A Framework to Guide Selection of Chemical Alternatives (2014) / Chapter Skim
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12 Case Studies
12 Case Studies
Pages 159-194
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From page 159... ...
. This case study illustrates Steps 1- 4 of the Committee's Framework how a chemical alternatives assessment was conducted by a single company as part of an internal feasibility study to determine whether there are Step 1: Identify Chemical of Concern alternatives to using materials with decaBDE in The substance of interest for this assessment is order to be able to sell their products in the EU.
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From page 160... ...
Supply chain: The direct supplier of the plastic KayDisplay has not conducted a formal enclosure will be consulted to identify potential alternatives assessment before and has no alternatives and to provide input on established principles or policies to guide the performance and economic issues. The supplier assessment.
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From page 161... ...
the analyses in the chemical alternatives assessment penta-, octa- , and decabromodiphenyl ether, because it does not have experts on certain tools or but each product is, in fact, a mixture of methods on staff. brominated diphenyl ethers." The commercial product decaBDE may contain up to 3% of other PBDEs, mostly Step 2b: Problem Formulation nonabromodiphenyl ether.
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From page 162... ...
10* 4 sp=62mm 7 kJ/m² THERMAL Value Unit Vicat Softening Temp, Rate B/50 140 °C HDT, 1.82 MPa, 3.2mm, unannealed 117 °C CTE, -40°C to 40°C, flow 9.2E-05 1/°C CTE, -40°C to 40°C, xflow 9.5E-05 1/°C CTE, -40°C to 40°C, flow 9.2E-05 1/°C CTE, -40°C to 40°C, xflow 9.5E-05 1/°C Ball Pressure Test, 125°C +/- 2°C Passes Vicat Softening Temp, Rate B/50 139 °C Vicat Softening Temp, Rate B/120 142 °C HDT/Bf, 0.45 MPa Flatw 80*
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From page 163... ...
will be completed through Occupational exposure occurs through the literature searches, relying heavily on the DfE's same routes, but at higher concentrations at DecaBDE alternatives assessment, as well as locations producing PBDEs or formulations guidance presented in Chapters 6-8. containing PBDEs, plastic component Step 7 (identify safer alternatives)
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From page 164... ...
Based on preliminary screening, KayDisplay will Step 9.3 (economic assessment) would be primarily consider PPE/HIPS with halogenated and completed to assess the internal costs and non-halogenated flame retardants and a material benefits of different options, including changes in change to PC/ABS with non-halogenated flame material cost, manufacturing costs and NRE retardants.
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From page 165... ...
- Significant material cost increase - Would require changing suppliers - Would require significant design changes - Would require significant manufacturing changes Having to change suppliers combined with significant material cost increases make this option an undesirable choice, and it will not be considered. aThe option of continuing to use decaBDE at levels below 1000ppm will not be considered because decaBDE is not effective as a flame retardant at that low level.
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From page 166... ...
For a Design for the Environment (DfE) chemical alternatives assessment, inhalation exposure is assumed to occur if the vapor pressure is greater than 1 x 10-8 mm Hg.
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From page 167... ...
. Conclusions: Aquatic toxicity: DecaBDE and TPP have logP > 2 and ∆E < 6.5 eV, which puts them in the high risk category for high acute and/or chronic aquatic toxicity.
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From page 168... ...
. The physicochemical properties of decaBDE, DBDPE, ATO, RDP, and TPP are compiled in DfE's Human exposure (occupational)
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From page 169... ...
* Fate Bioaccumulation Persistence Chronic Acute Chemical CASRN Decabromodiphenyl Ether 1163-19-5 L L VH H Decabromodiphenyl Ethane 84852-53-9 L L VH H Antimony Trioxidea 1309-64-4 H M HR L Resorcinol Bis-Diphenylphosphate; RDP 125997-21-9 VH VH M H‡ Triphenyl Phosphate 115-86-6 VH VH L M NOTE: VL = Very Low hazard L = Low hazard M = Moderate hazard H = High hazard VH = Very High hazard Endpoints (VL, L, M, H, and VH)
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From page 170... ...
Note: Italicized text taken from EPA 2014i. Step 7: Identify Safer Alternatives Relative hazards: In reviewing the hazard summary table for the alternatives, KayDisplay The combined hazard table for decaBDE, finds that DBDPE/ATO shows improvements DBDPE, ATO, RDP, and TPP from the DfE's over decaBDE in repeated dose toxicity and DecaBDE AA report is shown in Table 12-12.
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From page 171... ...
The atmospheric half life of decabromodiphenyl ethane is estimated to be 4.5 days, although it is expected to exist primarily in the particulate phase in air. Laboratory studies have demonstrated photolysis of decabromodiphenyl ethane, although the rate of this process under environmental conditions has not been established.
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From page 172... ...
Alternative Expected Transport DBDPE Based on the Level III fugacity models incorporating the located experimental property data, decabromodiphenyl ethane is expected to partition primarily to soil. Decabromodiphenyl ethane is expected to be immobile in soil based on its estimated Koc.
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From page 173... ...
Although the estimated bioaccumulation factor is low, the persistence of decabromodiphenyl ethane and its detection in many species from different habitats and trophic levels indicates high potential for bioaccumulation hazard in aquatic or terrestrial species. ATO LOW: Antimony trioxide is an inorganic compound and is not expected to bioaccumulate.
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From page 174... ...
. However, KayDisplay headquarters are located in Washington State, where water issues are of the highest priority, Steps 8-13 so the company will further investigate the potential Once alternatives based on DBDPE/ATO have aquatic toxicity of RDP/TPP.
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From page 175... ...
* Aquatic toxicity: EPA/DfE criteria are based in large part upon water column exposures which may not be adequate for poorly soluble substances such as many flame retardants that may partition to sediment and particulates.
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From page 177... ...
In this case study, an alternatives assessment will be performed on three chemicals that were originally developed as pharmaceutical agents. The Steps 1- 4 of the Framework rationale for choosing this example was driven in part by the committee's statement of task requiring examples demonstrating "how high throughput and Step 1: Identify Chemical of Concern high content data streams could inform assessment of potentially safer substitutes early in the chemical Concerns for human health have been identified development process" (see Chapter 1)
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From page 178... ...
These groups may have differing views on the relative importance of the various 6. Identify safer alternatives: In Step 7, assessments aspects of an alternatives assessment, such as of in vivo data will be completed using the the relative weight given to functional GreenScreen® tool.
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From page 179... ...
and the Assessment of Ecological Impact Based on potential alternatives. Physicochemical Properties Comparison of the physicochemical properties of Glitazone-T with the other two Glitazone Step 3: Identify Potential Alternatives alternatives show the same thiazolidinone ring Numerous structural analogs to Glitazone-T are structure, but Glitazone-T has a phenolic functional available, but for the most part these were deemed group as well as a prospectively liable, if masked, to have either lower potency against the PPARγ carbonyl group (Weltman et al 2011)
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From page 180... ...
Vapor pressure at 25°C 0.0 ± 2.1 mmHg 0.0 ± 1.6 mmHg 0.0 ± 1.6 mmHg (pred.) aValues for cLogP in this table were determined using the Biobyte software package.
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From page 181... ...
In if the two alternatives, R-ThZD and P-ThZD, addition, since the pharmacological action of a would have an improved safety profile when compound is generally driven by the unbound compared to the hepatotoxic Glitazone-T fraction in vivo, then a higher free fraction compound. indicates that lower total drug doses would be Mitochondrial dysfunction and BSEP inhibition: Many needed to elicit the desired effect of the eukaryotic cells derive the majority of their compound.
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From page 182... ...
. physicochemical properties to R-ThZD, along Interfering with mitochondrial production of with similar in silico predictions for passive ATP will deplete cellular energy stores, and may permeability, Vdss and protein binding, it might result in cellular stress and cell death.
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From page 183... ...
Rtwo compounds in the Attagene nuclear hormone ThZD has a greater impact on inducing ER stress receptor panels in Figure 12-6, it can be seen that aside from the intended biological activity of these based on the XBP1 reporter assay, and so may be molecules, Glitazone-T is having an effect on more expected to show in vivo toxicity at lower plasma of these receptors than P-ThZD. Based on these concentrations than P-ThZD.
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From page 184... ...
P-ThZD, however, has an acute chromosomal aberration, unscheduled DNA, and in oral LD50 = 181mg/kg in mice, which is considered to vivo mouse micronucleus were all negative, while the be Very High. Similarly, R-ThZD has a mouse LD50 = incidence of forward mutations at the thymidine 300 mg/kg, so its acute mammalian toxicity is kinase locus of mouse lymphoma LS 178Y cells was categorized as High.
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From page 185... ...
FIGURE 12-6 Attagene Nuclear Hormone Receptor panel assay profiles for Glitazone-T (Trogliatazone) and P-ThZD (Pioglitazone)
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From page 186... ...
Based on this hazard categorization is considered Moderate. information, the repeat dose hazard categorization is In a 13-week dietary range-finding study, mice Moderate.
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From page 187... ...
TABLE 12-17 Summary of Mammalian Toxicity Assessment Developmental Toxicity Respiratory and Skin Acute mammalian Carcinogenicity Repeated Dose Neurotoxicity Reproductive Mutagenicity/ Genotoxicity Sensitization Toxicity Alternative V V V V V H M L H M L H M L H M L H M L H M L H M L H H H L L Glita zone DG -T P ThZ DG D R ThZ DG D Note: Toxicity data has been benchmarked using the GreenScreen® system. The uncertainty associated with each toxicological finding is depicted by colors (green = minimal uncertainty, yellow= moderate uncertainty, orange = highly uncertain, gray = data gap)
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From page 188... ...
Table 12-18 summarizes the thresholds aquatic toxicity for P-ThZD is generally and categories provided by the four chemical characterized as high toxicity, with the exception of alternatives assessments that provide quantitative the characterization of NOEL under the P20ASys. characterizations of toxicity.
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From page 189... ...
Case Studies 189 TABLE 12-18 Aquatic Toxicological End Points and Assigned Category from Chemical Alternatives Assessments Acute Toxicity Chronic Toxicity End point End point Assigned Assigned End point Thresholds Endpoint Thresholds Category Category (mg/L)
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From page 190... ...
D magna overall 0.0753 mg/l NA NA NA Toxic NOEC Fish End Points Fish 32- day NOEC (early life stage body 0.0584 mg/L 2 Toxic weight)
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From page 191... ...
scores in increased to give exposure and performance the exposure, in vitro safety, off-target activities, and greatest emphasis, followed by in vivo safety, in vitro physicochemical properties. safety, preclinical ADME with in silico predictions, In Figure 12-9, greater emphasis was placed on and physicochemical properties, off-target activities the in vivo (e.g., animal)
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From page 192... ...
Category of Data End Point Glitazone-T P-ThZD R-ThZD Exposure assessment Estimated daily exposure 3 2 1 LogP/LogD 3 2 1 Physicochemical data Polar surface area 1 1 1 Aqueous solubility 3 2 1 Cytotoxicity LC50 3 1 1 hERG IC50 1 1 1 Volume of distribution 1 1 1 Free fraction in human plasma 3 1 2 Predicted properties Passive permeability 2 1 1 MDR efflux 1 1 1 Structural alerts 1 1 1 Mitochondrial dysfunction 3 2 2 BSEP inhibition @ 100μM 3 3 3 Cytotoxicity in THLE & HepG2 cells 3 1 1 XBP1 reporter assay (ER Stress) 2 1 3 BSEP inhibition 1 3 2 In vitro safety assays Mitochondrial uncoupling 3 1 2 Mitochondrial inhibition 3 1 1 Off-target pharmacology 3 1 1 Bioavailability 3 1 2 Mammalian exposure Protein binding 3 1 2 Acute toxicity 1 2 2 Carcinogenicity 2 2 2 Mutagenicity/Genotoxicity 2 1 2 Mammalian toxicity Reproductive toxicity 1 2 3 Developmental toxicity 1 2 3 Neurotoxicity 1 2 2 Repeated dose toxicity 2 2 2 Ecological toxicity Aquatic Toxicity 3 3 3 TOTAL SCORES 62 45 50
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From page 193... ...
In vitro safety Cytotoxicity LC50 in HepG2 cells at 24 hrs in glucose and galactose, XBP1 activation assay, Caspase 3/7 activation, Mitochondrial inhibition and uncoupling, BSEP inhibition, cytotoxicity LC50 in HepG2 and THLE cells at 72 hrs in glucose containing media In vivo safety Assessments of mutagenicity, carcinogenicity, reproductive toxicity, neurotoxicity, repeat dose toxicity, acute toxicity, developmental toxicity Physicochemical LogP, LogD, PSA, PSA/MW, cSolubility, Acidic pKa, Basic pKa properties NOTE: AUC = area under receiver operating characteristic curve; PPB = parts per billion; Cmax = maximum concentration; VDss = volume of distribution at steady-state; Tmax = time of maximum plasma concentration; BSEP = bile salt export pump; hERG = human Ether-à-go-go-Related Gene; MDR = multi-drug resistant; THLE = T-antigen-immortalized human liver epithelial; COX2 = cyclooxygenase-2; 5-HT = serotonin transporter; PPAR = peroxisome proliferator-activated receptor; PDE3 = phosphodiesterase 3; Na = sodium; Ca = calcium; CB1 = cannabinoid receptor 1; GABAA = γ-Aminobutyric acid a; NE = norepinephrine; 5HT2b = 5-Hydroxytryptamine receptor 2B; LC50 = lethal concentration 50; XBP1 = X-box binding protein 1; LogP = partition coefficient; LogD = distribution coefficient; PSA = prostate-specific antigen FIGURE 12-8 ToxPi visualization of data by data type and resultant rank ordering of chemicals.
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From page 194... ...
194 A Framework to Guide Selection of Chemical Alternatives FIGURE 12-9: ToxPi visualization of data with in vivo safety heavily weighted. FIGURE 12-10 ToxPi visualization of data with functional efficacy heavily weighted.
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