public chemical safety report - europa

PUBLIC

CHEMICAL SAFETY REPORT

Legal name of applicant(s): Life Technologies AS

Submitted by: Life Technologies AS

Substance: Diglyme: Bis(2-methoxyethyl)ether (EC Number 203-924-4; CAS Number 111-96-6)

Use title: Use of diglyme as a process chemical in the manufacture of

Dynabeads®

Use number: 1


Life Technologies AS

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9.0 EXPOSURE ASSESSMENT (AND RELATED RISK CHARACTERISATION) 9.0.1 Description of the use There are 14 different intermediate products that use diglyme in the production process (coded as A to N processes in the Analysis of Alternatives) in Lillestrøm. The production of Dynabeads occurs in several steps: preparation of porous polystyrene particles, precipitation of iron oxide in pores, coating, purifications and, for a part of the portfolio, functionalization and conjugation. Diglyme has a critical role in the coating, purification and functionalization steps of Dynabeads manufacture. Note that purification is performed after each step, but diglyme is not used in all purification processes. Most of the beads require diglyme during coating reactions and some are purified with diglyme after the reaction. Diglyme is also used in the reaction for a few functionalization processes. Not every intermediate product uses diglyme in each of these steps, however. Figure 2: Schematic diagram of production process M

A marginal amount of diglyme is used, in addition, in two manufacturing processes at the Lillestrøm facility, conducted only once every 2 to 3 years (processes P and Q). Three of the 14 intermediate products are transported to Oslo for post-production operations suspended in diglyme; solvent exchange to replace diglyme with other solvent takes place in Oslo prior to conjugation. Conjugation of the beads at the Oslo facility does not involve diglyme. Whilst the intermediate products differ in size, and/or chemistry of the coating, functionalization or conjugation, they also might be sold into different markets in different forms. The production procedure itself is, however, very similar across the intermediate products. Separate sub-



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scenarios were created for each intermediate product as well as for auxiliary activities such as raw material handling, cleaning and maintenance as noted below. Lillestrøm facility:

• SS1- WCS1 – WCS2: Raw material handling - Lillestrøm • SS2- WCS1 – WCS5: DP1 facility Production process I • SS3- WCS1 – WCS4: DP1 facility Production process J-K3 • SS4- WCS1 – WCS6: DP1 facility Production process L • SS5- WCS1 – WCS4: DP3 facility Production process O • SS6- WCS1 – WCS3: DP3 facility Production process G • SS7- WCS1 – WCS6: DP3 facility Production process H • SS8- WCS1 – WCS11: DP1 facility Production process B • SS9- WCS1 – WCS5: DP1 facility Production process E • SS10- WCS1 – WCS5: DP1 facility Production process A • SS11- WCS1 – WCS10: DP1 facility Production process C • SS12- WCS1 – WCS8: DP1 facility Production process F • SS13- WCS1 – WCS8: DP1 facility Production process M • SS14- WCS1 – WCS6: DP3 facility Production process N • SS15- WCS1: Cleaning - Lillestrøm • SS16- WCS1: Maintenance - Lillestrøm

Oslo facility:

• SS17- WCS1 – WCS3: Diglyme removal Oslo • SS18- WCS1: Maintenance Oslo

An environmental contributing scenario has been included for each facility to estimate exposure to man via the environment. The exposure scenario described hereafter addresses all of the industrial activities associated with the use of diglyme by LT in the production of Dynabeads. In chapter 10, as the production of some of the intermediate products takes more than one day, the processes that take place on the same day are grouped into blocks. Each of these blocks represents the risk associated with an 8-hour shift.

3 J and K are the same process; only a portion of the amount is sent to Oslo for further treatment (K).


Life Technologies AS 13

9.0.2 Environment Scope and type of assessment: All potential emission sources, pathways and life cycle steps have been identified and evaluated. All waste generated during the production processes is disposed of by incineration off-site via a licensed hazardous waste contractor. All waste water resulting from cleaning and maintenance procedures is also handled by a licensed hazardous waste contractor, except a 0.1 kg discharge of diglyme in cleaning waste water six times per year, which is sent to the neighbouring waste water treatment facility. This quantity is estimated from professional observation of the volume the operators were unable to discharge from reactor after draining. The volume of the primary settler is 10,000-20,000 m3, the concentration of diglyme before treatment is, therefore, diluted to 0.01 g/m3 (taking into account the lower end of the range); considering the elimination via the treatment and diglyme’s degradability, the concentration in the effluent is, therefore, considered negligible. The only significant release to the environment is expected via untreated exhaust gas. The exposure modelling for man via environment using ESVOC SpERC 1.1.v1 revealed RCRs well below 1. There is no environmental emission limit specific to diglyme and, therefore, no air emissions monitoring is conducted. To ensure the release to the environment is assessed robustly, in addition to the exposure modelling performed based on Easy TRA v4.0, a further estimation based on site-specific information and the vapour pressure of diglyme has been conducted and documented in Appendix 4. Diglyme is toxic to reproduction and, therefore, the main focus is the assessment and demonstration of safe use of the substance in relation to human health with respect to these Annex XIV properties. Therefore, a detailed assessment and quantification of risks to the environment was not performed. The importance of environmental assessment lies with the predicted environmental concentrations to assess exposure of man via the environment. 9.0.3 Man via Environment Scope and type of assessment:

Table 1: Type of risk characterisation required for man via environment

Route Type of effect Type of risk characterisation Hazard conclusion

Oral Systemic Long Term Quantitative 0.09 mg/kg bw /day

Inhalation Systemic Long Term Quantitative 0.30 mg/m3 Assessment of exposure to man via the environment using ESVOC SpERC 1.1.v1, considering 34 tonnes per year of diglyme, resulted in RCRs well below 1. All the potential exposure routes to humans via the environment (consumption of food (fish, crops, meat and milk) and drinking water, inhalation of air and ingestion of soil) have been summed up in regional and local total human doses via the environment of the substance. These values are compared with the DNEL.



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9.0.4 Workers Scope and type of assessment: In this exposure scenario, the occupational exposure estimation was conducted based on specific information on the processes, activities, operations, their duration and frequency, and the RMMs implemented for safe use. The most likely route of worker exposure to diglyme is through inhalation and/or dermal contact. To complement the modelling result, personal air monitoring has been conducted. Further information addressing the dermal risk is summarized in Appendix 4. Comments on assessment approach related to toxicological hazard: Diglyme is included on Annex XIV due to its inherent hazard to cause reproductive toxicity (Repr. 1B – H360FD). Reference DNELs published by ECHA for workers via the relevant exposure routes are summarized in Table 2.

Table 2: Type of risk characterisation required for workers

Route Type of effect Type of risk characterisation Hazard conclusion

Inhalation

Systemic Long Term Quantitative 1.68 mg/m³

Dermal Systemic Long Term Quantitative 0.24 mg/kg bw/day

No biomonitoring has been conducted at LT. Diglyme is readily excreted via the urine (86 – 90%).4 A standard biomonitoring method is currently not available. Comments on assessment approach related to physicochemical hazard: Diglyme is further classified as Flammable Liquid cat. 3 – H226 in Annex VI of Regulation (EC) No 1272/2008 (Classification, Labelling, and Packaging (CLP) regulation). The general approach aims to reduce/avoid contact or incidents with the substance. Prevention: Keep away from heat, hot surfaces, sparks, open flames and other ignition sources. No smoking. Keep container tightly closed. Ground and bond container and receiving equipment. Use explosion-proof [electrical/ventilating/lighting/] equipment. Use non-sparking tools. Take action to prevent static discharges. Wear protective gloves/protective clothing/eye protection/face protection. Disposal: Dispose of contents/container to burn in a chemical incinerator equipped with an afterburner and scrubber but exert extra care in igniting as this material is highly flammable. Offer surplus and non-recyclable solutions to a licensed disposal company. Dispose 4 Within 96 hours, approximately 86-90% of administered dose is excreted (GBK, 2010). Glycol ethers are readily distributed throughout the body and eliminated via urine. Significant accumulation does not occur (ECHA, 2011) https://echa.europa.eu/documents/10162/13579/rac_33_reference_dnels_diglyme_en.pdf.



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contaminated packaging as unused product. Response: IF ON SKIN (or hair): Take off immediately all contaminated clothing. Rinse skin with water [or shower]. In case of fire: Stop leak if safe to do so. Storage: Store in a well-ventilated place. Keep cool. Taking into consideration the precautionary statements all uses of the substance for all users can be considered safe. 9.0.5 Consumers Scope and type of assessment: Any residual reactants or solvents (including diglyme) may negatively affect the results of assays performed with the beads. Therefore, purification and drying steps have been implemented to keep residual levels of reactants and solvents on the beads very low. An analytical review showed that residual diglyme is below 0.1% in the final beads. Hence, no exposure to the general population or professionals running the IVD assays or immunodiagnostic assays in research and development (R&D) activities is anticipated, negating the assessment of consumer/professional use or the service-life life cycle step from the scope of this CSR.



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In the following sections, the exposure scenario for the industrial use of diglyme is presented. Table 3: Overview of exposure scenarios

ES # Use title

Contributing exposure scenarios

Tonnage

(tonnes per

year)

Life Cycle Stage(s) Applicable use descriptors

Man

ufac

ture

Form

ulat

ion

Use

at i

ndus

tria

l si

te

Use

by

prof

essi

onal

w

orke

rs

Con

sum

er u

se

Art

icle

serv

ice

life SU PC PROC AC ERC or

spERC

ES1 Use of diglyme as a process chemical in the manufacture of Dynabeads 34 X SU 05

ESVOC SpERC 1.1.v1 based on ERC4

ES1-SS1-16

Lillestrøm facility (Raw material handling, Production processes A-Q, Cleaning, Maintenance)

PROC 2 PROC 3 PROC 4 PROC 5 PROC 8a PROC 8b PROC 9

ES1-SS17-18

Oslo facility (Diglyme removal, Maintenance)

PROC 3 PROC 8a PROC 8b PROC 9

5 SU 0: Other – Magnetic beads are used exclusively in IVD Medical Devices and for Scientific Research and Development (SRD), primarily academic, clinical and medical research.



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9.1. EXPOSURE SCENARIO AND RISK CHARACTERISATION: LILLESTRØM FACILITY

This chapter presents the outcomes of both the exposure assessment and risk characterisation of the industrial use of diglyme as a process chemical in the manufacture of Dynabeads.

Diglyme is used at two sites producing magnetic beads: Lillestrøm and Oslo (Norway).

Estimated and measured occupational exposures to diglyme at each site (i.e., magnetic beads-specific data from estimated modelling and occupational hygiene data from personal/static monitoring) is detailed in this chapter. It provides comprehensive details on the exposure and risk characterisation for each process. Combined exposures and risk characterisations specific to each bead are detailed in chapter 10.

The assessment of exposure to diglyme of workers and man via the environment during the production of Dynabeads is based on exposure modelling using the Easy TRA v4.0 model to determine use-specific exposures. Personal monitoring data is described in Section 9.1.2. 9.1.1 Environmental contributing scenario for Lillestrøm facility – Industrial use of

processing aids in processes and products, not becoming part of articles - Conditions of use and Releases

Operational conditions

Annual site tonnage 33.75 tonne/year

Daily amount used at site 168.75 kg/day

Release times per year 200 days/year

Local freshwater dilution factor 10

Local marine water dilution factor 100

Release fraction to air from process 0.100 %

Release fraction to wastewater from process

1 %

Release fraction to soil from process 0.010 %

Fraction tonnage to region 100 %

Fraction used at main source 100 %

STP Yes

River flow rate 18000 m3/day

Municipal sewage treatment plant discharge

2000000 L/day

Risk management measures SpERC ESVOC SpERC 1.1.v1 - Manufacture of

substances: Industrial (SU8, SU9)



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Table 5: Local releases to the environment

Release Release factor estimation method

Explanation / Justification

Water Release factor

(ESVOC1.1.v1)

Initial release factor: 1% Final release factor: 1% Local release rate: 1.69 kg/day Explanation / Justification: Releases to wastewater assume dry process; emission factors to WW conservatively calculated based on WW volume generated from cleaning tanks, rinsing transfer lines and condensates after fractionation and substance aqueous solubility.

Air Release factor

(ESVOC 1.1.v1)

Initial release factor: 0.1% Final release factor: 0.1% Local release rate: 0.169 kg/day Explanation / Justification: Releases to air before RMM based on Table A1.1; Assumed air RMM efficiency selected based on typical values in CEFIC RMM library for technologies used at large sites.

Soil Release factor

(ESVOC 1.1.v1)

Final release factor: 0.01% Explanation / Justification: Release to soil based on ERC default.

9.1.1.1 Exposure and risks for man via the environment

The exposure concentrations for man via the environment from local contribution are reported in Table 6. Table 6: Exposure concentrations and risks for man via the environment - local

Type of food Estimated daily dose Concentration in food

Drinking water 1.32E-3 mg/kg bw/d 0.046 mg/L

Fish 1.07E-4 mg/kg bw/d 0.065 mg/kg ww

Leaf crops 3.83E-5 mg/kg bw/d 2.24E-3 mg/kg ww

Root crops 2.33E-6 mg/kg bw/d 4.24E-4 mg/kg ww

Meat 9.20E-9 mg/kg bw/d 2.14E-6 mg/kg ww

Milk 1.72E-7 mg/kg bw/d 2.14E-5 mg/kg ww

The exposure concentrations and RCRs for man via the environment from regional contribution are reported in the following table.



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Table 7: Exposure concentrations and risks for the environment

Food source Exposure concentration (EC)

DNEL Risk characterisation ratio = EC/DNEL

MSafe kg/d

Fish 2.48E-8 mg/kgbw/day

0.090 mg/kgbw/day

2.75E-7 -

Root crop 3.67E-9 mg/kgbw/day

4.08E-8 -

Leaf crop 3.95E-9 mg/kgbw/day

4.39E-8 -

Milk 3.84E-11 mg/kgbw/day

4.27E-10 -

Meat 2.06E-12 mg/kgbw/day

2.29E-11 -

Drinking water 3.05E-7 mg/kgbw/day

3.39E-6 -

Inhalation 7.04E-10 mg/kgbw/day

7.83E-9 -

Total 3.39E-7 mg/kgbw/day

3.76E-6 4.49E7

Conclusion on risk characterisation Exposure to man via environment is below the DNELs. Releases to the environment were estimated based on the SpERC, which overestimates the release fractions significantly. This indicates that adverse effects to man via environment are not expected.

9.1.2 Estimated Occupational Exposure Data: Exposure Scenario 1 - Use of Diglyme as a

Process Chemical in the Manufacture of Dynabeads Systematic title based on use descriptor Sector of use: SU 0: Other - Scientific research and development (Magnetic beads are used exclusively in In Vitro Diagnostic Medical Devices (IVD) and for Scientific Research and Development (SRD), primarily academic, clinical and medical research) Environmental Release Category: ERC 4: Industrial use of processing aids in processes and products, not becoming part of articles Process categories: PROC 2: Use in closed, continuous process with occasional controlled exposure PROC 3: Use in closed batch process (synthesis or formulation) PROC 4: Use in batch and other process (synthesis) where opportunity for exposure arises PROC 5: Mixing and blending in batch processes (multistage and/or significant contact)



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PROC 8a: Transfer of chemical from/to vessels/large containers at non dedicated facilities PROC 8b: Transfer of chemical from/to vessels/large containers at dedicated facilities PROC 9: Transfer of chemical into small containers (dedicated filling line) Technical function: 46: Solvents Sub-Scenarios at the Lillestrøm facility Worker contributing scenario(s) SS1- WCS1 – WCS2: Raw material handling WCS1- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Raw material handling - Change of drums (Outdoors) WCS2- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Raw material handling - Change of drums (Indoors) SS2- WCS1 – WCS5: DP1 facility Production process I WCS1- PROC 9 - Transfer of chemicals into small containers (dedicated filling line) - Solvent Transfer - Manual weighing of diglyme WCS2- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Solvent Transfer - Transfer of diglyme into Duran flasks or semi-closed reactor WCS3- PROC 3 - Use in closed batch process (synthesis or formulation) - Solvent Transfer - Suspension is stirred in the reactor and beads are collected via electromagnet WCS4- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Solvent Transfer - Transfer of diglyme/supernatant into waste container via a vacuum pump system WCS5- PROC 9 - Transfer of chemicals into small containers (dedicated filling line) - Storage - Draining finished bead type into containers for storage SS3- WCS1 – WCS4: DP1 facility Production process J-K WCS1- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Solvent Transfer - Transfer of diglyme into Duran flasks WCS2- PROC 3 - Use in closed batch process (synthesis or formulation) - Solvent Transfer - Suspension is stirred in the reactor and beads are collected via electromagnet WCS3- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Solvent Transfer - Transfer of diglyme/supernatant into waste container WCS4- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Solvent Transfer - Draining finished bead type into containers SS4- WCS1 – WCS6: DP1 facility Production process L WCS1- PROC 9 - Transfer of chemicals into small containers (dedicated filling line) - Solvent Transfer - Manual weighing of diglyme WCS2- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Solvent Transfer - Transfer of diglyme into reactor WCS34- PROC 3 - Use in closed batch process (synthesis or formulation) - Solvent Transfer -Suspension is stirred in the reactor and beads are collected via electromagnet WCS4- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Solvent Transfer - Transfer of diglyme/supernatant into waste container WCS5- PROC 3 - Use in closed batch process (synthesis or formulation) - Coating Reaction - Reaction process overnight / DP1/ Production process L (duration of exposure for workers)



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WCS6- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Coating Reaction - Transfer of diglyme/supernatant into waste container SS5- WCS1 – WCS4: DP3 facility Production process O WCS1- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Solvent Transfer - Transfer of diglyme into the reactor WCS2- PROC 3 - Use in closed batch process (synthesis or formulation) - Solvent Transfer - Suspension is stirred in the reactor and beads are collected via electromagnet WCS3- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Solvent Transfer - Transfer of diglyme/supernatant into waste container WCS4- PROC 9 - Transfer of chemicals into small containers (dedicated filling line) - Storage - Draining finished bead type into containers for storage SS6- WCS1 – WCS3: DP3 facility Production process G WCS1- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Coating Reaction - Weighing and transfer of diglyme into the reactor WCS2- PROC 3 - Use in closed batch process (synthesis or formulation) - Coating Reaction - Reaction process overnight / DP3/ Production process G (duration of exposure for workers) WCS3- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Coating Reaction - Transfer of diglyme/supernatant into waste container SS7- WCS1 – WCS6: DP3 facility Production process H WCS1- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Solvent Transfer - Transfer of diglyme into the reactor WCS2- PROC 3 - Use in closed batch process (synthesis or formulation) - Solvent Transfer - Suspension is stirred in the reactor and beads are collected via electromagnet WCS3- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Solvent Transfer - Transfer of diglyme/supernatant into waste container WCS4- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Coating Reaction - Transfer of diglyme into the reactor WCS5- PROC 3 - Use in closed batch process (synthesis or formulation) - Coating Reaction - Reaction process overnight / DP3 / Production process H (duration of exposure for workers) WCS6- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Coating Reaction - Transfer of diglyme/supernatant into waste container SS8- WCS1 – WCS11: DP1 facility Production process B WCS1- PROC 9 - Transfer of chemicals into small containers (dedicated filling line) - Solvent Transfer - Beakers (containing beads and methanol) and funnel rinsed with diglyme from a squirt bottle WCS2- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Solvent Transfer - Transfer of diglyme into the reactor via a membrane pump WCS3- PROC 3 - Use in closed batch process (synthesis or formulation) - Solvent Transfer - Suspension is stirred in the reactor and beads are collected via electromagnet WCS4- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Solvent Transfer - Transfer of diglyme/supernatant into waste container via a vacuum pump system WCS5- PROC 9 - Transfer of chemicals into small containers (dedicated filling line) - Coating Reaction - Beakers (containing reactants) and funnel rinsed with diglyme



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WCS6- PROC 3 - Use in closed batch process (synthesis or formulation) - Coating Reaction - Reaction process overnight / DP1 Production process B (duration of exposure for workers) WCS7- PROC 9 - Transfer of chemicals into small containers (dedicated filling line) - Coating Reaction - Transfer of reactants via a glass-funnel into the reactor (reaction temperature) WCS8- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Purification - Transfer of diglyme via a membrane pump into the reactor WCS9- PROC 3 - Use in closed batch process (synthesis or formulation) - Purification - Suspension is stirred in the reactor and beads are collected via electromagnet WCS10- PROC 3 - Use in closed batch process (synthesis or formulation) - Purification - Purification process WCS11- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Purification - Transfer of diglyme/supernatant into waste container via a vacuum pump system SS9- WCS1 – WCS5: DP1 facility Production process E WCS1- PROC 9 - Transfer of chemicals into small containers (dedicated filling line) - Solvent Transfer - Manual weighing of diglyme and pouring from the beaker into the reactor WCS2- PROC 3 - Use in closed batch process (synthesis or formulation) - Solvent Transfer - Suspension is stirred in the reactor and beads are collected via electromagnet WCS3- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Solvent Transfer - Transfer of diglyme/supernatant into waste container via vacuum pump using a manually inserted teflon tube WCS4- PROC 3 - Use in closed batch process (synthesis or formulation) - Coating Reaction - Reaction process overnight / DP1 Production process E (duration of exposure for workers) WCS5- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Purification - Transfer of first waste (supernatant containing diglyme) into waste container via vacuum pump using a manually inserted teflon tube SS10- WCS1 – WCS5: DP1 facility Production process A WCS1- PROC 9 - Transfer of chemicals into small containers (dedicated filling line) - Solvent Transfer - Manual weighing of diglyme and pouring from the beaker into the reactor WCS2- PROC 3 - Use in closed batch process (synthesis or formulation) - Solvent Transfer - Suspension is stirred in the reactor and beads are collected via electromagnet WCS3- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Solvent Transfer - Transfer of diglyme/supernatant into waste container using a teflon tube; via vacuum pump WCS4- PROC 3 - Use in closed batch process (synthesis or formulation) - Coating Reaction - Reaction process overnight / DP1 Production process A (duration of exposure for workers) WCS5- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Purification - Transfer of first waste (supernatant containing diglyme) into waste container using a teflon tube; via vacuum pump SS11- WCS1 – WCS10: DP1 facility Production process C WCS1- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Solvent Transfer - Transfer of diglyme via a membrane pump into the reactor WCS2- PROC 3 - Use in closed batch process (synthesis or formulation) - Solvent Transfer - Suspension is stirred in the reactor and beads are collected via electromagnet



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WCS3- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Solvent Transfer - Transfer of diglyme/supernatant into waste container WCS4- PROC 9 - Transfer of chemicals into small containers (dedicated filling line) - Coating Reaction - Manual weighing of diglyme WCS5- PROC 9 - Transfer of chemicals into small containers (dedicated filling line) - Coating Reaction - Duran flasks (containing reactants) and funnel rinsed with diglyme WCS6- PROC 3 - Use in closed batch process (synthesis or formulation) - Coating Reaction - Reaction process overnight / DP1/ Production process C (duration of exposure for workers) WCS7- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Purification - Transfer of diglyme/supernatant via a membrane pump into the reactor WCS8- PROC 3 - Use in closed batch process (synthesis or formulation) - Purification - Suspension is stirred in the reactor and beads are collected via electromagnet WCS9- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Purification - Transfer of diglyme/supernatant into waste container via vacuum pump system WCS01- PROC 9 - Transfer of chemicals into small containers (dedicated filling line) - Storage - Transfer of beads and supernatant into glass beakers and Duran flasks SS12- WCS1 – WCS8: DP1 facility Production process F WCS1- PROC 9 - Transfer of chemicals into small containers (dedicated filling line) - Solvent Transfer - Beakers (containing beads), funnel, tubes and pump rinsed with diglyme WCS2- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Solvent Transfer - Transfer of diglyme via a peristaltic pump into the reactor WCS3- PROC 3 - Use in closed batch process (synthesis or formulation) - Solvent Transfer - Suspension is stirred in the reactor and beads are collected via electromagnet WCS4- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Solvent Transfer - Transfer of diglyme/supernatant into waste container via gravity flow WCS5- PROC 9 - Transfer of chemicals into small containers (dedicated filling line) - Coating Reaction and Purification - Beakers and funnel rinsed with diglyme via a squirt bottle WCS6- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Coating Reaction and Purification - Transfer of diglyme via peristaltic pump into the reactor WCS7- PROC 3 - Use in closed batch process (synthesis or formulation) - Coating Reaction and Purification - Reaction and purification processes overnight / DP1 Production process F (duration of exposure for workers) WCS8- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Coating Reaction and Purification - Transfer of diglyme/supernatant into waste container via gravity flow SS13- WCS1 – WCS8: DP1 facility Production process M WCS1- PROC 9 - Transfer of chemicals into small containers (dedicated filling line) - Coating Reaction - Manual weighing of diglyme (filling a flask from filling pistol or from small bottle with cap, manually filling beaker from flask and weighing beaker) WCS2- PROC 4 - Use in batch and other process (synthesis) where opportunity for exposure arises - Coating Reaction - Diglyme suspended beads moved into ultrasonicator WCS3- PROC 5 - Mixing or blending in batch processes (multistage and/or significant contact) - Coating Reaction - Mixing operation (add remaining reactants to suspended beads) WCS4- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities



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- Coating Reaction - Transfer of diglyme into reactor for overnight reaction step WCS5- PROC 3 - Use in closed batch process (synthesis or formulation) - Coating Reaction - Reaction process overnight / DP1/ Production process M (duration of exposure for workers) WCS6- PROC 9 - Transfer of chemicals into small containers (dedicated filling line) - Coating Reaction - Transfer from reactor to beakers for purification process WCS7- PROC 9 - Transfer of chemicals into small containers (dedicated filling line) - Purification - Transfer of diglyme into beakers for the purification process WCS8- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Purification - Pumping-off of diglyme from the purification process SS14- WCS1 – WCS6: DP3 facility Production process N WCS1- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Coating Reaction and Purification - Charging of the reactor using a control-system WCS2- PROC 9 - Transfer of chemicals into small containers (dedicated filling line) - Coating Reaction and Purification - Manual discharge via a valve tube into two safety containers (piped system leading to a valve) WCS3- PROC 9 - Transfer of chemicals into small containers (dedicated filling line) - Coating Reaction and Purification - Safety containers put on a balance, transfer of exact amount into mixing-tank via an air operated diaphragm pump WCS4- PROC 5 - Mixing or blending in batch processes (multistage and/or significant contact) - Coating Reaction and Purification - Mixing operation (after adding dry beads into the mixing-tank) by pumping through a loop on the mixing-tank WCS5- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities - Coating Reaction and Purification - Transfer of the suspended beads in diglyme to the reactor via an operated diaphragm pump WCS6- PROC 2 - Use in closed, continuous process with occasional controlled exposure - Coating Reaction and Purification - Reaction and purification processes overnight / DP3 Production process N (duration of exposure for workers) SS15- WCS1: Cleaning WCS1- PROC 8a - Transfer of chemicals from/to vessels/ large containers at non dedicated facilities - Cleaning of the reactors (across all production processes) SS16- WCS1: Maintenance WCS1- PROC 8a - Transfer of chemicals from/to vessels/ large containers at non dedicated facilities - Cleaning and Maintenance - Periodic/planned and unplanned maintenance 9.1.2.1 Sub-Scenario 1 – Raw Material Handling Lillestrøm Worker contributing scenario 1 – Transfer of chemical from/to vessels/large containers at dedicated facilities (PROC 8b) Conditions of use Name of contributing scenario 8b - Transfer of chemicals from/to vessels/ large

containers at dedicated facilities



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Scenario subtitle Raw material handling - Change of drums (Outdoors)

Qualitative Risk Assessment General Chemical Protective Clothing (CPC): Safety

shoes, protective goggles, protective gloves and protective apron are permanently worn by the operators while handling diglyme.

Product characteristics Physical state liquid

Concentration in substance 100 %

Fugacity / Dustiness low

Frequency and duration of use Duration of activity 5 min/day, duration of activity has been

considered linearly (justification: Duration of activity is up to 5 minutes)

Frequency of use 5 days / week

Human factors not influenced by risk management Exposed skin surface 960 cm2

Other given operational conditions affecting workers exposure Location outdoors (30%)

Domain industrial

Technical conditions and measures to control dispersion and exposure Local exhaust ventilation no

Conditions and measures related to personal protection, hygiene and health evaluation



62

Protective gloves 98 %, breakthrough time: >4 hours (default) (justification: Based on typical values in ESIG-ESVOC RMM library: Wear chemically resistant gloves (tested to EN374) in combination with intensive management supervision controls. Workers wear a combination of two protective gloves: Ansell Barrier #02-100 and Ansell Neoprene #25-101. Ansell Barrier #02-100 is a 5 Layer-Laminated Material 2.5mil, 380-410mm length. This type of glove has a breakthrough time of >480 minutes, determined specifically with diglyme, following standard EN374, and has the highest rating a glove can achieve under this standard. In addition, Ansell Neoprene #25-101 is used as an overglove for enhanced tactility. Safety shoes, protective goggles and protective aprons are required to be worn by the workers while handing diglyme. Workers receive task specific training on how to use personal protective equipment (PPE). To ensure correct use of PPE, intensive management supervision controls are implemented, i.e. correct use of PPE is supervised regularly and the fit, storage, cleaning, and maintenance of PPE is inspected by management at regular intervals.

Respiratory protection 95 % Use of suitable Full Face respirator against dust (type P2) and organic vapours (type A2) or equivalent suitable respirator is required for handling of the raw material during routine working shifts where exposure to diglyme is possible.

Use of drum pump (with closed container lids)

dermal: 80 % (justification: Based on typical values in ESIG-ESVOC RMM library: Use of drum pump (with closed container lids))


inhalation: 80 % (justification: Based on typical values in ESIG-ESVOC RMM library: Use of drum pump (with closed container lids))

Exposure and risks for workers The exposure concentrations and RCRs are reported in the following table. Table 8: Exposure concentrations and risks for workers

Route Exposure concentration (EC)


dermal, long-term systemic 0.000571 mg/kgbw/day

0.240 mg/kgbw/day 0.002381



63



inhalation, long-term systemic 0.002038 mg/m3 1.68 mg/m3 0.001213

Combined routes 0.000863 mg/kgbw/day

- 0.003594

Conclusion on risk characterisation Exposure by the inhalation and dermal routes is below the DNELs. This indicates that adverse effects due to long-term inhalation and dermal exposure are not expected.

Worker contributing scenario 2 – Transfer of chemical from/to vessels/large containers at dedicated facilities (PROC 8b) Conditions of use Name of contributing scenario 8b - Transfer of chemicals from/to vessels/ large


Scenario subtitle Raw material handling - Change of drums (Indoors)


shoes, protective goggles, protective gloves and protective apron are permanently worn by the operators while handling diglyme. Drums placed in vessels for security reasons








Other given operational conditions affecting workers exposure Location indoors

Domain industrial

Technical conditions and measures to control dispersion and exposure



64

Local exhaust ventilation no

Conditions and measures related to personal protection, hygiene and health evaluation Protective gloves 98 %, breakthrough time breakthrough time: >4

hours (default) (justification: Based on typical values in ESIG-ESVOC RMM library: Wear chemically resistant gloves (tested to EN374) in combination with intensive management supervision controls. Workers wear a combination of two protective gloves: Ansell Barrier #02-100 and Ansell Neoprene #25-101. Ansell Barrier #02-100 is a 5 Layer-Laminated Material 2.5mil, 380-410mm length. This type of glove has a breakthrough time of >480 minutes, determined specifically with diglyme, following standard EN374, and has the highest rating a glove can achieve under this standard. In addition, Ansell Neoprene #25-101 is used as an overglove for enhanced tactility. Safety shoes, protective goggles and protective aprons are required to be worn by the workers while handing diglyme. Workers receive task specific training on how to use personal protective equipment (PPE). To ensure correct use of PPE, intensive management supervision controls are implemented, i.e. correct use of PPE is supervised regularly and the fit, storage, cleaning, and maintenance of PPE is inspected by management at regular intervals.



dermal: 80 % (justification: Based on typical values in ESIG-ESVOC RMM library: Use of drum pump (with closed container lids))


inhalation: 80 % (justification: Based on typical values in ESIG-ESVOC RMM library: Use of drum pump (with closed container lids))

Exposure and risks for workers The exposure concentrations and RCRs are reported in the following table.



65

Table 9: Exposure concentrations and risks for workers




0.240 mg/kgbw/day 0.002381



- 0.004114


9.1.2.2 Sub-Scenario 2 – DP1 Facility Production Process I

Worker contributing scenario 1 – Transfer of chemicals into small containers (dedicated filling line) (PROC 9) Conditions of use Name of contributing scenario 9 - Transfer of chemicals into small containers

(dedicated filling line)

Scenario subtitle Solvent Transfer - Manual weighing of diglyme










Other given operational conditions affecting workers exposure



66

Location indoors

Domain industrial


Conditions and measures related to personal protection, hygiene and health evaluation Protective gloves 98 %, breakthrough time: >4 hours (default)

(justification: Based on typical values in ESIG-ESVOC RMM library: Wear chemically resistant gloves (tested to EN374) in combination with intensive management supervision controls. Workers wear a combination of two protective gloves: Ansell Barrier #02-100 and Ansell Neoprene #25-101. Ansell Barrier #02-100 is a 5 Layer-Laminated Material 2.5mil, 380-410mm length. This type of glove has a breakthrough time of >480 minutes, determined specifically with diglyme, following standard EN374, and has the highest rating a glove can achieve under this standard. In addition, Ansell Neoprene #25-101 is used as an overglove for enhanced tactility. Safety shoes, protective goggles and protective aprons are required to be worn by the workers while handing diglyme. Workers receive task specific training on how to use personal protective equipment (PPE). To ensure correct use of PPE, intensive management supervision controls are implemented, i.e. correct use of PPE is supervised regularly and the fit, storage, cleaning, and maintenance of PPE is inspected by management at regular intervals.


Ventilation control: cabinet inhalation: 80 % (justification: Based on typical values in CEFIC RMM library: Ventilation control: cabinet)




67





0.240 mg/kgbw/day 0.02381



- 0.030742

Conclusion on risk characterisation Exposure by inhalation and dermal is below the DNELs. This indicates that adverse effects due to long-term inhalation and dermal exposure are not expected.

Worker contributing scenario 2 – Transfer of chemicals from/to vessels/ large containers at dedicated facilities (PROC 8b) Conditions of use Name of contributing scenario 8b - Transfer of chemicals from/to vessels/ large


Scenario subtitle Solvent Transfer - Transfer of diglyme into Duran flasks or semi-closed reactor













68

Domain industrial









69





0.240 mg/kgbw/day 0.071429



- 0.081827

Conclusion on risk characterisation Exposure by the inhalation and dermal routes is below the DNELs. This indicates that adverse effects due to long-term inhalation and dermal exposure are not expected. Worker contributing scenario 3 – Use in closed batch process (synthesis or formulation) (PROC 3) Conditions of use Name of contributing scenario 3 - Use in closed batch process (synthesis or

formulation)

Scenario subtitle Solvent Transfer - Suspension is stirred in the reactor and beads are collected via electromagnet






Frequency and duration of use Duration of activity 1 - 4 hours




Domain industrial




70










0.240 mg/kgbw/day 0.057143



71





- 0.11704

Conclusion on risk characterisation Exposure by the inhalation and dermal routes is below the DNELs. This indicates that adverse effects due to long-term inhalation and dermal exposure are not expected. Worker contributing scenario 4 – Transfer of chemicals from/to vessels/ large containers at dedicated facilities (PROC 8b) Conditions of use Name of contributing scenario 8b - Transfer of chemicals from/to vessels/ large


Scenario subtitle Solvent Transfer - Transfer of diglyme/supernatant into waste container via a vacuum pump system











Domain industrial




72









0.240 mg/kgbw/day 0.071429




73




- 0.081827




Scenario subtitle Storage - Draining finished bead type into containers for storage



Product characteristics Physical state Liquid


Fugacity / Dustiness Low





Other given operational conditions affecting workers exposure Location Indoors

Domain Industrial

Technical conditions and measures to control dispersion and exposure Local exhaust ventilation No



74









0.240 mg/kgbw/day 0.005952




75




- 0.007686


9.1.2.3 Sub-Scenario 3 -- SS3- WCS8 – WCS11: DP1 Facility Production Process J-K Worker contributing scenario 1 – Transfer of chemicals from/to vessels/ large containers at dedicated facilities (PROC 8b) Conditions of use Name of contributing scenario 8b - Transfer of chemicals from/to vessels/ large


Scenario subtitle Solvent Transfer - Transfer of diglyme into Duran flasks











Domain Industrial




76

Local exhaust ventilation No




Ventilation control: fume cupboard inhalation: 80 % (justification: Based on typical values in CEFIC RMM library: Ventilation control: fume cupboard)





0.240 mg/kgbw/day 0.071429



77





- 0.081827


Worker contributing scenario 2 – Use in closed batch process (synthesis or formulation) (PROC 3) Conditions of use Name of contributing scenario 3 - Use in closed batch process (synthesis or

formulation)












Domain industrial




78










0.240 mg/kgbw/day 0.021429



79





- 0.058864




Scenario subtitle Solvent Transfer - Transfer of diglyme/supernatant into waste container











Domain industrial




80










0.240 mg/kgbw/day 0.071429



81





- 0.081827




Scenario subtitle Solvent Transfer - Draining finished bead type into containers











Domain industrial




82



(justification: Based on typical values in ESIG-ESVOC RMM library: Wear chemically resistant gloves (tested to EN374) in combination with intensive management supervision controls. Workers wear a combination of two protective gloves: Ansell Barrier #02-100 and Ansell Neoprene #25-101. Ansell Barrier #02-100 is a 5 Layer-Laminated Material 2.5mil, 380-410mm length. This type of glove has a breakthrough time of >480 minutes, determined specifically with diglyme, following standard EN374, and has the highest rating a glove can achieve under this standard. In addition, Ansell Neoprene #25-101 is used as an overglove for enhanced tactility. Safety shoes, protective goggles and protective aprons are required to be worn by the workers while handing diglyme. Workers receive task specific training on how to use personal protective equipment (PPE). To ensure correct use of PPE, intensive management supervision controls are implemented, i.e. correct use of PPE is supervised regularly and the fit, storage, cleaning, and maintenance of PPE is inspected by management at regular intervals.)







0.240 mg/kgbw/day 0.011905



83





- 0.013638

Conclusion on risk characterisation Exposure by the inhalation and dermal routes is below the DNELs. This indicates that adverse effects due to long-term inhalation and dermal exposure are not expected. 9.1.2.4 Sub-Scenario 4 – SS4- WCS12 – WCS17: DP1 Facility Production Process L Worker contributing scenario 1 – Transfer of chemicals into small containers (dedicated filling line) (PROC 9) Conditions of use Name of contributing scenario 9 - Transfer of chemicals into small containers


Scenario subtitle Solvent Transfer - Manual weighing of diglyme











Domain industrial




84










0.240 mg/kgbw/day 0.02381



85





- 0.030742



Scenario subtitle Solvent Transfer - Transfer of diglyme into reactor











Domain industrial




86










0.240 mg/kgbw/day 0.071429



87





- 0.081827


formulation)

Scenario subtitle Solvent Transfer -Suspension is stirred in the reactor and beads are collected via electromagnet







considered linearly (justification: The maximum duration for this process is 120 minutes)




Domain industrial




88










0.240 mg/kgbw/day 0.014286



89





- 0.039243














Domain Industrial




90










0.240 mg/kgbw/day 0.071429



91





- 0.081827


formulation)

Scenario subtitle Coating Reaction - Reaction process overnight / DP1/ Production process L (duration of exposure for workers)






Frequency and duration of use Duration of activity 15 mins to 1 hour




Domain Industrial




92










0.240 mg/kgbw/day 0.057143



93





- 0.077109



Scenario subtitle Coating Reaction - Transfer of diglyme/supernatant into waste container











Domain Industrial




94










0.240 mg/kgbw/day 0.071429



95





- 0.081827


9.1.2.5 Sub-Scenario 5 – SS5- WCS18 – WCS21: DP3 facility Production process O



Scenario subtitle Solvent Transfer - Transfer of diglyme into the reactor













96

Ventilation enhanced (70%)

Domain Industrial





Use in semi-automated and enclosed filling lines

dermal: 95 % (justification: Based on ESIG-ESVOC RMM library: Use in semi-automated and enclosed filling lines, into a closed-reactor)


inhalation: 95 % (justification: Based on ESIG-ESVOC RMM library: Use in semi-automated and enclosed filling lines, into a closed-reactor)




97





0.240 mg/kgbw/day 0.007143



- 0.008703


formulation)














98


Domain Industrial





Ventilation control: closed-reactor sealed and connected to an exhaust system

inhalation: 80 % (justification: Ventilation control: closed-reactor sealed and connected to an exhaust system)




99





0.240 mg/kgbw/day 0.021429



- 0.032659
















100

Location Indoors


Domain Industrial











101





0.240 mg/kgbw/day 0.005357



- 0.006527

Conclusion on risk characterisation Exposure by the inhalation and dermal routes is below the DNELs. This indicates that adverse effects due to long-term inhalation and dermal exposure are not expected. Worker contributing scenario 4 – Transfer of chemicals into small containers (dedicated filling line) (PROC 9) Conditions of use Name of contributing scenario 9 - Transfer of chemicals into small containers


Scenario subtitle Storage - Draining finished bead type into containers for storage












102



Domain industrial








103





0.240 mg/kgbw/day 0.011905



- 0.017104


9.1.2.6 Sub-Scenario 6 – SS6- WCS22 – WCS24: DP3 Facility Production Process G Worker contributing scenario 1 – Transfer of chemicals from/to vessels/ large containers at dedicated facilities (PROC 8b) Conditions of use Name of contributing scenario 8b - Transfer of chemicals from/to vessels/ large


Scenario subtitle Coating Reaction - Weighing and transfer of diglyme into the reactor










104





Domain industrial









105







0.240 mg/kgbw/day 0.003571



- 0.004351


formulation)

Scenario subtitle Coating Reaction - Reaction process overnight / DP3 Production process G (duration of exposure for workers)









106





Domain industrial









107





0.240 mg/kgbw/day 0.057143



- 0.063133










Frequency and duration of use Duration of activity less than 15 mins





108



Domain industrial











109





0.240 mg/kgbw/day 0.057143



- 0.058391


9.1.2.7 Sub-Scenario 7 -- SS7- WCS25 – WCS30: DP3 Facility Production Process H Worker contributing scenario 1 – Transfer of chemicals from/to vessels/ large containers at dedicated facilities (PROC 8b) Conditions of use Name of contributing scenario 8b - Transfer of chemicals from/to vessels/ large


Scenario subtitle Solvent Transfer - Transfer of diglyme into the reactor











110




Domain industrial









111







0.240 mg/kgbw/day 0.003571



- 0.004351



formulation)







Frequency and duration of use



112

Duration of activity 90 min/day, duration of activity has been considered linearly (justification: The maximum duration for this process is 90 minutes)





Domain industrial







113







0.240 mg/kgbw/day 0.010714



- 0.01633














114




Domain industrial









115







0.240 mg/kgbw/day 0.057143



- 0.059639




Scenario subtitle Coating Reaction - Transfer of diglyme into the reactor










116




Domain industrial









117







0.240 mg/kgbw/day 0.057143



- 0.058391



formulation)

Scenario subtitle Coating Reaction - Reaction process overnight / DP3 Production process H (duration of exposure for workers)





Process temperature 70 °C

Fugacity / Dustiness medium




118

Duration of activity 15 mins to 1 hour





Domain industrial







119







0.240 mg/kgbw/day 0.011429



- 0.031394














120




Domain industrial









121







0.240 mg/kgbw/day 0.057143



- 0.058391


9.1.2.8 Sub-Scenario 8 -- SS8- WCS31 – WCS41: DP1 Facility Production Process B Worker contributing scenario 1 – Transfer of chemicals into small containers (dedicated filling line) (PROC 9) Conditions of use Name of contributing scenario 9 - Transfer of chemicals into small containers


Scenario subtitle Solvent Transfer - Beakers (containing beads and methanol) and funnel rinsed with diglyme from a squirt bottle








122






Domain industrial

Technical conditions and measures to control dispersion and exposure Local exhaust ventilation yes (inhalation 90 %)






123





0.240 mg/kgbw/day 0.005952



- 0.006819

Conclusion on risk characterisation Exposure by the inhalation and dermal routes is below the DNELs. This indicates that adverse effects due to long-term inhalation and dermal exposures are not expected.



Scenario subtitle Solvent Transfer - Transfer of diglyme into the reactor via a membrane pump











124



Domain industrial








125





0.240 mg/kgbw/day 0.071429



- 0.074028



formulation)











Domain industrial




126

Local exhaust ventilation yes (inhalation 90 %)








0.240 mg/kgbw/day 0.057143



- 0.067126



127



Scenario subtitle Solvent Transfer - Transfer of diglyme/supernatant into waste container via a vacuum pump system











Domain industrial





128







0.240 mg/kgbw/day 0.071429



- 0.074028



129




Scenario subtitle Coating Reaction - Beakers (containing reactants) and funnel rinsed with diglyme











Domain industrial





130








0.240 mg/kgbw/day 0.005952


Combined routes 0.001845 - 0.007686



131



mg/kgbw/day



formulation)

Scenario subtitle Coating Reaction - Reaction process overnight / DP1 Production process B (duration of exposure for workers)











Domain industrial




132




Closed-reactor with corks, combined with ventilation control: fume cupboard

inhalation: 95 % (justification: Closed-reactor with corks, combined with ventilation control: fume cupboard)





0.240 mg/kgbw/day 0.011429




133




- 0.028067




Scenario subtitle Coating Reaction - Transfer of reactants via a glass-funnel into the reactor (reaction temperature)

Qualitative Risk Assessment General Chemical Protection Clothing (CPC): Safety

shoes, protective goggles, protective gloves and protective apron are permanently worn by the operators while handling diglyme










Domain industrial




134










0.240 mg/kgbw/day 0.005952



135





- 0.023284




Scenario subtitle Purification - Transfer of diglyme via a membrane pump into the reactor











Domain industrial



136









0.240 mg/kgbw/day 0.071429




137




- 0.074028



formulation)

Scenario subtitle Purification - Suspension is stirred in the reactor and beads are collected via electromagnet










Domain industrial





138







0.240 mg/kgbw/day 0.057143



- 0.087092



139



formulation)

Scenario subtitle Purification - Purification process











Domain industrial





140



Closed-reactor with corks, combined with local exhaust ventilation

inhalation: 95 % (justification: Closed-reactor with corks, combined with local exhaust ventilation )





0.240 mg/kgbw/day 0.011429





141



mg/kgbw/day



Scenario subtitle Purification - Transfer of diglyme/supernatant into waste container via a vacuum pump system











Domain industrial




142








0.240 mg/kgbw/day 0.071429



- 0.074028



143

Conclusion on risk characterisation Exposure by the inhalation and dermal routes is below the DNELs. This indicates that adverse effects due to long-term inhalation and dermal exposure are not expected. 9.1.2.9 Sub-Scenario 9 -- SS9 - WCS42 – WCS46: DP1 facility Production process E Worker contributing scenario 1 – Transfer of chemicals into small containers (dedicated filling line) (PROC 9) Conditions of use Name of contributing scenario 9 - Transfer of chemicals into small containers


Scenario subtitle Solvent Transfer - Manual weighing of diglyme and pouring from the beaker into the reactor











Domain industrial





144








0.240 mg/kgbw/day 0.011905





145



mg/kgbw/day


Worker contributing scenario 2 – Transfer of chemicals into small containers (dedicated filling line) (PROC 9) Conditions of use Name of contributing scenario 3 - Use in closed batch process (synthesis or

formulation)












Domain industrial





146








0.240 mg/kgbw/day 0.017857





147



mg/kgbw/day




Scenario subtitle Solvent Transfer - Transfer of diglyme/supernatant into waste container via vacuum pump using a manually inserted teflon tube











Domain industrial




148










0.240 mg/kgbw/day 0.047619



149





- 0.054552



formulation)

Scenario subtitle Coating Reaction - Reaction process overnight / DP1 Production process E (duration of exposure for workers)











Domain industrial



150









dermal, long-term systemic 0.002743 0.240 mg/kgbw/day 0.011429



151



mg/kgbw/day



- 0.077981




Scenario subtitle Purification - Transfer of first waste (supernatant containing diglyme) into waste container via vacuum pump using a manually inserted teflon tube













152

Location indoors

Domain industrial









153





0.240 mg/kgbw/day 0.011905



- 0.013638


9.1.2.10 Sub-Scenario 10 -- SS10- WCS47 – WCS51: DP1 facility Production

process A



Scenario subtitle Solvent Transfer - Manual weighing of diglyme and pouring from the beaker into the reactor











154



Domain industrial








155





0.240 mg/kgbw/day 0.005952



- 0.007686



formulation)












156


Domain industrial









157





0.240 mg/kgbw/day 0.057143



- 0.077109




Scenario subtitle Solvent Transfer - Transfer of diglyme/supernatant into waste container using a teflon tube; via vacuum pump












158


Domain industrial









159





0.240 mg/kgbw/day 0.011905



- 0.013638



formulation)

Scenario subtitle Coating Reaction - Reaction process overnight / DP1 Production process A (duration of exposure for workers)













160

Location indoors

Domain industrial









161





0.240 mg/kgbw/day 0.011429



- 0.077981




Scenario subtitle Purification - Transfer of first waste (supernatant containing diglyme) into waste container using a teflon tube; via vacuum pump












162


Domain industrial









163





0.240 mg/kgbw/day 0.011905



- 0.013638


9.1.2.11 Sub-Scenario 11 -- SS11- WCS52 – WCS61: DP1 Facility Production

Process C Worker contributing scenario 1 – Transfer of chemicals from/to vessels/ large containers at dedicated facilities (PROC 8b) Conditions of use Name of contributing scenario 8b - Transfer of chemicals from/to vessels/ large


Scenario subtitle Solvent Transfer - Transfer of diglyme via a membrane pump into the reactor











164



Domain industrial








165





0.240 mg/kgbw/day 0.011905



- 0.012338


Worker contributing scenario 2 – Use in closed batch process (synthesis or formulation) (PROC 3) Conditions of use

Name of contributing scenario 3 - Use in closed batch process (synthesis or formulation)












Domain industrial



166









0.240 mg/kgbw/day 0.019048




167




- 0.035686















Domain industrial




168








0.240 mg/kgbw/day 0.047619



- 0.049352



169




Scenario subtitle Coating Reaction - Manual weighing of diglyme











Domain industrial





170



Ventilation control: two points of ventilation pipes

inhalation: 80 % (justification: Ventilation control: Two points of ventilation pipes (one fixed to the rear of the reactor and one flexible at the top of the reactor))





0.240 mg/kgbw/day 0.005952




171




- 0.007686




Scenario subtitle Coating Reaction - Duran flasks (containing reactants) and funnel rinsed with diglyme











Domain industrial




172




Ventilation control: two points of ventilation pipes

inhalation: 80 % (justification: Ventilation control: Two points of ventilation pipes (one fixed to the rear of the reactor and one flexible at the top of the reactor))





0.240 mg/kgbw/day 0.005952



173





- 0.007686



formulation)

Scenario subtitle Coating Reaction - Reaction process overnight / DP1 Production process C (duration of exposure for workers)






Fugacity / Dustiness high





Domain industrial




174





Closed-reactor with corks, combined with ventilation control: two points of ventilation pipes

inhalation: 95 % (justification: Closed-reactor with corks, combined with ventilation control: two points of ventilation pipes (one fixed to the rear of the reactor and one flexible at the top of the reactor))






175




0.240 mg/kgbw/day 0.011429



- 0.094619




Scenario subtitle Purification - Transfer of diglyme/supernatant via a membrane pump into the reactor











Domain industrial



176









0.240 mg/kgbw/day 0.071429




177




- 0.074028

Conclusion on risk characterisation The exposure by inhalation and dermal routes is below the DNELs. This indicates that the likelihood of adverse effects due to long-term inhalation and dermal exposure is low.


formulation)

Scenario subtitle Purification - Suspension is stirred in the reactor and beads are collected via electromagnet










Domain industrial





178







0.240 mg/kgbw/day 0.057143



- 0.087092



179



Scenario subtitle Purification - Transfer of diglyme/supernatant into waste container via vacuum pump system











Domain industrial





180







0.240 mg/kgbw/day 0.071429



- 0.074028



181

Conclusion on risk characterisation Exposure by the inhalation and dermal routes is below the DNELs. This indicates that adverse effects due to long-term inhalation and dermal exposure are not expected. Worker contributing scenario 10 – Transfer of chemicals into small containers (dedicated filling line) (PROC 9) Conditions of use Name of contributing scenario 9 - Transfer of chemicals into small containers


Scenario subtitle Storage - Transfer of beads and supernatant into glass beakers and Duran flasks











Domain industrial





182







0.240 mg/kgbw/day 0.011905



- 0.013638



183

Conclusion on risk characterisation Exposure by the inhalation and dermal routes is below the DNELs. This indicates that adverse effects due to long-term inhalation and dermal exposure are not expected. 9.1.2.12 Sub-Scenario 12 -- SS12- WCS62 – WCS69: DP1 Facility Production

Process F Worker contributing scenario 1 – Transfer of chemicals into small containers (dedicated filling line) (PROC 9) Conditions of use Name of contributing scenario 9 - Transfer of chemicals into small containers


Scenario subtitle Solvent Transfer - Beakers (containing beads), funnel, tubes and pump rinsed with diglyme











Domain industrial





184








0.240 mg/kgbw/day 0.035714





185



mg/kgbw/day




Scenario subtitle Solvent Transfer - Transfer of diglyme via a peristaltic pump into the reactor











Domain industrial




186


(justification: Based on typical values in ESIG-ESVOC RMM library: Wear chemically resistant gloves (tested to EN374) in combination with intensive management supervision controls. Workers wear a combination of two protective gloves: Ansell Barrier #02-100 and Ansell Neoprene #25-101. Ansell Barrier #02-100 is a 5 Layer-Laminated Material 2.5mil, 380-410mm length. This type of glove has a breakthrough time of >480 minutes, determined specifically with diglyme, following standard EN374, and has the highest rating a glove can achieve under this standard. In addition, Ansell Neoprene #25-101 is used as an overglove for enhanced tactility. Safety shoes, protective goggles and protective aprons are required to be worn by the workers while handing diglyme. Workers receive task specific training on how to use personal protective equipment (PPE). To ensure correct use of PPE, intensive management supervision controls are implemented, i.e. correct use of PPE is supervised regularly and the fit, storage, cleaning, and maintenance of PPE is inspected by management at regular intervals...)







0.240 mg/kgbw/day 0.071429




187




- 0.081827



formulation)












Domain industrial




188










0.240 mg/kgbw/day 0.007143



189





- 0.019621




Scenario subtitle Solvent Transfer - Transfer of diglyme/supernatant into waste container via gravity flow











Domain industrial



190









dermal, long-term systemic 0.017143 0.240 mg/kgbw/day 0.071429



191



mg/kgbw/day



- 0.081827




Scenario subtitle Coating Reaction and Purification - Beakers and funnel rinsed with diglyme via a squirt bottle













192

Domain industrial











193




0.240 mg/kgbw/day 0.005952



- 0.007686




Scenario subtitle Coating Reaction and Purification - Transfer of diglyme via peristaltic pump into the reactor













194

Domain industrial









195





0.240 mg/kgbw/day 0.071429



- 0.081827



formulation)

Scenario subtitle Coating Reaction and Purification - Reaction and purification processes overnight / DP1 Production Process F (duration of exposure for workers)






Fugacity / Dustiness high



Human factors not influenced by risk management



196

Exposed skin surface 240 cm2


Domain industrial





Closed-reactor combined with ventilation control: cabinet; plus condenser leading out into the hood.

inhalation: 98 % (justification: Closed-reactor combined with ventilation control: cabinet; plus condenser leading out into the hood. Any vapours are cooled and condensed back into the reactor. )



197





0.240 mg/kgbw/day 0.011429



- 0.044705




Scenario subtitle Coating Reaction and Purification - Transfer of diglyme/supernatant into waste container via gravity flow












198



Domain industrial









199





0.240 mg/kgbw/day 0.071429



- 0.081827



Process M Worker contributing scenario 1 – Transfer of chemicals into small containers (dedicated filling line) (PROC 9) Conditions of use Name of contributing scenario 9 - Transfer of chemicals into small containers


Scenario subtitle Coating Reaction - Manual weighing of diglyme (filling a flask from filling pistol or from small bottle with cap, manually filling beaker from flask and weighing beaker)


shoes, protective goggles, protective gloves and protective apron are permanently worn by the operators while handling diglyme Air exchanges per hour: The ventilation capacities, air flows and velocities have been measured in DP1 Production processes M and P, giving total air exchange rates between 25 to 35 air exchanges per hour. The air velocity or flow across open door is 0.5 m/s. As a default parameter, the “enhanced general ventilation” of at least 5-10 air exchanges per hour has been used.




200









Domain industrial






201


Minimise exposure by partial enclosure of the operation or equipment and provide extract ventilation at openings

dermal: 90 % (justification: o Based on typical values in ESIG-ESVOC RMM library: Minimise exposure by partial enclosure of the operation or equipment and provide extract ventilation at openings)


inhalation: 90 % (justification: Based on typical values in ESIG-ESVOC RMM library: Minimise exposure by partial enclosure of the operation or equipment and provide extract ventilation at openings)





0.240 mg/kgbw/day 0.00119



- 0.00171


Worker contributing scenario 2 – Use in batch and other process (synthesis) where opportunity for exposure arises (PROC 4) Conditions of use Name of contributing scenario 4 - Use in batch and other process (synthesis)

where opportunity for exposure arises

Scenario subtitle Coating Reaction - Diglyme suspended beads moved into ultrasonicator



202


shoes, protective goggles, protective gloves and protective apron are permanently worn by the operators while handling diglyme Air exchanges per hour: The ventilation capacities, air flows and velocities have been measured in DP1 Production processes M and P, giving total air exchange rates between 25 to 35 air exchanges per hour. The air velocity or flow across open door is 0.5 m/s. As a default parameter, the “enhanced general ventilation” of at least 5-10 air exchanges per hour has been used.









Domain industrial





203




dermal: 90 % (justification: Based on typical values in ESIG-ESVOC RMM library: Minimise exposure by partial enclosure of the operation or equipment and provide extract ventilation at openings)






204





0.240 mg/kgbw/day 0.057143



- 0.062134


Worker contributing scenario 3 – Mixing or blending in batch processes (multistage and/or significant contact) (PROC 5) Conditions of use Name of contributing scenario 5 - Mixing or blending in batch processes

(multistage and/or significant contact)

Scenario subtitle Coating Reaction - Mixing operation (add remaining reactants to suspended beads)


shoes, protective goggles, protective gloves and protective apron are permanently worn by the operators while handling diglyme Air exchanges per hour: The ventilation capacities, air flows and velocities have been measured in DP1 Production processes M and P, giving a total air exchange rates between 25 to 35 air exchanges per hour. The air velocity or flow across open door is 0.5 m/s. As a default parameter, the “enhanced general ventilation” of at least 5-10 air exchanges per hour has been used.







205

Duration of activity 20 min/day, duration of activity has been considered linearly (justification: Duration of activity is up to 20 minutes)





Domain industrial






206










0.240 mg/kgbw/day 0.004762



- 0.005802




Scenario subtitle Coating Reaction - Transfer of diglyme into reactor for overnight reaction step

Qualitative Risk Assessment



207

General Chemical Protection Clothing (CPC): Safety shoes, protective goggles, protective gloves and protective apron are permanently worn by the operators while handling diglyme Air exchanges per hour: The ventilation capacities, air flows and velocities have been measured in DP1 Production processes M and P, giving a total air exchange rates between 25 to 35 air exchanges per hour. The air velocity or flow across open door is 0.5 m/s. As a default parameter, the “enhanced general ventilation” of at least 5-10 air exchanges per hour has been used.









Domain industrial





208










209





0.240 mg/kgbw/day 0.114286



- 0.119277



formulation)

Scenario subtitle Coating Reaction - Reaction process overnight / DP1 Production process M (duration of exposure for workers)


shoes, protective goggles, protective gloves and protective apron are permanently worn by the operators while handling diglyme. Air exchanges per hour: The ventilation capacities, air flows and velocities have been measured in DP1 Production processes M and P, giving a total air exchange rates between 25 to 35 air exchanges per hour. The air velocity or flow across open door is 0.5 m/s. As a default parameter, the “enhanced general ventilation” of at least 5-10 air exchanges per hour has been used.








210

Duration of activity 15 mins to 1 hour





Domain industrial







211









0.240 mg/kgbw/day 0.001143



- 0.011126




Scenario subtitle Coating Reaction - Transfer from reactor to beakers for purification process




212





Fugacity / Dustiness Medium







Domain Industrial





213










214





0.240 mg/kgbw/day 0.003571



- 0.01917




Scenario subtitle Purification - Transfer of diglyme into beakers for the purification process


shoes, protective goggles, protective gloves and protective apron are permanently worn by the operators while handling diglyme Air exchanges per hour: The ventilation capacities, air flows and velocities have been measured in DP1 Production processes M and P, giving a total air exchange rates between 25 to 35 air exchanges per hour. The air velocity or flow across open door is 0.5 m/s. As a default parameter, the “enhanced general ventilation” of at least 5-10 air exchanges per hour has been used.







215





Domain Industrial







216




inhalation: 90 % (justification: o Based on typical values in ESIG-ESVOC RMM library: Minimise exposure by partial enclosure of the operation or equipment and provide extract ventilation at openings)





0.240 mg/kgbw/day 0.057143



- 0.059639




Scenario subtitle Purification - Pumping-off of diglyme from the purification process




217










Domain Industrial





218






inhalation: 90 % (justification: o Based on typical values in ESIG-ESVOC RMM library: Minimise exposure by partial enclosure of the operation or equipment and provide extract ventilation at openings)




219





0.240 mg/kgbw/day 0.114286



- 0.119277



Process N Worker contributing scenario 1 – Transfer of chemicals from/to vessels/ large containers at dedicated facilities (PROC 8b) Conditions of use Name of contributing scenario 8b - Transfer of chemicals from/to vessels/ large


Scenario subtitle Coating Reaction and Purification - Charging of the reactor using a control-system












220




Domain Industrial











221





0.240 mg/kgbw/day 0.003571



- 0.004351




Scenario subtitle Coating Reaction and Purification - Manual discharge via a valve tube into two safety containers (piped system leading to a valve)











222




Domain Industrial








223





0.240 mg/kgbw/day 0.005952



- 0.008552


Worker contributing scenario 3 – Transfer of chemicals into small containers (dedicated filling line) (PROC 9) Conditions of use Exposure and risks for workers Name of contributing scenario 9 - Transfer of chemicals into small containers


Scenario subtitle Coating Reaction and Purification - Safety containers put on a balance, transfer of exact amount into mixing-tank via an air operated diaphragm pump












224




Domain Industrial





Ventilation control: reactors connected to a ventilation cane system

inhalation: 80 % (justification: Ventilation control: reactors connected to a ventilation cane system)

The exposure concentrations and RCRs are reported in the following table.



225





0.240 mg/kgbw/day 0.005952



- 0.006472


Worker contributing scenario 4 – Mixing or blending in batch processes (multistage and/or significant contact) (PROC 5) Conditions of use Name of contributing scenario 5 - Mixing or blending in batch processes

(multistage and/or significant contact)

Scenario subtitle Coating Reaction and Purification - Mixing operation (after adding dry beads into the mixing-tank) by pumping through a loop on the mixing-tank












226




Domain Industrial









227





0.240 mg/kgbw/day 0.047619



- 0.049699




Scenario subtitle Coating Reaction and Purification - Transfer of the suspended beads in diglyme to the reactor via an operated diaphragm pump












228




Domain Industrial








229





0.240 mg/kgbw/day 0.011905



- 0.014504


Worker contributing scenario 6 – Use in closed, continuous process with occasional controlled exposure (PROC 2) Conditions of use Name of contributing scenario 2 - Use in closed, continuous process with

occasional controlled exposure

Scenario subtitle Coating Reaction and Purification - Reaction and purification processes overnight / DP3 Production process N (duration of exposure for workers)


shoes, protective goggles, protective gloves and protective apron are permanently worn by the operators while handling diglyme




Fugacity / Dustiness Medium







230

Location Indoors


Domain Industrial










231





0.240 mg/kgbw/day 0.022857



- 0.03284


9.1.2.15 Sub-Scenario 15 -- SS15- WCS84: Cleaning Lillestrøm Worker contributing scenario 1 –Transfer of chemicals from/to vessels/ large containers at non dedicated facilities (PROC 8a) Conditions of use Name of contributing scenario 8a - Transfer of chemicals from/to vessels/ large

containers at non dedicated facilities

Scenario subtitle Cleaning of the reactors (across all Production processes)




Concentration in substance <1%








232



Domain industrial





Ventilation control inhalation: 70 % (justification: Ventilation control: fume cupboard, extracted booth, cabinet, local exhaust ventilation or enhanced general ventilation)




233





0.240 mg/kgbw/day 0.022857



- 0.072772


9.1.2.16 Sub-Scenario 16 -- SS16- WCS85: Maintenance Lillestrøm Worker contributing scenario 1 –Transfer of chemicals from/to vessels/ large containers at non dedicated facilities (PROC 8a) Conditions of use Name of contributing scenario 8a - Transfer of chemicals from/to vessels/ large


Scenario subtitle Cleaning and Maintenance - Periodic/planned and unplanned maintenance




Concentration in substance 1-5%


Frequency and duration of use Duration of activity >4 hours (default)






234

Domain industrial









235





0.240 mg/kgbw/day 0.228571



- 0.3284

Conclusion on risk characterisation The exposure by inhalation and dermal is below the DNELs. This indicates that the likelihood of adverse effects due to long-term inhalation and dermal exposure is low.



236

9.2 EXPOSURE SCENARIO AND RISK CHARACTERISATION: OSLO FACILITY

9.2.1 Environmental contributing scenario 2 – Industrial use of processing aids in

processes and products, not becoming part of articles - ERC 4 9.2.1.1 Conditions of use and Releases Operational conditions Annual site tonnage 0.250 to/year

Daily amount used at site 1.25 kg/day

Release times per year 200 days/year

Local freshwater dilution factor 10

Local marine water dilution factor 100

Release fraction to air from process 0.100 %

Release fraction to wastewater from process

1 %

Release fraction to soil from process 0.010 %

Fraction tonnage to region 100 %

Fraction used at main source 100 %

STP yes

River flow rate 18000 m3/day

Municipal sewage treatment plant discharge

2000000 L/day

Risk management measures SpERC ESVOC SpERC 1.1.v1 - Manufacture of

substances: Industrial (SU8, SU9)

The local releases to the environment are reported in the following table. Table 93: Local releases to the environment

Release Release factor estimation

method Explanation / Justification

Water Release factor

(ESVOC1.1.v1)

Initial release factor: 1% Final release factor: 1% Local release rate: 0.0125 kg/day Explanation / Justification: Releases to wastewater assume dry process; emission factors to WW conservatively calculated based on WW volume generated from cleaning tanks, rinsing transfer lines and condensates after fractionation and substance



237

Release Release factor estimation method

Explanation / Justification

aqueous solubility. Air Release factor

(ESVOC 1.1.v1)

Initial release factor: 0.1% Final release factor: 0.1% Local release rate: 0.00125 kg/day Explanation / Justification: Releases to air before RMM based on Table A1.1; Assumed air RMM efficiency selected based on typical values in CEFIC RMM library for technologies used at large sites.

Soil Release factor

(ESVOC 1.1.v1)

Final release factor: 0.01% Explanation / Justification: Release to soil based on ERC default.

9.2.1.2 Exposure and risks for man via the environment

The exposure concentrations for man via the environment from local contribution are reported in Table 94. Table 94: Exposure concentrations and risks for man via the environment - local

Type of food Estimated daily dose Concentration in food

Drinking water 9.78E-6 mg/kg bw/d 3.42E-4 mg/L

Fish 7.93E-7 mg/kg bw/d 4.83E-4 mg/kg ww

Leaf crops 2.84E-7 mg/kg bw/d 1.66E-5 mg/kg ww

Root crops 1.72E-8 mg/kg bw/d 3.14E-6 mg/kg ww

Meat 6.82E-11 mg/kg bw/d 1.59E-8 mg/kg ww

Milk 1.27E-9 mg/kg bw/d 1.59E-7 mg/kg ww

The exposure concentrations and RCRs for man via the environment from regional contribution are reported in the following table.

Table 95: Exposure concentrations and risks for the environment



MSafe kg/d

Fish 2.48E-8 mg/kgbw/day

0.090 mg/kgbw/day

2.75E-7 -

Root crop 3.67E-9 mg/kgbw/day

4.08E-8 -

Leaf crop 3.95E-9 mg/kgbw/day

4.39E-8 -

Milk 3.84E-11 mg/kgbw/day

4.27E-10 -



238



MSafe kg/d

Meat 2.06E-12 mg/kgbw/day

2.29E-11 -

Drinking water 3.05E-7 mg/kgbw/day

3.39E-6 -

inhalation 7.04E-10 mg/kgbw/day

7.83E-9 -

Total 3.39E-7 mg/kgbw/day

3.76E-6 3.32E5

Conclusion on risk characterisation This is a worst-case approach as the SpERC assumptions include releases to wastewater from cleaning processes and disposal of sludge from the sewage treatment plat on soil, which is not the case in Oslo. Even with these worst-case assumptions, the exposure to man via environment is below the DNELs. This indicates that adverse effects to man via environment are not expected.

9.2.2 Estimated Occupational Exposure Data: Exposure Scenario 1 - Use of Diglyme as a

Process Chemical in the Manufacture of Dynabeads Sub-Scenarios at the Oslo facility SS17- WCS1 – WCS3: Diglyme removal WCS1- PROC 9 - Transfer of chemicals into small containers (dedicated filling line) – (Production processes C-Oslo, I-Oslo, K-Oslo): Transfer of beads stored in diglyme into new bottle WCS2- PROC 3 - Use in closed batch process (synthesis or formulation) (Production processes I-Oslo, K-Oslo, C-Oslo): Stirred of the suspension in the bottle and collection of the beads via electromagnet WCS3- PROC 8b - Transfer of chemicals from/to vessels/ large containers at dedicated facilities (Production processes C-Oslo, I-Oslo, K-Oslo): Transfer of diglyme into steel waste container SS18- WCS1: Maintenance WCS1- PROC 8a - Transfer of chemicals from/to vessels/ large containers at non dedicated facilities - Cleaning and Maintenance - Periodic/planned and unplanned maintenance 9.2.2.1 Sub-Scenario 17 -- SS17- WCS86 – WCS88: Diglyme removal Oslo Worker contributing scenario 1 – Transfer of chemicals into small containers (dedicated filling line) (PROC 9)



239

Conditions of use Name of contributing scenario 9 - Transfer of chemicals into small containers


Scenario subtitle Production processes C-Oslo, I-Oslo, K-Oslo): Transfer of beads stored in diglyme into new bottle











Domain industrial





240









0.240 mg/kgbw/day 0.005952




241




- 0.007686

Conclusion on risk characterisation The exposure by the inhalation and dermal routes is below the DNELs. This indicates that the likelihood of adverse effects due to long-term inhalation and dermal exposure is low.


formulation)

Scenario subtitle Production processes C-Oslo, I-Oslo, K-Oslo): Suspension is stirred in the reactor and beads are collected via electromagnet










Domain industrial





242








0.240 mg/kgbw/day 0.057143





243



mg/kgbw/day

Conclusion on risk characterisation Exposure by the inhalation and dermal routes is below the DNELs. This indicates that the likelihood of adverse effects due to long-term inhalation and dermal exposure is low.



Scenario subtitle Production processes C-Oslo, I-Oslo, K-Oslo): Transfer of diglyme/supernatant into steel waste container











Domain industrial




244










0.240 mg/kgbw/day 0.095238



245





- 0.109103


9.2.2.2 Sub-Scenario 18 -- SS18- WCS89: Maintenance Oslo Worker contributing scenario 1 – Transfer of chemicals from/to vessels/ large containers at non dedicated facilities (PROC 8a) Conditions of use Name of contributing scenario 8a - Transfer of chemicals from/to vessels/ large


Scenario subtitle Oslo: Cleaning and Maintenance - Periodic/planned and unplanned maintenance




Concentration in substance 1-5%


Frequency and duration of use Duration of activity >4 hours (default)




Domain industrial



246









247





0.240 mg/kgbw/day 0.228571



- 0.3284




248

9.3 Measured occupational exposure data: Exposure Scenario 1 - Use of diglyme as a process chemical in the manufacture of Dynabeads

Personal air monitoring was conducted in 2014 in the DP3 and DP1 (111 A-C lab) facilities, and repeated in 2015 in the DP1 facility (111 A-C and 113 laboratories) in Lillestrøm and at the Oslo facility to determine worker’s shift-average exposures to diglyme during the manufacture of Dynabeads.

The shift-average sampling results reflect the mean exposure of the workers during the sampling time. The results comprise the workers’ entire shift that includes activities with anticipated exposure to diglyme and includes the remainder of the work shift, which was less than 8 hours (shortened exposure time). In all cases, no further exposure to diglyme took place for the rest of the shift. The Threshold Limit values (TLV) and/or the DNELs are based on an 8-hour work shift. To compare the measured values with the limit values, a factor “k” has been derived and applied to calculate the RCR presented as follows:

𝑘 =𝑡𝑡𝑡𝑡𝑡 𝑠𝑡𝑠𝑠𝑡𝑠𝑠𝑠 𝑡𝑠𝑠𝑡

480

𝑅𝑅𝑅 =𝑠𝑡𝑡𝑠𝑚𝑚𝑡𝑚 𝑡𝑒𝑠𝑡𝑠𝑚𝑚𝑡

𝐷𝐷𝐷𝐷× 𝑘

Further sampling was performed for technical purposes; the aim was to obtain detailed exposure data for process-steps with potential emissions to evaluate the effectiveness of re-engineered/improved engineering controls. The duration of these process-steps were different, taking from 4 minutes to about 40 minutes.

Most of the short operations like filling of beakers or pumping-off diglyme were repeated several times throughout the day. To obtain information about how such short operations contribute to potential exposures to diglyme during the work shift, several of these short operations were sampled concomitantly with the shift-average monitoring. A separate sampling tube worn by the operator was opened at the beginning of each event measured, capped at the end of each monitoring episode, and then uncapped to monitor the next process task. This kind of sampling results in a cumulative exposure measurement for specific operations of short duration. These values are not directly comparable to the long-term reference DNELs and, therefore, no RCRs have been calculated. The monitoring reports are located in Appendix 5.

Tables 100-104 summarize the measured personal shift-average exposure for the following intermediate products.

Lillestrøm facility Monitoring value for Production process B Monitoring value for Production process M Monitoring value for Production process N Monitoring value for Production process B and M Oslo facility Monitoring value for Oslo

Two workers were monitored, as typically two workers take part in the production; the below



249

data reflect the worst case for each sub-scenario.

9.3.1 Lillestrøm facility 9.3.1.1 Monitoring value for SS8: DP1 Facility Production Process B Table 100: Monitoring values DP1 Production process B



inhalation, long-term systemic (measured / external: Diglyme concentration 0.43 mg/m³; a factor of 0.62 needs to be applied due to the reduced exposure time)

0.266 mg/m3 1.68 mg/m3 0.158333

The exposure by inhalation based on the monitoring data (0.266 mg/m3) is below the DNEL (1.68 mg/m3). This indicates that the likelihood of adverse effects due to long-term inhalation exposure is low. The calculated exposure via inhalation route with EasyTRA is 0.2 mg/m3. The modelling considers respiratory protection of 95%. Without the respiratory protective equipment (to make it comparable to the monitoring value), calculated exposure via inhalation route 4 mg/m3.

9.3.1.2 Monitoring value for Production process M Table 101: Monitoring values SS13 - DP1 facility / Production process M



inhalation, long-term systemic (measured / external: Diglyme concentration 0.5 mg/m³; a factor of 0.71 needs to be applied due to the reduced exposure time )

0.355 mg/m3 1.68 mg/m3 0.21131

The exposure by inhalation based on the monitoring data (0.355 mg/m3) is below the DNEL (1.68 mg/m3). This indicates that the likelihood of adverse effects due to long-term inhalation exposure is low. The calculated exposure via the inhalation route with EasyTRA for SS13 Day 1 is 0.0382 mg/m3. The modelling considers respiratory protection of 95%. Without RPE (to make it comparable to the monitoring value), calculated exposure via inhalation route is 0.764 mg/m3.



250

9.3.1.3 Monitoring value for Production process N Table 102: Monitoring values SS14- WCS78 – WCS83: DP3 facility / Production process N 2014



inhalation, long-term systemic (measured / external: Diglyme concentration 1 mg/m³; a factor of 0.63 needs to be applied due to the reduced exposure time)

0.630 mg/m3 1.68 mg/m3 0.375

The exposure by inhalation based on the monitoring data (0.630 mg/m3) is below the DNEL (1.68 mg/m3). This indicates that the likelihood of adverse effects due to long-term inhalation exposure is low. The calculated exposure via the inhalation route with EasyTRA for SS14 is 0.1012 mg/m3. The modelling considers respiratory protection of 95%. Without RPE (to make it comparable to the monitoring value), calculated exposure via inhalation route is 2.024 mg/m3. 9.3.1.4 Monitoring value for Production processes M and B Table 103: Monitoring values SS8 - DP1 facility Production process B Day 1 and SS13- DP1 facility Production process M Day 2



inhalation, long-term systemic (measured / external: Diglyme concentration 1.2 mg/m³; a factor of 0.77 needs to be applied due to the reduced exposure time)

0.924 mg/m3 1.68 mg/m3 0.550

The exposure by inhalation based on the monitoring data (0.924 mg/m3) is below the DNEL (1.68 mg/m3). This indicates that the likelihood of adverse effects due to long-term inhalation exposure is low. The calculated exposure via inhalation route with EasyTRA for cumulative exposure from SS8 Day 1 operations and SS13 Day 2 operations is 0.1825 mg/m3. The modelling considers respiratory protection of 95%. Without RPE (to make it comparable to the monitoring value), calculated exposure via inhalation route is 3.65 mg/m3.



251

9.3.2 Oslo Facility 9.3.2.1 Monitoring value for Oslo Table 104: Monitoring values for SS17-Diglyme removal Oslo



inhalation, long-term systemic (measured / external: Diglyme concentration less than the limit of detection of 0.013 mg/m³)

0.013 mg/m3 1.68 mg/m3 0.007738

The exposure by inhalation based on the monitoring data (0.013 mg/m3) is below the DNEL (1.68 mg/m3). This indicates that the likelihood of adverse effects due to long-term inhalation exposure is low. The calculated exposure via inhalation route with EasyTRA for the SS17 sub-scenario is 0.1268 mg/m3. The modelling considers respiratory protection of 95%. Without RPE (to make it comparable to the monitoring value), calculated exposure via inhalation route is 2.536 mg/m3.

The above comparison shows that the modelling overestimated the exposure compared to the actual monitored exposure; the exposure modelling is therefore considered to be conservative.



252

10. RISK CHARACTERISATION RELATED TO COMBINED EXPOSURE Exposure Scenario 1 - Use of diglyme as a process chemical in the manufacture of Dynabeads, described in chapter 9, results in combined exposure for workers over several Worker Contributing Scenarios (WCS). The combined exposure for workers (combinations of activities for one worker) is evaluated in the following section.

10.1 LILLESTRØM FACILITY In Lillestrøm, 85 WCSs are described for the use of diglyme as a process chemical in the manufacture of Dynabeads. A value of two hundred days per year was used as the frequency of exposure for this worst-case scenario. The use of diglyme as a process chemical in the manufacture of Dynabeads at Lillestrøm is described by the following sub-scenarios, each representing the production of an intermediate product and additional auxiliary activities such as raw material handling, cleaning, and maintenance as follows:

• SS1- WCS1 – WCS2: Raw material handling - Lillestrøm • SS2- WCS1 – WCS5: DP1 facility Production process I • SS3- WCS1 – WCS4: DP1 facility Production processes J-K9 • SS4- WCS1 – WCS6: DP1 facility Production process L • SS5- WCS1 – WCS4: DP3 facility Production process O • SS6- WCS1 – WCS3: DP3 facility Production process G • SS7- WCS1 – WCS6: DP3 facility Production process H • SS8- WCS1 – WCS11: DP1 facility Production process B • SS9- WCS1 – WCS5: DP1 facility Production process E • SS10- WCS1 – WCS5: DP1 facility Production process A • SS11- WCS1 – WCS10: DP1 facility Production process C • SS12- WCS1 – WCS8: DP1 facility Production process F • SS13- WCS1 – WCS8: DP1 facility Production process M • SS14- WCS1 – WCS6: DP3 facility Production process N • SS15- WCS1: Cleaning - Lillestrøm • SS16- WCS1: Maintenance - Lillestrøm

A total of seven workers take part in the production and are potentially exposed to diglyme at the Lillestrøm site. Each worker is assigned to the production of several intermediate products (primary and backup operators), rotating following the production plan. Two other workers are present at the Lillestrøm site; they do not, however, use diglyme (a new employee and a person in charge of logistics). For some of the intermediate products, the entire production process takes two to three days. This is because the coating reaction lasts 24 hours and the purification may be interrupted at the end of the shift and started again the next day, depending on what time during the day the 9 J and K are the same process, only a portion of the amount is sent to Oslo for further treatment (K).



253

purification started. Each line of Table 105 describes activities within a certain intermediate production the operators can complete on the same day, representing an 8-hour shift of the relevant sub-scenario. Each day, however, the actual duration of the activities operators conduct is less than 8 hours. Any remaining time is spent by the operators outside the laboratories. Therefore, no potential exposure to diglyme occurs during this timeframe. This assumes that each worker is involved in production of one intermediate product per day. Table 105 presents the combined exposure concentrations via the dermal and inhalation routes; the combined RCRs via the dermal and inhalation routes; and the total RCRs for each sub-scenario per production day. The exposure estimates are divided by the relevant DNELs to characterise quantitatively the worker’s risk.



254

Table 105: Combined 8-hour RCRs for workers taking part in the production of only a single intermediate product on the same day

Combination of WCS Combined inhalation exposure (mg/m³)

Combined dermal

exposure (mg/kg bw/day)

RCR inhalation

RCR dermal

Combined RCR

Number of batches per year

Workers needed

for productio

n/ workers assigned

to Single production process SS2- DP1 facility Production process I

SS1WCS1+SS15WCS1+SS2 WCS1+WCS2+WCS3+WCS4+WCS5

0.2360 0.0612 0.1405 0.2550 0.3955 1/2

SS3- DP1 Production process J-K

SS1WCS1+SS15WCS1+SS3 WCS1+WCS2+WCS3+WCS4

0.1866 0.0484 0.1111 0.2017 0.3128 1/3

SS4- DP1 facility / Production process L (Day 1)

SS1WCS1+SS4 WCS1+WCS2+WCS3+WCS4+WCS5

0.1241 0.0576 0.0739 0.2400 0.3139 1/3

SS4- DP1 facility Production process L (Day 2)

SS15WCS1+SS4WCS6 0.1013 0.0226 0.0603 0.0942 0.1545 1/3

SS5- DP3 facility Production process O

SS1WCS2+ SS15WCS1+SS5WCS1+WCS2+WCS3+WCS4

0.1190 0.0170 0.0708 0.0708 0.1416 2/5

SS6- DP3 facility Production process G (Day 1)

SS1WCS2+SS6WCS1+WCS2 0.0143 0.0151 0.0085 0.0628 0.0713 2/5

SS6- DP3 facility / Production process

SS15WCS1+SS6WCS3 0.0859 0.0192 0.0512 0.0800 0.1312



255

G (Day 2) SS7- DP3 facility Production process H (Day 1)

SS1WCS2+SS7WCS1+WCS2+WCS3+WCS4+WCS5

0.0535 0.0335 0.0318 0.1396 0.1714 2/3

SS7- DP3 facility Production process H (Day 2)

SS15WCS1+SS7WCS6 0.0859 0.0143 0.0511 0.0596 0.1107

SS8- DP1 facility Production process B (Day 1)

SS1WCS1+SS8WCS1+WCS2+WCS3+WCS4+WCS5+WCS6

0.0598 0.0542 0.0356 0.2258 0.2614 1/3

SS8- DP1 facility Production process B (Day 2)


0.2000 0.0577 0.1190 0.2404 0.3594

SS9- DP1 facility Production process E (Day 1)

SS1WCS1+SS9WCS1+WCS2+WCS3+WCS4

0.1837 0.0218 0.1093 0.0908 0.2001 1/3

SS9- DP1 facility Production process E (Day 2)

SS15WCS1+SS9WCS5 0.0868 0.0083 0.0517 0.0346 0.0863

SS10- DP1 facility Production process A (Day 1)


0.1532 0.0212 0.0912 0.0883 0.1795 1/1

SS10- DP1 facility Production process A (Day 2)

SS15WCS1+SS10WCS5 0.0868 0.0083 0.0517 0.0346 0.0863

SS11 DP1 facility Production process C (Day 1)

SS1WCS1+SS11WCS1+WCS2+WCS3+WCS4+WCS5+WCS6

0.1792 0.0250 0.1067 0.1042 0.2109 1/3

SS11- DP1 facility Production process C (Day 2)


0.1458 0.0563 0.0868 0.2346 0.3214

SS12- DP1 facility / SS1WCS1+SS12WCS1+WCS2+WCS 0.1517 0.0665 0.0903 0.2771 0.3674 1/2



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Production process F (Day 1)

3+WCS4+WCS5+WCS6+WCS7

SS12- DP1 facility / Production process F (Day 2)

SS15WCS1+SS12WCS8 0.1013 0.0226 0.0603 0.0942 0.1545

SS13- DP1 facility / Production process M (Day 1)


0.0382 0.0434 0.0227 0.1808 0.2035 2/3

SS13- DP1 facility / Production process M (Day 2)

SS15WCS1+SS13WCS6+WCS7+WCS8

0.1226 0.0475 0.0730 0.1979 0.2709

SS14- DP3 facility Production process N

SS1WCS2+SS15WCS1+SS14WCS1+WCS29+WCS3+WCS4+WCS5+WCS6

0.1012 0.0295 0.0602 0.1229 0.1831 2/3



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Table 106 describes scenarios where the same worker may be involved in the production of two different intermediate products on the same day. Based on thorough investigation, all the plausible combinations are listed. Table 106: Combined 8-hour RCRs for workers taking part in the production of two different intermediate products on the same day

Combination of

WCS Combined inhalation exposure (mg/m³)

Combined dermal


RCR inhalation

RCR dermal

Combined RCR

Number of batches per

year

Workers needed for production/

workers assigned to

SS13- DP1 facility / Production process M (Day 2) + SS8- DP1 facility Production process B (Day 1)

SS1WCS1+SS15WCS1+SS13WCS6+WCS7+WCS8+SS8WCS1+WCS2+WCS3+WCS4+ WCS5+ WCS6

0.1825 0.1017 0.1086 0.4237 0.5323 2

SS13- DP1 facility / Production process M (Day 2) + SS8- DP1 facility Production process B (Day 2)

SS1WCS1+SS15WCS1+SS15WCS1+SS13WCS6+WCS7+WCS8+SS8WCS7+WCS8+ WCS9+ WCS10+ WCS11

0.3247 0.1058 0.1933 0.4408 0.6341 2

SS13- DP1 facility Production process M (Day 2) + SS12- DP1 facility Production process F (Day 2)

SS1WCS1+SS15WCS1+SS15WCS1+SS13WCS6+WCS7+WCS8+SS12WCS8

0.2261 0.0707 0.1346 0.2946 0.4292 1



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10.2 OSLO FACILITY In Oslo, 4 WCSs are described for the use of diglyme as a process chemical in the manufacture of Dynabeads. A value of two hundred days per year was used as the frequency of exposure for this worst-case scenario. The use of diglyme as a process chemical in the manufacture of Dynabeads at Oslo is described by the following sub-scenarios:

• SS17- WCS1 – WCS3: Diglyme removal - Oslo • SS18- WCS1: Maintenance - Oslo

At the Oslo site a total of 5 workers are involved in production and are potentially exposed to diglyme. Each worker is involved in the removal of diglyme for the production of different Dynabeads. Table 107 presents the combined exposure concentrations via the dermal and inhalation routes; the combined RCRs via the dermal and inhalation routes; and the total RCRs. The exposure estimates are divided by the relevant DNELs to characterise quantitatively the worker’s risk.



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Table 107: Combined 8-hour RCRs for workers taking part in diglyme removal at the Oslo site

Combination of WCS Combined inhalation exposure (mg/m³)

Combined dermal


RCR inhalation

RCR dermal

Combined RCR

SS2- Diglyme removal WCS16+WCS2+WCS3 0.1268 0.0380 0.0755 0.1583 0.2338



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10.3 QUALITATIVE ASSESSMENT Qualitative risk assessment was conducted for intermediate productions P and Q. The objective was to establish whether additional RRMs are required to minimise the likelihood of adverse health effects. The conditions of use were reviewed to determine similarities with other sub-scenarios.

Intermediate production P has the same chemistry and a very similar production process to production M. The starting bead is different and there is a further step in production before the after-treatment, which is similar to the purification steps. This process is conducted in the same room using the same equipment as the rest of the production process. RMMs and the requirements for PPE are therefore the same. Process P is performed once every 2-3 years. Production process Q is performed in the DP1 small rooms. The processes are performed less than once per year. Upon considering the facilities, processes, and RMMs (same PPE is worn), it was concluded that production process P is sufficiently described by sub-scenario 13 due to the similarities with production process M. Therefore, no additional RMMs are needed and the risk is adequately controlled. Based on the same considerations, production process Q is sufficiently described by sub-scenario 4 (production process L); no additional RMMs are necessary and the risk is adequately controlled.



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APPENDIX 1 GLOSSARY

Term Explanation

Biomolecules Polypeptides (peptides, antibodies, streptavidin, enzymes) and nucleic acids.

Coating

An epoxide or polyurethane type material that provides: (a) a surface with characteristic balance between hydrophobic and hydrophilic properties; (b) filling media for the inherent pores of the particles; (c) a seal to keep the iron particles within the beads; and (d) a reaction surface for functionalization of the beads to bind biomolecules.

Conjugation

Production step through which biomolecules are chemically attached to the bead. The “attachment” of biomolecules can be of non-covalent nature (physical adsorption onto the surface) or covalent nature (attached with a chemical bond). A word that is often used interchangeably to conjugation is “immobilization.”

DP1 and DP3

Two production facilities located at the Lillestrøm, Norway, facility. DP1 is a laboratory production facility where Dynabeads are produced in batches of 450g of dry particles in a semi-closed process. DP3 is a medium-scale flexible factory facility where Dynabeads are produced in batches of approximately 4kg per batch. This is a semi-closed and fully automated production process.

Dynabeads®

Superparamagnetic spherical polystyrene particles with a consistent, defined surface for the adsorption or coupling of various bioreactive molecules or cells. They can be used for numerous biochemical and medical applications. (Patent for example EP1693387) http://www.thermofisher.com/us/en/home/brands/product-brand/dynal.html

Functionalization Introducing reactive groups, reactive chemistry augmented to the coating to enable conjugation of the biomolecules.

http://www.thermofisher.com/us/en/home/brands/product-brand/dynal.html



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IVD

In vitro diagnostic medical devices. IVD products are regulated and defined by Directive 98/79/EC, meaning any medical device which is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, equipment, or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information: Concerning a physiological or pathological state, or

Concerning a congenital abnormality, or

To determine the safety and compatibility with potential recipients, or

To monitor therapeutic measures.


Life Technologies AS is the Norwegian-based subsidiary of the Life Sciences Solutions Group within Thermo Fisher Scientific.

Magnetic particles/beads

Superparamagnetic spherical polymer particles used in the same applications as Dynabeads.

Purification Removing excess reactants and solvents to a concentration where there is no impact on subsequent reaction steps.

Reaction Coating reaction or functionalization reaction.

SRD Scientific research and development. Any scientific experimentation, analysis or chemical research carried out under controlled conditions in a volume less than 1 tonne per year.

Suspension of beads

Uniform suspension of beads into solvent at a specified concentration enabling equal dispensing into smaller containers.

Thermo Fisher Scientific

Thermo Fisher Scientific (TMO) is the world-leading company in providing analytical, diagnostic and laboratory solutions.

(Re-)validation

Any change to the production process that could change the form, fit or function of the beads (including moving the production to a new facility) must be validated. Validation is a process of establishing documentary evidence demonstrating that a procedure, process, or activity carried out in the production or testing maintains the desired level of compliance and performance at all stages.

public chemical safety report - europa

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