 3) is the only alternative solvent which may meet the specifications of the intermediate product, but the reprotoxic classification of tetraglyme and the lower yield (resulting in a loss of the operating profit) implies the alternative cannot be considered suitable. The applicant also provided additional information on the technical and economic feasibility of using an alternative reducing agent. This information shows that none of the alternative reducing agents are both economically and technically feasible. SEAC agrees with this conclusion. Although the change to an alternative synthesis route was not analysed in detail by the applicant, SEAC can agree that the transition process would require a minimum of 11 years and that it would not be possible to be implemented before sunset date. Conclusion SEAC concurs with the applicant that there are no technically and economically feasible alternatives available before the sunset date. 43

45 7.3 To what extent are the risks of alternatives described and compared with the Annex XIV substance? After assessment of a number of aliphatic ethers, the applicant identified 4 short-listed alternatives (2 substances as such and 2 mixtures of substances were discussed covering in total 3 different substances): Tetraglyme (CAS No , EC No ) is a polar solvent. - CLP harmonised classification not available. - According to the information provided by the companies for C&L inventory: Repr.1B, H360 - CLH proposal submitted by Austria Repr.1B, H360. Tetrahydrofuran THF (CAS No , EC No ) is a polar solvent. - CLP harmonised classification: Flam. Liq. 2, H225; Eye Irrit. 2, H319; STOT SE 3, H335; Carc. 2, H351. EUH Substance is included in Community Action Rolling Plan (CoRAP), evaluating Member State Germany. The decision was issued on January 2015 the additional information submission deadline was 18 months. Mixture of Tetraglyme and THF. Mixture of Tetraglyme and Tetrahydro -2-methylfuran (MeTHF). Tetrahydro -2- methylfuran - MeTHF (CAS No , EC No ): - CLP harmonised classification not available. - Self-classification information provided by the companies (C&L inventory): Flam.Liq.2, H225; Acute Tox.4, H302, Skin Irrit.2, H315; Eye Dam. 1, H318; STOT SE 3, H336 (central nervous ); STOT SE 3, H335 (respiratory system, inhalation.. nacrosis..), EUH019, H301. The comparison of alternatives with the diglyme was done by the applicant based on their classification in accordance with the CLP regulation. Based on a comparison with the classification of diglyme, the applicant concludes that tetraglyme and mixtures containing it (tetraglyme + THF; tetraglyme + MeTHF) would not be suitable alternatives in long term perspective, in terms of risks. 7.4 Would the available information on alternatives appear to suggest that substitution with alternatives would lead to overall reduction of risk? YES NO NOT APPLICABLE Justification: As mentioned above, diglyme is classified as Repr. 1B, while Tetraglyme has been proposed also as Repr.1B, THF is a suspected carcinogen Carc. 2 and MeTHF does not, according to self-classification, possess CMR properties. MeTHF was not assessed as such by the applicant, only in a mixture with Tetraglyme, which already has harmonised classification Repr.1B. The applicant did not provide conclusions regarding the risk reduction using THF as such. RAC made their conclusion based on the information included in the application. RAC s 44

46 opinions is that as THF is suspected carcinogen, it does not appear to qualify as a long term alternative. RAC also notes that SEAC has also discussed a number of alternative reducing agents, not included in the initial assessment by the applicant, which could be used in solvents other than diglyme. Some of those substances are still reported to be used in THF, in which the case the same applies as above. Conclusion Based on a comparison of the currently available hazard information, RAC agrees with the applicant`s conclusion that the 4 alternatives short-listed in the application would not appear to result in a risk reduction for human health (workers and general population via the environment). RAC does not have appropriate information on the solvents at which alternative reducing agents discussed by SEAC can be used. Therefore RAC cannot conclude on whether use of those would lead to overall reduction of risk. 7.5 If alternatives are suitable (i.e. technically, economically feasible and lead to overall reduction of risk), are they available before the sunset date? YES NO NOT RELEVANT Justification: SEAC agrees with the applicant s conclusion that there are no suitable alternatives available before the sunset date. 8. For non-threshold substances, or if adequate control was not demonstrated, have the benefits of continued use been adequately demonstrated to exceed the risks of continued use? YES NO NOT RELEVANT, THRESHOLD SUBSTANCE Justification: The application was submitted under the adequate control route. In the draft opinion, RAC concluded that adequate control has not been demonstrated for workers exposure to diglyme. This means that the applicant would have to follow the socio-economic route and demonstrate that benefits of continued use outweigh the risks, just as for non-threshold substances. In the original application, the applicant had already performed a socioeconomic analysis (SEA), and the applicant elaborated on the socio-economic impacts during the opinion-development. Based on the comments provided by the applicant in response to the draft opinion, RAC has updated the opinion and comes to the conclusion that adequate control is now demonstrated. Therefore, the applicant is not required to demonstrate that the socio-economic benefits of continued use outweigh the risks. 45

47 Benefits of continued use (cost of non-use scenario) The benefits of continued use were assessed based on a non-use scenario, in which the applicant would stop manufacturing P2. This was the only non-use scenario which was considered in the application. In order to assess its credibility, SEAC requested additional information on the cost of i) switching to an alternative solvent, ii) changing the reducing agent, and iii) developing and implementing a new synthesis route. These three alternative options have been discussed in section 7 of this opinion. SEAC scrutinised the information provided and agrees with the applicant s conclusion that, in the non-use scenario, a switch to an alternative solvent, reducing agent, or synthesis route would be neither technically nor economically feasible for them. SEAC asked the applicant whether it would be possible to eliminate the use of diglyme by importing the intermediate P1 and only performing the final production steps of P2 at the applicant s site. According to the applicant, this would not be a viable option as they would not make profits from the final production step alone. Furthermore, the applicant mentions several time-consuming approval steps, which are required for revalidation of the API production process. SEAC finds this reasoning plausible and comes to the conclusion that the applicant has excluded this scenario for acceptable reasons. Therefore, SEAC considers that the applicant s stop of production of P2 is a credible non-use scenario. The non-use scenario might entail significant implications for other actors in the supply chain including the competitors of both the applicant and its client. The client of the applicant is an EEA-based company that uses P2 to manufacture an anti-protozoal drug for treating vaginitis of various origins (infection, parasite or mixed). The client has two suppliers of P2: the applicant and another company located outside the EEA. These two suppliers are currently the only manufacturers of P2 globally. According to the applicant, it is not possible to predict whether the competing supplier (or a third supplier) would be in the position to fully meet the client s demand for P2 in the non-use scenario. If the competing supplier would not be able to fully cover demand, the production of the anti-protozoal drug would decrease at least in the short run (assuming that new suppliers would not be able to immediately enter the market). SEAC notes that there are alternative anti-protozoan drugs available which are based on a different API. According to the applicant, these drugs are considered direct substitutes to the drug manufactured by the client. The two main competitors of the client (for the antiprotozoan drug) are both EEA-based companies. In case the client s production would decrease, it can be expected that the competitors would take over its market share. SEAC notes, however, that part of the market share could also be taken over by local manufacturers of anti-protozoan drugs in the markets served by the client (both within and outside the EEA). 46

48 The supply chain and the links to the competitors are outlined in Figure 1. Figure 1. Illustration of supply chain and competitors The applicant estimated the welfare cost associated with ceasing the production of P2 based on the expected value added forgone (VAF) over the requested review period of 12 years. Taking into account the volatility of demand, the applicant calculated both an upper and lower estimate of the expected VAF based on the lowest and highest historical sales volumes of P2 through the years SEAC evaluated these confidential sales figures as well as additional arguments supporting the expected future demand. Based on this information, SEAC considers it credible that sales in the continued use scenario would not fall below the lower bound estimate provided by the applicant. The VAF was calculated by subtracting the costs for materials and services directly consumed in the manufacturing process (i.e. excluding capital and labour costs) from the net turnover. Over the 12-year period, the (present value of) VAF estimates range from 3 to 11 million. In SEAC s view, the VAF approach overestimates the welfare loss to society as it implicitly assumes that jobs would be lost over the entire period of assessment and suggests that loss in operating profits would have been a better starting point for the assessment. On request, the applicant provided additional information on the expected loss in operating profits. These were estimated to be in the range of 1.5 to 7.5 million over 12 years. SEAC notes, however, that whilst profits expected from the use applied for would be irrevocably lost, it could well be that the applicant, or another actor, would make use of the production factors in a second-best use. To clarify this issue and substantiate the assessment of economic impacts, SEAC requested additional information on possible alternative uses of the equipment which could partly offset the profit losses. The applicant confirmed that some parts of the standard equipment (e.g. tanks, reactors and filters) could be used for other manufacturing processes (with the exception of the safety equipment specific for P2 manufacturing), but economic impacts to off-set profit losses are not expected. The residual value of the standard equipment is considered to be zero because it is currently impossible to find buyers for this equipment and the applicant already has equipment standing idle. Furthermore, large parts of the equipment (including the safety equipment) are specific to the production of P2 and cannot be used to produce other (intermediate) products. SEAC considers it therefore plausible that alternative uses of the 47

49 installed equipment will not balance off the profit losses in the non-use scenario in any significant way. In light of the above information and given that the applicant would continue its other operations, SEAC finds the applicant s expected operating profit loss of 1.5 to 7.5 million plausible. SEAC acknowledges the difficulty for the applicant to include detailed information on impacts to other actors and notes that the applicant provided additional (partly confidential) information about the expected impacts on its direct competitor and its client upon request. This information can be summarised as follows. The competing supplier of P2 is expected to take over parts of the applicant s market share after scaling up their production capacity. SEAC notes that the competing supplier would be the only remaining supplier of P2 and they would therefore be in a monopoly position. This may result in deadweight loss as the client would be dependent on one supplier. In order to calculate the deadweight-loss, private information on the price setting strategy of the second supplier of P2 is necessary, which the applicant could not provide. Therefore, SEAC is not able to quantify the extent of such competition-related impacts but acknowledges that restricting competition will likely have negative impacts on output and production. SEAC notes that this may also result in consumer surplus losses. Since the competing P2 supplier is located outside the EEA, the profits taken over by them would comprise a permanent welfare loss to the EEA (assuming that the competing supplier is also owned by an actor outside the EEA). The production capacity of the competing P2 supplier is unknown to the applicant, resulting in uncertainty about the actual economic impacts on the whole supply chain, including the client of the applicant. In case the competing supplier could take over the full market share of the applicant, impacts on the supply chain can be expected to be limited to the aforementioned effects from imperfect competition. However, based on information provided by the applicant and its client, the competing supplier may not be able to scale up the P2 production sufficiently to meet the full demand of the client (at least in the short run), possibly resulting in undersupply of P2. Although the applicant and the competing supplier are currently the only known suppliers of P2, SEAC notes that new suppliers may enter the market particularly, if the applicant has to cease the use applied for. Then, again, it seems plausible to SEAC that any new supplier would have to gradually ramp up its production such that it would most likely take some time before the current supply of P2 would be restored. Whilst it is difficult for SEAC to gauge the impact of the non-use scenario on the client as this is a function of the competing supplier s prospective production capacity and price setting, the client has provided confidential estimates of what the losses to them and their subcontractor might be if neither the applicant s competitor nor any other supplier would take over the production volume of P2 to be lost in the non-use scenario. As noted before, there are two other companies (i.e. the client s competitors) manufacturing drugs, which are considered direct substitutes to the client s drug. There is, however, no information available on the business models or production capacities of these two companies. Asked about this, the client stated that it expects the competing drug manufacturers would take over the client s market share in the non-use scenario, assuming no capacity constraints. SEAC recognises that there may be a net producer surplus loss to the drug manufacturers in the short term, but in the long run, and since the competitors are located in the EEA, any changes in market structure can be considered to be mainly distributional in nature. Since SEAC does not have the necessary information to conclude on the size and development of producer surpluses, this remains an area of uncertainty. 48

50 SEAC notes that the anti-protozoal drugs provided by the main competitors are based on a different API to P2. The applicant s client did not have specific information on the efficacy of this other API. SEAC also notes that, in case the efficacy of the alternative drugs is different, the non-use scenario may entail an impact on consumer welfare (with the sign of this impact depending on the efficacy of the competing products relative to the client s product). Lastly, SEAC recognises that the competitors would need some time to adapt their production capacities to meet market demand and, in between, a local shortage in anti-protozoal drugs may arise, which could, again, entail a surplus loss to consumers in and outside the EEA. In terms of unemployment impacts in the non-use scenario, the applicant stated in its original application that it would try to assign its workers to other departments and/or tasks linked to other products. In its comment on the draft opinion, the applicant stated that, due to recent market developments, it might not be possible to assign workers involved in the P2 production process to other departments and/or tasks linked to other products. According to the applicant, at least 5 to 10 employees would lose their job as a direct consequence of a refused authorisation. Based on the consultancy report Valuing the social costs of job losses in applications for authorisation 22 and an average social cost of 126,000 per lost job, the applicant calculated the social cost to be between 630,000 (5 job losses) and 1,260,000 (10 job losses). SEAC considers these values as plausible. Potential unemployment impacts related to other actors in the supply chain may be accompanied by new jobs at the competitors sites. To sum up, the current application is a complex case with many unknowns and contingencies. SEAC has tried to grasp the most likely impacts of the non-use scenario and considers it plausible that the applicant would cease the production of P2. SEAC also agrees that this would result in profit losses to the applicant. SEAC recognises that in the non-use scenario the competing supplier of P2 would be in a monopoly position, which may result in deadweight loss entailing negative welfare impacts. In case the competing supplier could not meet the full demand for P2, there would also be profit losses to the applicant s client and the subcontractors of the client. Yet, given that alternative anti-protozoal drugs exist, it seems plausible that large parts of the profit losses to these actors would be distributional from society s point of view. This is also likely to be the case for potential unemployment impacts in the long run. SEAC notes that there may be other costs not considered here, such as costs related to scaling up production for the manufacturers of alternative drugs. However, as no information is available on such costs, SEAC is not able to assess their magnitude. In light of all these uncertainties, the applicant s profit losses of 1.5 to 7.5 million plus the social costs of 630,000 to 1,260,000 related to unemployment are taken forward as benefits of continued use. Summed up, the benefits of continued use are 2.13 to 8.76 million, and hence outweigh the risks (which are zero since adequate control has been shown by the applicant). However, it has to be kept in mind that the benefit figures may not represent the actual welfare losses that would occur in the non-use scenario

51 9. Do you propose additional conditions or monitoring arrangements YES NO Description of conditions and monitoring arrangements for the authorisation before the applicants comments on DO: Should the authorisation be granted: 1. In order to limit the potential exposure and risk, the applicant shall immediately investigate and within the review period implement appropriate risk management measures as follows: a) a closed system for the transfer of diglyme must be installed, which eliminates or minimises the potential for exposure via inhalation and skin. All tasks related to transfer to the reactor, between the reactors, and to storage must be considered. Within the transfer system, fixed piping and connections must be used where possible and dry coupling where fixed piping is not possible; pump(s) designed to minimise emissions to air and exposure via dermal contact must be utilised; b) an appropriately designed LEV system, e.g. capturing hood(s), must be installed to address remaining sources of exposure c) closed sampling must be installed; 2. The applicant shall implement programmes of occupational exposure measurements (for inhalation exposure, and, if possible, for dermal exposure) for all the activities with potential for worker exposure, at least once per year. The results shall be used to review the applied RMMs. These monitoring programmes shall be based on relevant standard methodologies or protocols and be representative of the range of tasks undertaken in the WCSs and number of workers performing them. The results of the above monitoring, review of RMMs, as well as a report describing the improvements of the RMMs implemented must be included in any subsequent authorisation review report submitted. Justification: Uncertainties have been identified in terms of the methodology used for exposure assessment. The available monitoring dataset for this use is considered by RAC to be small and of only in part covers the described use, whilst the applied measurement methodology is not sufficiently reliable for workers exposure assessment. The proposed monitoring arrangements should address these uncertainties. Furthermore, inhalation and dermal protection during manual, not enclosed transfer operations is based mainly on PPE plus an LEV system of questionable design. The recently initiated efforts of the applicant to store recycled diglyme into bulk containers 23 and to investigate with their supplier whether fresh diglyme could be delivered in bulk containers too, may be a step in the right direction, however a design of the transfer system allowing for minimal manual interventions during transfers needs to be considered. The applicant needs to ensure proper control and reduction of exposure from further high exposure 23 Introduced by the applicant in October

52 potential sources during transfer tasks, such as unloading of recycled diglyme back to the storage containers, loading of reagents to diglyme-containing reactors, the need to disconnect, transport, and connect the same flexible pipe for various transfers, including between the reactors, as well as emissions from the pump. Description of conditions and monitoring arrangements for the authorisation after the applicant s comments on the draft opinion: 1. In order to further limit the potential for exposure, the applicant shall implement within 2 years appropriate risk management measures as follows: a) for the transfer of diglyme, i) a system must be implemented which minimises the potential for dermal and inhalation exposure; the system must prevent, to the extent possible, the possibility of contact with contaminated outer surfaces of dippipes used to drain containers and / or drums by, preferably, implementation of a technique not requiring removal of once immersed pipes; ii) pump(s) designed to minimise emissions to air and exposure via dermal contact must also be utilised; iii) sources of further diglyme emissions (including during the addition of reducing agent) and potential dermal exposure need to be identified and addressed by sufficiently closed systems / tight connections; b) closed sampling must be installed; c) the areas where diglyme is not handled directly must be kept free from contamination by implementing adequate housekeeping / cleaning procedures and practices. 2. The applicant shall continue programmes of occupational exposure measurements (for inhalation exposure, and, if possible, for dermal exposure) for all the activities with potential for worker exposure, at least once per year. The results shall be used to review the applied RMMs and OCs. 3. The applicant must implement a regular measurement programme (for example wipe testing of contaminated surfaces) ensuring that general housekeeping and work practices are observed. The above monitoring programmes shall be based on relevant standard methodologies or protocols and be representative of the range of tasks undertaken in the WCSs and number of workers performing them. Their results, review of RMMs, as well as a report describing the improvements of the RMMs implemented must be available to the national enforcement authorities on request and be included in any subsequent authorisation review report submitted. 10. Proposed review period: Normal (7 years) Long (12 years) Short (. _years) Other: None Justification: 51

53 RAC s advice Taking into account the identified uncertainties (Section 4 and 5), and in case that authorisation would be recommended by SEAC, RAC recommends a shorter review period in addition to the conditions above. RAC s advice after the applicants comments on the draft opinion: RAC accepts the amended exposure estimation provided in the comments to the draft opinion, which reflect the newly implemented RMMs, and concludes that the risks are adequately controlled. However, RAC also notes that the exposure estimation is linked with moderate to high uncertainty. Therefore RAC recommends a review period no longer than 7 years. Socio economic considerations SEAC takes note of the following considerations relevant to the review period: RAC confirmed that the risks related to the use have been demonstrated to be adequately controlled. In contrast, there are socio-economic benefits of continued use, although there are some uncertainties regarding the social cost of the expected profit losses in the non-use scenario. SEAC notes that the information provided in the analysis of alternatives was poor and not presented in a detailed and clear manner and that some of the assumptions underlying the original analysis were not outlined by the applicant, making it difficult to follow the applicant s justifications. Nevertheless, the applicant provided some clarifications in the additional information requested by SEAC and during the trialogue. SEAC notes that the analysis of alternatives was poorly described in the application and only limited information was provided on the research and development efforts (including tests) in the application and in response to SEAC s requests. The applicant elaborated further on the feasibility of alternative reducing agents and alternative synthesis routes upon SEAC s request. RAC agrees with the applicant s conclusion that the four alternative solvents shortlisted in the application would not appear to result in a risk reduction for human health (workers and general population via the environment). Alternative reducing agents or synthesis routes could allow reaction without Diglyme or solvents with similar hazards, but these are associated with economical or other challenges. SEAC agrees with the applicant s conclusion that there are no suitable alternative solvents, reducing agents or synthesis routes available before the sunset date. No comments were provided in the public consultation. Taking into account the specific regulatory requirements for APIs under national medicines legislation where the product is sold and the steps required for development and implementation of any alternatives, the applicant estimates that it will take at least 11 years until a yet unknown alternative solvent or synthesis route could be implemented, which is considered as plausible by SEAC. As a toll manufacturer, there is limited opportunity for the applicant to alter the production process without the consent of its client. Nevertheless, there is only one other company supplying the API, meaning that it may be in the client s interest to support the applicant. 52

54 While one criterion for a long review period can be regarded as fulfilled (the possible alternatives would require specific legislative measures in order to ensure safe use), one criterion for a short review period can also be regarded as fulfilled (the Analysis of Alternatives is not thorough enough in demonstrating that no suitable alternatives will become available during the normal period or the applicant has not made an effort to demonstrate why potential alternatives on the market would not be suitable and available for him). Taking all the arguments into account, SEAC recommends a seven-year review period. 11. Did the applicant provide comments to the draft final opinion? YES NO 11a. Action/s taken resulting from the analysis of the applicant s comments: YES NO NOT APPLICABLE Justification: Reasons for introducing the changes RAC has amended the opinion because of the clarifications received from the applicant, and to take into account information on the effect of the RMMs gradually introduced up to the time of the preparation of this opinion since the submission of the application. The re-evaluation of the dermal and or inhalation exposure as well of the newly implemented RMMs was performed by RAC. In more details, RAC took into account the comments made by the applicant in relation to the text of the draft opinion and implemented the proposed changes in most cases. RAC also considered the information provided in relation to the WCS 1 description with the RMMs implemented since the application has been submitted. The implementation of these RMMs results in the lower exposure potential and duration and therefore affects the exposure level and the risk characterisation. RAC has analysed the information provided and updated the analysis presented in Sections 4, 5, 6 and the resulting conditions and recommendations in sections 9 and 10. For WCS 3, RAC has taken into account the updated evaluation of dermal exposure potential performed by the applicant along the lines of the RAC conclusions presented in the draft opinion. Resulting RCR for this WCS is <1. RAC noted that the new RCRs calculated mean that adequate control has been demonstrated by the applicant. As explained in section 8, RAC had concluded in the draft opinion that adequate control had not been demonstrated for workers exposure to diglyme. This meant that the applicant had to follow the socio-economic route and demonstrate that benefits of continued use outweigh the risks. In its evaluation of the socio-economic analysis, SEAC had identified several uncertainties with regard to both the benefits and risks associated with the 53

55 applicant s continued use of diglyme. These had been described in the draft opinion. In addition, uncertainties with regard to the analysis of alternatives had been raised since the analysis had not been considered comprehensive and thorough by SEAC. In its comments on the draft opinion, the applicant provided some clarifying and editorial comments on the analysis of alternatives which resulted in a few editorial changes in section 7.1 of this opinion. In relation to the socio-economic analysis, the applicant provided additional quantified information on the expected consumer welfare losses, based on the assumption of a 3 month drug shortage as a result of a refused authorisation and the related QALY loss. The applicant also stated that recent developments meant that there would be additional social costs of unemployment. SEAC considers it plausible that, given the (partly confidential) information provided, it might not be possible to assign workers involved in the P2 production process to other departments and/or tasks linked to other products. The social cost of the expected minimum number of job losses was quantified based on SEAC s approach for valuing the social costs of job losses in applications for authorisation and added to section 8 of this opinion. Furthermore, the applicant provided a scenario analysis of what the cost of continued use could be, based on different scenarios of excess cases of birth defects and infertility. Importantly, based on the applicant s comments, RAC concluded that adequate control is now demonstrated. As such, the applicant no longer needs to demonstrate that the socio-economic benefits of continued use outweigh the risks. Therefore, the break-even analysis and the evaluation of the costs of continued use, which were included in the draft opinion, are no longer outlined in this opinion. In the draft opinion SEAC had not seen grounds to recommend a review period, however further considerations for the proposed review period had been outlined in an Annex to the draft opinion. Since RAC has concluded that risks have been demonstrated to be adequately controlled, SEAC has removed the respective Annex and has amended section 10, which now outlines the considerations for the recommended review period. Changes made to the opinion OR Reasons for not amending the opinion Following the analysis of the information provided, RAC has made changes in Sections 4, 5, 6, and the resulting conditions and recommendations in sections 9 and 10. The major changes are presented in the opinion in text boxes. SEAC made a few editorial changes in section 7.1, removed the break-even analysis and the evaluation of the costs of continued use in section 8, and amended section

56 Annex I. Figures Assessment prior to comments on draft opinion Figure 1: Measurement of air concentration during loading of diglyme to reactor by using a MiniRAE 3000 Device (WCS1) Assessment after comments on draft opinion Figure 2: Connection to the drum for loading of virgin diglyme to the reactor, including the connection for LEV 55

57 Figure 3: Connection to the container for loading of recycled diglyme to the reactor, including the connection for nitrogen purging 56