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French Agency for Food, Environmental and Occupational Health & Safety,

14, rue Pierre et Marie Curie, 94701 Maisons-Alfort Cedex - Téléphone : + 33 (0)1 49 77 13 50 - Télécopie : + 33 (0)1 49 77 26 26

www.anses.fr 1 Expert appraisal on recommending occupational exposure 2 limits for chemical agents 3 Assessment of health effects and methods for the measurement of exposure levels 4 in workplace atmospheres for 5

Toluene diisocyanate mixed isomers (TDI) 6

CAS N° 26471-62-5 7

8

OEL Permanent Mission 9

Request n°2012-SA-0080 10

11

Collective expert appraisal 12

REPORT 13

14 15

Working group on " metrology » 16

17

Mars 2019 18

19 Anses Collective expert appraisal Request 2012-SA-0080 OEL TDI

Version for consultation page 2 / 138 March 2019

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Mots clés 21

VLEP, valeurs limites, professionnel, agents chimiques, effets sur la 22

santé, métrologie, méthodes de mesure, lieux de travail, valeur référence, Diisocyanate de Toluène, 23

TDI, 2,4-TDI, 2,6-TDI, 24

25

Key words 26

OEL, limit values, exposure levels, occupational, chemical agents, health effects, metrology, 27

measurement methods, workplaces, reference value, Toluene Diisocyanate, TDI, 2,4-TDI, 2,6-TDI. 28 29
30
Anses Collective expert appraisal Request 2012-SA-0080 OEL TDI

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Presentation of participants 1

PREAMBLE : The expert members of the Expert Committees and Working Groups or designated 2 rapporteurs are all appointed in a personal capacity, intuitu personae, and do not represent their 3 parent organisations. 4

EXPERT COMMITTEE (CES) 5

The work carried out as part of this report was adopted by: 6 7 9

Chair 10

Mr Fabrice MICHIELS Occupational physician-toxicologist, Intercompany association for 11 occupational health, Corrèze 12

Vice-Chair 13

Mr Raymond VINCENT Retired (formerly project manager at the Direction of Prevention 14

Applications (INRS)) Expertise: chemistry, pollutants metrology, occupational health risks 15

assessment. 16

Members 17

Mr Marc BARIL Associate professor, University of Montréal, Canada Expertise: 18 Toxicologist/chemist, occupational exposure limits (OELs) 19 Mr Stéphane BINET Pharmacist toxicologist at the scientific head of INRS Expertise: general 20 and occupational toxicology 21 Ms Michèle BISSON Study director, INERIS Expertise: Pharmacist-toxicologist, general 22 toxicology 23 Ms Anne CHEVALIER Retired epidemiologist, French Institute for Public Health Surveillance 24 (InVS) - Expertise: Epidemiology 25 Ms Fatiha EL-GHISSASSI Scientist, IARC Monographs Section (IMO) International Agency for 26 Research on Cancer Expertise: biochemistry. Cancerogenicity and genotoxicity 27 Ms Mounia EL-YAMANI Unit head, InVS Expertise: Biochemistry, toxicology 28 Mr Claude EMOND Assistant clinical professor, University of Montréal, Canada 29 Expertise: Toxicology, Physiologically based pharmacokinetic (PBPK) modelling, toxicokinetics, 30 nanotoxicology, endocrine disruptors 31 Mr Rex FITZGERALD Regulatory toxicology expert at the Swiss Centre for Applied Human 32 Toxicology Expertise: Reprotoxicity, developmental neurotoxicity, human risk assessment 33 Mr Robert GARNIER Toxicologist physician, Paris poison control center Expertise: Medical 34 toxicology, occupational medicine 35 Ms Perrine HOET Professor, Université catholique de Louvain. Institute of Experimental and 36 Clinical Research Expertise: Medicine, occupational and environmental toxicology 37 Ms Yuriko IWATSUBO Epidemiologist physician, SPF Expertise: occupational risks 38 epidemiology 39 Ms Cécile KAIRO Health risks assessor, SPF Expertise: Doctor of Pharmacy specialized in 40 environmental medicine, general toxicology and risks assessment 41 Anses Collective expert appraisal Request 2012-SA-0080 OEL TDI

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Ms Laila LAKHAL Engineer, INRA, Toxalim unit Expertise: toxicology, metabolism, endocrine 1 disruptors 2 Mr Frédéric LIRUSSI Lecturer Hospital doctor (PU-PH), Health Sciences & Dijon University 3

Hospital UFR Expertise: Clinical toxicology, analytical toxicology, innate immunity, reprotoxicity 4

Ms Anne MAITRE Professor Hospital doctor (PU-PH), Occupational and environmental 5 6

Expertise: Medicine, toxicology, 7

biomarkers of exposure, pollutants metrology, occupational hygiene 8 Ms Florence PILLIERE Medical advisor, INRS Expertise: occupational medicine, toxicology, 9 biomarkers of exposure 10 Ms Anne PLATEL Lecturer, Faculty of biological and pharmaceutical sciences of Lille Genetic 11 toxicology laboratory, Institut Pasteur de Lille Expertise: toxicology, genotoxicity, QSAR 12 Mr Henri SCHROEDER Professor Associate, CALBINOTOX, EA 7488, Faculty of Sciences and 13

Technologies, University of Lorraine Pharmacist, neurobiologist Expertise: Neurotoxicity, animal 14

behaviour, cerebral development, perinatal exposure 15 Mr Olivier SORG Head of research group, University of Geneva, Switzerland Doctor of science 16 in biochemistry, experimental toxicology, dermatotoxicology 17 Mr Jérôme THIREAU Research assistant, CNRS Doctor of science, animal physiology, cell 18 biology, cardiotoxicity 19 Mr Claude VIAU Retired full professor and currently adjunct professor Department of 20

Environmental and Occupational Health, School of Public Health, University of Montreal Expertise: 21

Toxicology, Biological Exposure Indices, pollutant metrology, 22 23
The work carried out as part of this report was adopted by: 24

Chairman 26

Mr Claude VIAU - Professor (University of Montreal) - Expertise: toxicology, biomarkers of exposure, 27

industrial hygiene, metrology of pollutants 28

Members 29

Mr. Marc BARIL Associate professor, University of Montréal, Canada Toxicologist/chemist, 30 occupational exposure limits (OELs) 31 Mr Stéphane BINET - Head of the carcinogenesis and developmental toxicity laboratory (National 32 Research and Safety Institute, INRS) - Expertise: toxicology 33 Mrs. Anne CHEVALIER Retired epidemiologist, French Institute for Public Health Surveillance 34 (InVS) 35 Mrs Irina CANU - Epidemiologist at the French Institute for Public Health Surveillance (INVS) - 36

Expertise: epidemiology 37

Mrs Carole DUPLAINE - IPRP (specialist in prevention of occupational risks) at Sud Loire Santé au 38

Travail - Expertise: toxicology 39

Ms Perrine HOET Professor, Université catholique de Louvain. Institute of Experimental and 40 Clinical Research Expertise: Medicine, occupational and environmental toxicology 41 Ms Yuriko IWATSUBO Epidemiologist physician, SPF Expertise: occupational risks 42 epidemiology 43 Anses Collective expert appraisal Request 2012-SA-0080 OEL TDI

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Ms Anne MAITRE Professor Hospital doctor (PU-PH), Occupational and environmental 1 2

Expertise: Medicine, toxicology, 3

biomarkers of exposure, pollutants metrology, occupational hygiene 4 Mr Fabrizio PARISELLI - Toxicologist at the French National Centre for Scientific Research (CNRS) 5 - Expertise: toxicology 6 Mrs Florence PILLIERE - Medical advisor in toxicology (INRS) - Expertise: occupational medicine, 7 toxicology, biomarkers of exposure 8 Mr Davy ROUSSET - Head of the inorganic analysis and aerosol characterisation laboratory (INRS) 9 - Expertise: metrology of pollutants in workplace atmospheres, inorganic chemistry 10

Mr David VERNEZ - Head of group and co-director (ad interim) (IST) - Expertise: industrial hygiene 11

Mr Raymond VINCENT Retired (formerly project manager at the Direction of Prevention 12 Applications (INRS)) Expertise: chemistry, pollutants metrology, occupational health risks 13 assessment. 14 Mr Adolf VYSKOCIL - Professor (University of Montréal) - Expertise: toxicology, biomarkers of 15 exposure, industrial hygiene 16 17

2017) 19

Chairman 20

Mr. Michel GUERBET Professor in toxicology, UFR Medicine-Pharmacy, Rouen Pharmacist-21 toxicologist 22

Vice-chairman 23

Mr. Dominique LAFON Toxicology physician, Nexter Group Occupational medicine, toxicology, 24 reprotoxicity 25

Members 26

Mr. Marc BARIL Associate professor, University of Montréal, Canada Toxicologist/chemist, 27 occupational exposure limits (OELs) 28

Mr. Sylvain BILLET Research fellow / University lecturer in toxicology, Université du Littoral Côte 29

Respiratory toxicology, nanomaterials 30

Mrs. Michèle BISSON Study director, INERIS Pharmacist-toxicologist, general toxicology 31 toxicity reference values (TRVs) 32 Mrs. Anne CHEVALIER Retired epidemiologist, French Institute for Public Health Surveillance 33 (InVS) 34 Mr. François CLINARD Epidemiologist, InVS Pharmacist-toxicologist, epidemiology, health risk 35 assessment 36 Mrs. Fatiha EL-GHISSASSI Scientist, IARC Monographs Section (IMO) International Agency for 37 Research on Cancer Doctor of science in biochemistry, specialist in carcinogenesis and 38 genotoxicity 39 Mrs. Mounia EL-YAMANI Unit head, InVS Doctor of science in biochemistry, toxicology, OELs 40 Mr. Claude EMOND Assistant clinical professor, University of Montréal, Canada Toxicology, 41 Physiologically based pharmacokinetic (PBPK) modelling, toxicokinetics, nanotoxicology, endocrine 42 disruptors 43

Mr. Guillaume GARCON Professor of toxicology, University of Lille 2 General toxicology, 44

cancerology, experimental models, respiratory toxicology, air pollution 45 Anses Collective expert appraisal Request 2012-SA-0080 OEL TDI

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Mr. Ludovic LE HEGARAT Deputy head, Unit of Toxicology of contaminants Anses Fougères 1 Laboratory Toxicology, genotoxicity, nanomaterials 2 Mrs. Véronique MALARD Research engineer in toxicology, CEA, Cadarache Centre. Doctor in 3 science In vitro toxicology, cell biology, nanotoxicology, proteomics. 4 Mr. Fabrice MICHIELS Occupational physician-toxicologist, Intercompany association for 5 occupational health, Corrèze 6 Mr. Jean-Paul PAYAN Head of Laboratory for Skin penetration, kinetics and metabolism, INRS, 7

Nancy Pharmacist-toxicologist, toxicokinetics 8

Mr. Henri SCHROEDER Research fellow, URAFPA (Research unit Animal and functionality of 9 animal products), INRA USC 340, Faculty of Sciences and Technologies, University of Lorraine 10 Pharmacist-biologist Neurotoxicity, animal behaviour, cerebral development, perinatal exposure 11 Mr. Alain SIMONNARD Pharmacist-toxicologist, European registered toxicologist retired from the 12

INRS 13

Mr. Olivier SORG Head of research group, University of Geneva, Switzerland Doctor of science 14 in biochemistry, experimental toxicology, dermatotoxicology 15 Mrs. Lydie SPARFEL Professor at the University of Rennes 1 / IRSET (Research Institute for 16 Environmental and Occupational Health) UMR INSERM 1085 Pharmacist-toxicologist, 17 immunotoxicology, toxicogenomics, oncology, molecular and cell biology 18 Mr. Jérôme THIREAU Research assistant, CNRS Doctor of science, animal physiology, cell 19 biology, cardiotoxicity 20 21

WORKING GROUPS 22

23

Chairman 25

M. Benoît OURY Head of studies at the organic analytical chemistry laboratory of the Institut 26 National de Recherche et de Sécurité (INRS) - Skills: development of measurement methods, 27 organic chemistry. 28

Members 29

Mrs. Aline BOUCHAIN Technical Manager and QSE (ATMO Franche Comté) - Skills: Ambient air 30 quality, metrology, uncertainty. 31 Mrs. Catherine HEDOIUN-LANGLET Head of the Industrial Toxicology Laboratory (CRAMIF) - 32 Skills: workplace air quality, industrial hygiene, measurement of pollutants. 33 Mr. Horacio HERRERA Head of department (Institut universitaire romand de santé au travail) -34 Skills : industrial hygiene, work environment monitoring (metrology, analytical chemistry). 35 Mme Nadine LOCOGE Professor at the Ecole des Mines de Douai - Skills: indoor air quality, 36 chemistry, VOC metrology. 37 Mrs. Virginie MATERA Head of studies at the inorganic analytical chemistry laboratory of the 38

Institut National de Recherche et de Sécurité (INRS) - Skills: air quality in workplaces, development 39

of measurement methods, inorganic chemistry. 40 Mrs. Jessica QUERON Design and research engineer (Institut national de l'environnement 41 industriel et des risques (Ineris)) - Skills: indoor and workplace air quality, VOC metrology. 42 Anses Collective expert appraisal Request 2012-SA-0080 OEL TDI

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Mr. Olivier RAMALHO Multi-exposure project manager at the Centre Scientifique et Technique du 1

Bâtiment (CSTB) and metrology manager at the Observatoire de la Qualité de l'Air Intérieur (OQAI) 2

- Skills: indoor air quality, metrology, 3 Mrs. Caroline RIO Head of Interregional Chemistry Laboratory (LIC) - Skills: ambient and indoor 4 air quality, physical chemistry, organic aerosol, metrology. 5

Mr.Michel SLOIM Retired (formerly Chemical Engineer at the Laboratoire Central de la Préfecture 6

de Police (LCPP)) - Skills: air quality in workplaces, metrology, analytical chemistry. 7 Mrs. Sophie SOBANSKA Research Officer (Centre national de la recherche scientifique (CNRS)) 8 - Skills: Air quality, biochemistry, particles, metals. 9

Mr. THIAULT Guénaël Section Head (CPPL) - Skills: indoor and workplace air quality, metrology, 10

chemistry. 11 M. Steven VERPAELE head of department (Mensura ASBL) - Skills: workplace air quality, 12 industrial hygiene, aerosols (Resignation on 16/10/2017)M. Raymond VINCENT Retired (formerly 13

Project Manager at the Applications Division (INRS)) - Skills: workplace air quality, chemistry, 14

pollutant metrology, occupational risk assessment. 15 16

Chairman 18

M. Raymond VINCENT Retired (formerly Project Manager at the Applications Division (INRS)) - 19 Skills: workplace air quality, chemistry, pollutant metrology, occupational risk assessment. 20

Vice-chairman 21

Mme Caroline MARCHAND Engineer at the Institut national de l'environnement industriel et des 22 risques (Ineris) - Skills: metrology - indoor air quality 23

Members 24

Mme Ghislaine GOUPIL Head of the Air and Measurements Section at the Laboratoire Central de 25 la Préfecture de Police (LCPP) - Skills: Metrology - Air Quality 26 M. Roger GROSJEAN Retired (formerly Chemist - Head of laboratory of the Federal Public Service 27

FPS Employment, Labour and Social Dialogue (Belgium) - Skills: metrology of pollutants in the air, 28

industrial hygiene, chemistry 29 Mr. Horacio HERRERA Head of department (Institut universitaire romand de santé au travail) -30 Skills : industrial hygiene, work environment monitoring (metrology, analytical chemistry). 31

M. Jérôme NICOLLE - TiPEE platform project manager - Skills: Analytical chemistry - metrology - 32

indoor air - health environment 33 Mme Nathalie LECLERC ASPA Indoor Air Project Manager - Skills: metrology - indoor air quality 34 - health environment 35 Mme Nadine LOCOGE Professor at the Ecole des Mines de Douai - Skills: indoor air quality, 36 chemistry, VOC metrology. 37 Mrs. Virginie MATERA Head of studies at the inorganic analytical chemistry laboratory of the 38

Institut National de Recherche et de Sécurité (INRS) - Skills: air quality in workplaces, development 39

of measurement methods, inorganic chemistry. 40 M. Benoît OURY Head of studies at the organic analytical chemistry laboratory of the Institut 41 National de Recherche et de Sécurité (INRS) - Skills: development of measurement methods, 42 organic chemistry. 43 Anses Collective expert appraisal Request 2012-SA-0080 OEL TDI

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Mr. Olivier RAMALHO Multi-exposure project manager at the Centre Scientifique et Technique du 1

Bâtiment (CSTB) and metrology manager at the Observatoire de la Qualité de l'Air Intérieur (OQAI) 2

- Skills: indoor air quality, metrology, 3 Mrs. Caroline RIO Head of Interregional Chemistry Laboratory (LIC) - Skills: ambient and indoor 4 air quality, physical chemistry, organic aerosol, metrology. 5

Mr.Michel SLOIM Retired (formerly Chemical Engineer at the Laboratoire Central de la Préfecture 6

de Police (LCPP)) - Skills: air quality in workplaces, metrology, analytical chemistry. 7 8 9

ANSES PARTICIPATION 10

Scientific Coordination 11

Mrs Aurélie MATHIEU-HUART 12

Mrs Fatoumata SISSOKO 13

Mrs Dominique BRUNET 14

Scientific Contribution 15

Mr. Laurent BODIN 16

Mrs Farida LAMKARKACH 17

Mrs Amandine PAILLAT 18

Christophe ROUSSELLE 19

Administration 20

Mrs Séverine BOIX-PETRE 21

22

HEARING OF EXTERNAL PERSONALITIES 23

Jürgen Pauluhn, Bayer Pharma (retired) · Experimental Toxicology 24 Expert of Pulmonary Pharmacology and Toxicology and Risk Assessment 25 26
27
Anses Collective expert appraisal Request 2012-SA-0080 OEL TDI

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Table of contents 1

Collective expert appraisal report ..................................................................... 40 2

Acronyms and abbreviations ............................................................................. 41 3

List of figures ..................................................................................................... 43 4

Preamble ............................................................................................................ 44 5

Part A ² Report on assessment of health effects .............................................. 46 6

1 General information .................................................................................... 47 7

1.1 Substance identification ................................................................................................... 47 8

1.2 Physicochemical properties ............................................................................................. 48 9

1.3 European Classification .................................................................................................... 49 10

1.4 Majors uses and sources .................................................................................................. 49 11

2 Overview of recent recommended occupational limit values .................... 51 12

3 Toxicokinetics and metabolism ................................................................. 52 13

3.1 Introduction ....................................................................................................................... 52 14

3.2 Absorption ......................................................................................................................... 53 15

3.2.1 By inhalation ......................................................................................................................................... 53 16

3.2.2 By dermal route ..................................................................................................................................... 53 17

3.2.3 By oral route .......................................................................................................................................... 57 18

3.3 Distribution ........................................................................................................................ 57 19

3.3.1 By inhalation ......................................................................................................................................... 57 20

3.3.2 By dermal route ..................................................................................................................................... 57 21

3.3.3 By oral route .......................................................................................................................................... 57 22

3.4 Metabolism ........................................................................................................................ 57 23

3.4.1 By inhalation ......................................................................................................................................... 58 24

3.4.2 By dermal route ..................................................................................................................................... 59 25

3.4.3 By oral route .......................................................................................................................................... 59 26

3.5 Excretion ............................................................................................................................ 59 27

3.5.1 By inhalation ......................................................................................................................................... 59 28

3.5.2 By dermal route ..................................................................................................................................... 62 29

3.5.3 By oral route .......................................................................................................................................... 62 30

3.6 Conclusion on toxicokinetics ........................................................................................... 62 31

4 Toxicity data ............................................................................................... 63 32

4.1 Acute toxicity ..................................................................................................................... 63 33

4.2 Irritation ............................................................................................................................. 64 34

Anses Collective expert appraisal Request 2012-SA-0080 OEL TDI

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4.2.1 Respiratory tract irritation ...................................................................................................................... 64 1

4.2.2 Skin and eye irritation ........................................................................................................................... 65 2

4.3 Sensitisation ...................................................................................................................... 66 3

4.3.1 Respiratory sensitisation ....................................................................................................................... 66 4

4.3.2 Skin sensitisation .................................................................................................................................. 67 5

4.4 Chronic toxicity on Respiratory effects ........................................................................... 67 6

4.4.1 Deutsche Forschungsgemeinschaft (DFG) report (2003) ..................................................................... 68 7

4.4.2 US EPA report (2012) ........................................................................................................................... 68 8

4.4.3 OEHHA report (2016) ........................................................................................................................... 69 9

4.4.4 Dutch expert Committee on Occupational Safety (DECOS) of the Health Council of the Netherlands10

70 11

4.5 Mechanism of action- sensitisation/irritation .................................................................. 71 12

4.6 Genotoxicity ...................................................................................................................... 74 13

4.6.1 In Vitro data ........................................................................................................................................... 74 14

4.6.1.1 DNA damage ................................................................................................................................................. 74 15

4.6.1.2 Mutagenesis .................................................................................................................................................. 74 16

4.6.1.3 Genotoxicity of TDA ...................................................................................................................................... 74 17

4.6.2 Animal data ........................................................................................................................................... 75 18

4.6.2.1 Protein adducts ............................................................................................................................................. 75 19

4.6.2.2 DNA adducts ................................................................................................................................................. 75 20

4.6.2.3 DNA damage ................................................................................................................................................. 75 21

4.6.3 Human data .......................................................................................................................................... 75 22

4.6.4 Conclusion on TDI genotoxicity ............................................................................................................ 76 23

4.7 Carcinogenicity ................................................................................................................. 76 24

4.7.1 Human data .......................................................................................................................................... 77 25

4.7.2 Animal data ........................................................................................................................................... 79 26

5 Construction of the OELs ........................................................................... 81 27

5.1 Construction of a short-term exposure level (STEL) ...................................................... 81 28

5.2 Construction of an 8 hours occupational exposure level (8-hour OEL) ........................ 82 29

5.3 .................................................................................................................. 83 30

5.4 ................................................................................................................ 83 31

6 Conclusions of the collective expert appraisal .......................................... 84 32

7 References .................................................................................................. 85 33

Partie B ² Report on the assessment of methods for measurement of 34 exposure levels in workplace atmospheres ............................................... 94 35

1 Presentation and discussion of methods for measuring TDI in 36

workplace air .............................................................................................. 95 37

1.1 Mapping measurement methods ...................................................................................... 96 38

1.2 Detailed assessment of the methods ............................................................................... 99 39

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