A Class Approach to Hazard Assessment of Organohalogen Flame Retardants (2019) / Chapter Skim
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3 A Class Approach to Evaluating Organohalogen Flame Retardants: Case Studies
3 A Class Approach to Evaluating Organohalogen Flame Retardants: Case Studies
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class. The committee's analyses included the following: CAN ORGANOHALOGEN FLAME RETARDANTS • Prediction of structure–activity relationships BE DEFINED AS A SINGLE CLASS?
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Additional details are provided in Appendix B showed that the seed chemicals have similar physi- DEFINITION OF SUBCLASSES OF ORGANO cochemical, toxicological and environmental fate HALOGEN FLAME RETARDANTS properties that were not distinguishable from those of the expanded set of chemical analogues.3 The committee used cheminformatic approaches to create OFR subclasses.
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plore PubChem for toxicity data on each seed chemical. It first conducted an initial mapping exercise to evaluate The query focused on chronic toxicity, reproductive and the types of toxicity data available on each subgroup and developmental toxicity, mutagenicity, and cancer, which then conducted several literature surveys to identify end were end points that were specifically listed in the compoints of possible interest.
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TABLE 3-2 OFR Subclasses Formulated by Using Chemotypes and Predicted Biologic Activity OFR Subclass No. Chemicals in Subclassa Polyhalogenated alicycles 17 Polyhalogenated aliphatic carboxylate 4 Polyhalogenated aliphatic chains 12 Polyhalogenated benzene alicycles 4 Polyhalogenated benzene aliphatics and functionalized 19 Polyhalogenated benzenes 19 Polyhalogenated bisphenol aliphatics and functionalized 11 Polyhalogenated carbocycles 15 Polyhalogenated diphenyl ethers 12 Polyhalogenated organophosphates (OPs)
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Each bar indicates the data coverage in the eight database sources for each subclass.
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Each bar indicates the data coverage in the eight database sources for each subclass.
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, have suggested that NAM data can be used in the context of hazard assessment. The use of non traditional data has been suggested as an addition to the traditional data to bolster confidence in the hypothesis of common mechanisms or effects or as an additional data stream when traditional toxicology data are too sparse to support a hypothesis of common effects among group members confidently (NASEM 2017)
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and polyhalogenated bisphenol aliphatics -- did, however, search multiple databases for toxicity data were selected to serve as case studies to illustrate various in vertebrates on each member of the subclasses chosen aspects of the hazard-assessment scoping plan. for the case studies.9 The searches were intended to gather the available literature on the two subclasses and to illus SEARCH OF THE LITERATURE trate the process that could be used (see Appendix C for details)
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TCPP Negative in Ames assays; equivocal results in mouse lymphoma assays, unscheduled DNA synthesis assays, and comet assays; positive in in vitro mouse lymphoma assay when tested with metabolic activation; negative in in vivo micronucleus tests and comet assays; equivocal or negative in in vivo assays of unscheduled DNA synthesis and chromosomal aberrations; and in vivo micronucleus tests in mice and rats had positive results only in male mice (Environment Canada and Health Canada 2016)
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. The committee illustrates the Developmental Toxicity Data on use of zebrafish data in the following case studies because Polyhalogenated Organophosphates such data were available on several OFRs.
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phosphate; OPFR, organophosphate flame retardant; TDCPP, tris(1,3-dichloro-2propyl) phosphate; TPP, triphenyl phosphate; TSH, thyrotropin; TT4, total thyroxine.
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TABLE 3-8 Zebrafish Teratology and Developmental Neurotoxicity Studies of Polyhalogenated Organophosphates Studies of developmental neurotoxic effects or altered Chemical Studies of malformations locomotor activity TDCPP Increased incidence found by Alzualde et al. 2018; Increased incidence found by Cheng et al.
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. Mammalian Toxicity Studies Several laboratories conducted zebrafish studies with multiple polyhalogenated OPs that allowed more di Developmental toxicity data were available on four rect comparisons between subclass members.
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. The data also CASE STUDY 2: POLYHALOGENATED indicate that differences among the chemicals regarding BISPHENOL ALIPHATICS neurotoxic, teratogenic, and developmental toxicity depend on the exposure period.
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. TABLE 3-12 Subchronic and Chronic Toxicity Studies of Polyhalogenated Bisphenol Aliphatics Chemical Experimental Results Subchronic Studies TBBPA Rats: NOAEL, 100 mg/kg-day; ↓T4 (no change in T3 or TSH)
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TABLE 3-14 Mammalian Developmental Toxicity Studies of Polyhalogenated Bisphenol Aliphatics Chemical Experimental Results TBBPA Prenatal studies in rodents: no effects in standard studies at doses up to 10,000 mg/kg-day (ECB 2006a)
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(2008) TABLE 3-16 Summary of Evidence on Developmental Effects in Mammals and Zebrafish Associated with Polyhalogenated Bisphenol Aliphatics Mammalsa Zebrafishb Chemical Developmental toxicity Teratogenesis Locomotor Activity TBBPA +/− + +/− TBBPA-DBPE +/− − − TBBPA-BHEE Not determined + + TBBPA-BME Not determined − Not determined a See Table 3-14.
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. Class Hazard Assessment Based on Developmental Toxicity Zebrafish Studies The committee's evaluation initially considered the TBBPA is toxic to zebrafish embryos, and there is a best-studied chemicals in the polyhalogenated bisphenol database on TBBPA-related effects on thyroid hormone aliphatic subclass (Table 3-16)
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Although a standardized OECD guidelack of effects seen in rodent developmental toxicity stud- line (Test No. 236: Fish Embryo Acute Toxicity Test)
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mittee's initial literature survey exercise suggests that this grouped 67 brominated flame retardants on the basis of could be the case for several OFR subclasses. For subtheir chemical structures and then made QSAR predic- classes on which there are adequate data, there might be a tions of selected environmental and health effects.
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De Coen. organophosphate flame retardant metabolites, fertility 2008.
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2011c. Scientific opinion on hexabromocyclodo- related chemicals cluster flame retardants.
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2014. of two organophosphate flame retardants–TCPP and TD- Urinary tetrabromobenzoic acid (TBBA)
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2016a. An automated curation procedure to brominated flame retardants in adolescents: a cross- for addressing chemical errors and inconsistencies in sectional study.
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genated and organophosphate flame retardants. Toxicol.
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2009. Developmental toxicity of bro residential exposure to organophosphate ester flame re- minated flame retardants, tetrabromobisphenol A and tardants and plasticizers: Investigating exposure path- 1,2,5,6,9,10-hexabromocyclododecane, in rat offspring ways in the TESIE study.
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2017. reference from Environment Canada and Health Canada In vivo metabolism of organophosphate flame retardants 2016]
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Res. assessment of phosphorus-containing flame retardants by (Camb.)
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