Report to the U.S. Consumer Product Safety Commission by the CHRONIC HAZARD ADVISORY PANEL ON PHTHALATES AND PHTHALATE ALTERNATIVES July 2014 U.S. Consumer Product Safety Commission Directorate for Health Sciences Bethesda, MD 20814 Chronic Hazard Advisory Panel on Phthalates and Phthalate Alternatives Chris Gennings, Ph.D. Virginia Commonwealth University Richmond, VA Russ Hauser, M.D., Sc.D., M.P.H. Harvard School of Public Health Boston, MA Holger M. Koch, Ph.D. Ruhr University Bochum, Germany Andreas Kortenkamp, Ph.D. Brunel University London, United Kingdom Paul J. Lioy, Ph.D. Robert Wood Johnson Medical School Piscataway, NJ Philip E. Mirkes, Ph.D. University of Washington (retired) Seattle, WA Bernard A. Schwetz, D.V.M., Ph.D. Department of Health and Human Services (retired) Washington, DC TABLE OF CONTENTS LIST OF TABLES ....................................................................................................................... iv LIST OF FIGURES ..................................................................................................................... vi ABBREVIATIONS ..................................................................................................................... vii 1 Executive Summary .............................................................................................................. 1 2 Background and Strategy................................................................................................... 11 2.1 Introduction and Strategy Definition ............................................................................ 11 2.2 Selection of Toxicity Endpoints and Life Cycle Stages ............................................... 13 2.2.1 The Rat Phthalate Syndrome ................................................................................................ 15 2.2.2 The Phthalate Syndrome in Other Species (excluding humans) .......................................... 16 2.2.3 Mechanism of Phthalate Action ........................................................................................... 18 2.3 Toxicology Data............................................................................................................ 19 2.3.1 Use of Animal Data to Assess Hazard and Risk .................................................................. 19 2.3.2 Developmental Toxicity of Phthalates in Rats ..................................................................... 22 2.3.3 Reproductive and Other Toxicity Data ................................................................................ 25 2.3.4 Cumulative Exposure Considerations .................................................................................. 26 2.4 Epidemiology ................................................................................................................ 27 2.4.1 Phthalates and Male Reproductive Tract Developmental Outcomes ................................... 28 2.4.2 Phthalates and Neurodevelopmental Outcomes ................................................................... 29 2.5 Human Biomonitoring ................................................................................................. 34 2.5.1 Introduction .......................................................................................................................... 34 2.5.2 Objectives ............................................................................................................................. 34 2.5.3 Methodology ........................................................................................................................ 35 2.5.4 Results .................................................................................................................................. 36 2.5.5 Conclusion ........................................................................................................................... 37 2.6 Scenario-Based Exposure Assessment ......................................................................... 49 2.6.1 Introduction .......................................................................................................................... 49 2.6.2 Objectives ............................................................................................................................. 49 2.6.3 Methodology ........................................................................................................................ 50 2.6.4 Results .................................................................................................................................. 50 2.6.5 Phthalate Substitutes ............................................................................................................ 51 2.6.6 Summary of Design.............................................................................................................. 52 2.6.7 Conclusions .......................................................................................................................... 52 2.6.8 General Conclusion and Comment ...................................................................................... 53 2.7 Cumulative Risk Assessment ........................................................................................ 61 2.7.1 Choice of Approach for Cumulative Risk Assessment ........................................................ 61 2.7.2 Summary Description of Methods Used .............................................................................. 63 2.7.3 Summary Results ................................................................................................................. 64 i 3 Phthalate Risk Assessment ................................................................................................. 68 4 Discussion............................................................................................................................. 71 4.1 Variability and Uncertainty........................................................................................... 71 4.1.1 Developmental/Reproductive Toxicity Data ........................................................................ 71 4.1.2 Exposure Scenarios .............................................................................................................. 72 4.1.3 HBM Data, Daily Intake Calculations, Hazard Index Calculations ..................................... 73 4.2 Species Differences in Metabolism, Sensitivity, and Mechanism ................................ 75 5 Recommendations ............................................................................................................... 79 5.1 Criteria for Recommendations ...................................................................................... 79 5.2 Recommendations on Permanently Banned Phthalates ................................................ 82 5.2.1 Di-n-butyl Phthalate (DBP) (84-74-2) ................................................................................. 82 5.2.2 Butylbenzyl Phthalate (BBP) (85-68-7) ............................................................................... 85 5.2.3 Di(2-ethylhexyl) Phthalate (DEHP) (117-81-7) ................................................................... 88 5.3 Recommendations on Interim Banned Phthalates ........................................................ 91 5.3.1 Di-n-octyl Phthalate (DNOP) (117-84-0) ............................................................................ 91 5.3.2 Diisononyl Phthalate (DINP) (28553-12-0 and 68515-48-0) .............................................. 95 5.3.3 Diisodecyl Phthalate (DIDP) (26761-40-0 and 68515-49-1) ............................................. 100 5.4 Recommendations on Phthalates Not Banned ............................................................ 105 5.4.1 Dimethyl Phthalate (DMP) (131-11-3) .............................................................................. 105 5.4.2 Diethyl Phthalate (DEP) (84-66-2) .................................................................................... 107 5.4.3 Diisobutyl Phthalate (DIBP) (84-69-5) .............................................................................. 110 5.4.4 Di-n-pentyl Phthalate (DPENP) (131-18-0) ....................................................................... 112 5.4.5 Di-n-hexyl Phthalate (DHEXP) (84-75-3) ......................................................................... 114 5.4.6 Dicyclohexyl Phthalate (DCHP) (84-61-7) ........................................................................ 116 5.4.7 Diisooctyl Phthalate (DIOP) (27554-26-3) ........................................................................ 118 5.4.8 Di(2-propylheptyl) Phthalate (DPHP) CAS 53306-54-0 ................................................... 120 5.5 Recommendations on Phthalate Substitutes ............................................................... 121 5.5.1 2,2,4-trimethyl-1,3 pentanediol diisobutyrate (TPIB) (6846-50-0) ................................... 121 5.5.2 Di(2-ethylhexyl) adipate (DEHA) CAS 103-23-1 ............................................................. 125 5.5.3 Di(2-ethylhexyl) terephthalate (DEHT) CAS 6422-86-2 ................................................... 129 5.5.4 Acetyl Tributyl Citrate (ATBC) CAS 77-90-7 .................................................................. 133 5.5.5 Diisononyl hexahydrophthalate (DINX) CAS 166412-78-8.............................................. 135 5.5.6 Tris(2-ethylhexyl) trimellitate (TOTM) CAS 3319-31-1 ................................................... 139 6 References .......................................................................................................................... 143 ii 7 Appendices A Developmental Toxicity................................................................................................A-1 B Reproductive Toxicity ..................................................................................................B-1 C Epidemiology ................................................................................................................C-1 D Hazard Index Approach ................................................................................................D-1 E Scenario-Based Exposure Assessment E1 Phthalates ............................................................................................................................. E1-1 E2 Phthalate Substitutes ............................................................................................................ E2-1 E3 Phthalate Exposure from Diet .............................................................................................. E3-1 iii LIST OF TABLES Table 2.1 Summary of NOAELs (mg/kg-d) for developmental endpoints affecting male reproductive development. ......................................................................................................... 24 Table 2.2 Phthalates and reproductive tract development. .................................................... 29 Table 2.3 Phthalates and neurological outcomes in newborns, infants, and children. ......... 31 Table 2.4 Molar urinary excretion fractions (f ) of phthalate metabolites related to the ue ingested dose of the parent phthalate determined in human metabolism studies within 24 hours after oral application........................................................................................................ 38 Table 2.5 Median (95th percentile)a concentrations (in µg/L) of DEHP and DINP metabolites in various study populations. ................................................................................. 39 Table 2.6 Median (95th percentile)a concentrations (in µg/L) of DMP, DEP, DBP, DIBP, BBP, DNOP, and DIDP metabolites in various study populations. ....................................... 42 Table 2.7 Daily phthalate intake (median, in µg/kg bw/day) of selected populations back- calculated from urinary metabolite levels. ............................................................................... 45 Table 2.8 Pearson correlation coefficient estimates between estimated daily intakes (DI) of the eight phthalate diesters (log 10 scale) for pregnant women in NHANES 2005–2006 (estimated using survey weights). Highlighted values indicate clusters of low molecular weight diesters and high molecular weight diesters................................................................. 47 Table 2.9 Pearson correlation estimates (* p<0.05) for estimated daily intake (DI) values (log 10 scale) for postnatal values with DI values estimated in their babies in the SFF study. N=251, except for *DINP and DIDP, where N=62. .................................................................. 48 Table 2.10 Sources of exposure to PEs included by exposure route. .................................... 54 Table 2.11 Estimated mean and 95th percentile total phthalate ester exposure (µg/kg-d) by subpopulation. ............................................................................................................................. 55 Table 2.12 Estimated oral exposure (µg/kg-d) from mouthing soft plastic objects except pacifiers.a...................................................................................................................................... 56 Table 2.13 Comparison of modeled estimates of total phthalate ester exposure (µg/kg-d). 57 Table 2.14 Comparison of modeled exposure estimates of total phthalate ester (PE) exposure (µg/kg-d) with estimates from biomonitoring studies. ............................................ 58 Table 2.15 Points of Departure (PODs; mg/kg-day), UFs and potency estimates for antiandrogenicity (PEAAs; µg/kg-day) in the three cases for the five phthalates considered in the cumulative risk assessment. ............................................................................................. 66 iv Table 2.16 Summary statistics (median, 95th, 99th percentiles) for HQs and HIs calculated from biomonitoring data from pregnant women (NHANES 2005–2006; CDC, 2012b) (SFF; Sathyanarayana et al., 2008a; 2008b) and infants (SFF; Sathyanarayana et al., 2008a; 2008b). NHANES values include sampling weights and thus infer to 5.3 million pregnant women in the U.S. population. SFF sample sizes range: Prenatal, N=340 (except N=18 for DINP); Postnatal, N=335 (except N=95 for DINP); Baby, N=258 (except N=67 for DINP); HI values are the sum of nonmissing hazard quotients. .......................................................... 67 Table 5.1 Margin of exposure (MOE) estimates for pregnant women (NHANES) and infants (SFF) using median and 95th percentile (0.95) daily intake estimates from biominotoring data using the range of PODs across the three cases. .................................... 80 v LIST OF FIGURES Figure 2.1 Sources of phthalate ester exposure. ...................................................................... 59 Figure 2.2 Estimated phthalate ester exposure (µg/kg-d) for eight phthalates and four subpopulations............................................................................................................................. 60 vi