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Scientific Review Panel Review Draft November May 20142015
Appendix D1 Methylene diphenyl diisocyanate
OFFICE OF ENVIRONMENTAL HEALTH HAZARD ASSESSMENT
Methylene Diphenyl Diisocyanate (Monomer and Polymeric Forms) Reference Exposure Levels
Technical Support Document for the
Derivation of Noncancer Reference
Exposure Levels
Appendix D1
SRP Review Draft May 2015
Air, Community, and Environmental Research Branch Office of Environmental Health Hazard Assessment California Environmental Protection Agency
Air Toxics Hot Spots Program

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Methylene Diphenyl Diisocyanate
Reference Exposure Levels
(Monomer and Polymeric Forms) Technical Support Document for the Derivation of
Noncancer Reference Exposure Levels Appendix D1
SRP Review Draft
Prepared by the Office of Environmental Health Hazard Assessment
George V. Alexeeff, Ph.D., Director
Authors Daryn E. Dodge, Ph.D.
Rona Silva, Ph.D.
Technical Reviewers Lauren Zeise, Ph.D.
David M. Siegel, Ph.D. Melanie A. Marty, Ph.D. James F. Collins, Ph.D
Rajpal Tomar, Ph.D. Marlissa Campbell, Ph.D.
November May 20142015

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Methylene Diphenyl Diisocyanate Reference Exposure Levels
(Monomer and Polymeric Forms)
(Diphenylmethane diisocyanate, Methylene bisphenyl diisocyanate, 4,4-Methylenediphenyl diisocyanate, Diphenylmethane-4,4-diisocyanate)
CAS: 101-68-8
1. Summary
The Office of Environmental Health Hazard Assessment (OEHHA) is required to develop guidelines for conducting health risk assessments under the Air Toxics Hot Spots Program (Health and Safety Code Section 44360 (b) (2)). In response to this statutory requirement, OEHHA developed a Technical Support Document (TSD) that was adopted in 2008 and describes acute, 8 hour and chronic Reference Exposure Levels (RELs). The TSD presents methodology for deriving Reference Exposure Levels. In particular, the methodology explicitly considers possible differential effects on the health of infants, children and other sensitive subpopulations, in accordance with the mandate of the Childrens Environmental Health Protection Act (Senate Bill 25, Escutia, chapter 731, statutes of 1999, Health and Safety Code Sections 39669.5 et seq.). These guidelines have been used to develop the following RELs for methylene diphenyl diisocyanate; this document will be added to Appendix D of the TSD.
Exposure to diisocyanates, including monomeric methylene diphenyl diisocyanate (MDI) and polymeric MDI (PMDI), has been found to cause adverse effects on the respiratory system in both animals and humans. These effects include 1) acute impacts such as sensory irritation and respiratory inflammation, 2) and sensitization and the induction of asthma in sensitive subjectswith repeated exposures, and 3) . Chronic effects include long-term decrements in lung function without evidence of sensitization with chronic exposure. and sensitization toOnce asthma has been induced in sensitized individuals, triggering of asthmatic attacks can occur following very low exposures to diisocyanates MDI or PMDI (1 ppb). The RELs are intended to reasonably protect the general population from these health effects resulting from exposure to MDI and PMDI, but may not protect all individuals previously sensitized to MDI or PMDI. The RELs are applicable for both MDI and PMDI due to similar toxicological effects and potencies, and similar regional deposition in the lungs in key studies. Literature summarized and referenced in this document covers the relevant published literature for MDI through Spring 20142015.
Appendix D1 1 Methylene diphenyl diisocyanate

1.1 Methylene diphenyl diisocyanate MDI/PMDIAcute REL
Reference eExposure lLevel 12 g/m3 (1.2 ppb) Critical effect(s) Increased total protein in bronchoalveolar
lavage fluid of rats - marker of pulmonary irritation
Hazard index target(s) Respiratory system
1.2 Methylene diphenyl diisocyanate MDI/PMDI8-hour REL
Reference eExposure lLevel 0.16 g/m3 (0.015 ppb) Critical effect(s) Bronchiolo-alveolar hyperplasia and
pulmonary interstitial fibrosis Hazard index target(s) Respiratory system
1.3 Methylene diphenyl diisocyanate MDI/PMDIChronic REL
Reference eExposure lLevel 0.08 g/m3 (0.008 ppb) Critical effect(s) Pulmonary interstitial fibrosis Hazard index target(s) Respiratory system

List of Acronyms AEC Asymptomatic exposed controls MDI Methylene diphenyl diisocyanate AIC Akaike information criterion MMAD Mass median aerodynamic ACE Angiotensin converting enzyme diameter ANOVA Analysis of variance MMEF Maximum mid-expiratory flow BALF Bronchoalveolar lavage fluid NAG N-acetyl glucosaminidase BMC Benchmark Concentration NAT N-acetyl transferase BMC05 Benchmark concentration NDI Naphthylene diisocyanate producing a 5% response rate NOAEL No observed adverse effect level BMCL05 the 95% lower confidence limit of OA Occupational asthma the dose producing a 5% response rate OR Odds Ratio BMD Benchmark Dose PD20 Provocation dose of methacholine DA Diisocyanate-induced asthma (in mg) to cause a 20% drop in FEV1 DLco Carbon monoxide diffusion test PEFR Peak expiratory flow rate ELISA Enzyme-linked immunosorbent PEL Permissible exposure limit assay PMDI Polymeric methylene diphenyl FEF25-75% Forced respiratory flow (25-75% diisocyanate of forced vital capacity) PMN Neutrophilic granulocytes FEV1 Forced expiratory volume in 1 POD Point of departure second ppb Parts per billion FVC Forced vital capacity ppm Parts per million GSH Glutathione RADS Reactive airways dysfunction GST glutathione-S-transferase syndrome HDI Hexamethylene diisocyanate RAST Radioallergosorbent test HEC Human equivalent concentration RDDR Regional deposited dose ratio HLA Human leucocyte antigen REL Reference exposure level HPLC High pressure liquid RGDR Regional gas deposition ratio chromatography SNP Single nucleotide polymorphism HSA Human serum albumin TAC Toxic air contaminant IPDI Isophorone diisocyanate TDI Toluene diisocyanate IgE Immunoglobulin E antibody type TLV Threshold limit value IgG Immunoglobulin G antibody type TRPA transient receptor potential A LC50 Median lethal concentration TSD Technical support document LDH Lactate dehydrogenase TWA Time-weighted average LOAEL Lowest observed adverse effect UF Uncertainty factor level VC Vital capacity LOQ Limit of quantitation VOC Volatile organic compound MDA 4,4-methylenedianiline

2. Physical & Chemical Properties Sources: HSDB (2015); US EPA, (1998c); Booth et al., (2009)
Chemical form CAS Vapor pressure
Methylene diphenyl diisocyanate monomer (4,4-MDI)
101-68-8 510 -6 mm Hg @ 25C, or 6.710 -4 Pa @ 25C
Polymeric methylene diphenyl diisocyanate (PMDI)
9016-87-9 210 -6 mm Hg @ 20C, or 3.110 -4 Pa @ 20C
Description MDI: White waxy solid @ 20C PMDI: Viscous amber- to dark-colored liquid @ 20C
Molecular formula C15H10N2O2 (MDI) Molecular weight Density
250.25 g/mol (MDI) 1.23 g/cm3 @ 25C (MDI)
Boiling point 314C (MDI) Melting point Saturated vapor conc.
37C (MDI) MDI: 60 g/m3 (6 ppb) @ 20C PMDI: 32 g/m3 (3 ppb) @ 20C
Odor threshold odorless Solubility Soluble in acetone, benzene, kerosene,
and nitrobenzene. Water solubility
Conversion factor estimated at 1.51 mg/L at 25 C (MDI) 10.24 mg/m3 = 1 ppm @ 25 C (MDI)
3. Major Uses and Sources
Methylene diphenyl diisocyanate (MDI) is used in the preparation of polyurethane resin and spandex fibers, and to bond rubber to rayon and nylon. Its use in polyurethane foams accounts for approximately 80% percent of the MDI consumed worldwide. The commercial form of MDI that isprimarily used in foaming operations is called polymeric MDI, or PMDI, and is typically a mixture of about 50% percent monomeric MDI and 50% percent higher molecular weight oligomers of MDI, mainly three-ring (~26%), four-ring (~13%) and five-ring (~7%) oligomers MDI dimers and trimers (Figure 1) (U. S. EPA, 1998a; Feron et al., 2001). The monomer 4,4-MDI is the predominant isomer found in most MDI and PMDI formulations, but small amounts of the 2,4-MDI and 2,2-MDI isomers are also likely present (Marand et al., 2004; Booth et al., 2009). Although toxicological information is lacking for these other isomeric forms of MDI, they would be expected to have similar toxicological properties as the 4,4-MDI isomer.
Estimated facility emissions of MDI to the atmosphere in California was were 3.6 tons per year in 2008, and 0.6 tons per year in a 2010 draft report (CARB, 2013). However, emission levels may be underestimated in any particular year due to

the quadrennial method of updating emission inventories in the Hot Spots program (i.e., some emitting facilities may be missing from the list for a specific year because they do n

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