EPA/690/R-18/003 | August 16, 2018 | FINAL United States Environmental Protection Agency Provisional Peer-Reviewed Toxicity Values for Stable (Nonradioactive) Soluble Lutetium (CASRN 7439-94-3) U.S. EPA Office of Research and Development National Center for Environmental Assessment, Superfund Health Risk Technical Support Center (Cincinnati, OH) ------- A rnA United States ^jup^ Environmental Protection EPA/690/R-18/003 FINAL 08-16-2018 Provisional Peer-Reviewed Toxicity Values for Stable (Nonradioactive) Soluble Lutetium (CASRN 7439-94-3) Superfund Health Risk Technical Support Center National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Cincinnati, OH 45268 ------- AUTHORS, CONTRIBUTORS, AND REVIEWERS CHEMICAL MANAGER Scott C. Wesselkamper, PhD National Center for Environmental Assessment, Cincinnati, OH CONTRIBUTOR Chris Cubbison, PhD National Center for Environmental Assessment, Cincinnati, OH DRAFT DOCUMENT PREPARED BY SRC, Inc. 7502 Round Pond Road North Syracuse, NY 13212 PRIMARY INTERNAL REVIEWERS Paul G. Reinhart, PhD, DABT National Center for Environmental Assessment, Research Triangle Park, NC Q. Jay Zhao, PhD, DABT National Center for Environmental Assessment, Cincinnati, OH This document was externally peer reviewed under contract to: Eastern Research Group, Inc. 110 Hartwell Avenue Lexington, MA 02421-3136 Questions regarding the content of this PPRTV assessment should be directed to the U.S. EPA Office of Research and Development's National Center for Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300). li Soluble Lutetium ------- TABLE OF CONTENTS COMMONLY USED ABBREVIATIONS AND ACRONYMS iv BACKGROUND 1 DISCLAIMERS 1 QUESTIONS REGARDING PPRTVs 1 INTRODUCTION 2 REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) 6 HUMAN STUDIES 9 Oral Exposures 9 Inhalation Exposures 9 ANIMAL STUDIES 9 Oral Exposures 9 Inhalation Exposures 10 OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 10 Supporting Toxicity Studies 10 Metabolism/Toxicokinetic Studies 14 Mechanistic Studies 15 DERIVATION 01 PROVISIONAL VALUES 17 DERIVATION OF ORAL REFERENCE DOSES 17 Derivation of a Subchronic Provisional Reference Dose 17 Derivation of a Chronic Provisional Reference Dose 20 DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 21 CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 21 DERIVATION OF PROVISIONAL CANCER POTENCY VALUES 21 APPENDIX A. REFERENCES 22 in Soluble Lutetium ------- COMMONLY USED ABBREVIATIONS AND ACRONYMS1 a2u-g alpha 2u-globulin MN micronuclei ACGIH American Conference of Governmental MNPCE micronucleated polychromatic Industrial Hygienists erythrocyte AIC Akaike's information criterion MOA mode of action ALD approximate lethal dosage MTD maximum tolerated dose ALT alanine aminotransferase NAG 7V-acetyl-P-D-glucosaminidase AR androgen receptor NCEA National Center for Environmental AST aspartate aminotransferase Assessment atm atmosphere NCI National Cancer Institute ATSDR Agency for Toxic Substances and NOAEL no-observed-adverse-effect level Disease Registry NTP National Toxicology Program BMD benchmark dose NZW New Zealand White (rabbit breed) BMDL benchmark dose lower confidence limit OCT ornithine carbamoyl transferase BMDS Benchmark Dose Software ORD Office of Research and Development BMR benchmark response PBPK physiologically based pharmacokinetic BUN blood urea nitrogen PCNA proliferating cell nuclear antigen BW body weight PND postnatal day CA chromosomal aberration POD point of departure CAS Chemical Abstracts Service PODadj duration-adjusted POD CASRN Chemical Abstracts Service registry QSAR quantitative structure-activity number relationship CBI covalent binding index RBC red blood cell CHO Chinese hamster ovary (cell line cells) RDS replicative DNA synthesis CL confidence limit RfC inhalation reference concentration CNS central nervous system RfD oral reference dose CPN chronic progressive nephropathy RGDR regional gas dose ratio CYP450 cytochrome P450 RNA ribonucleic acid DAF dosimetric adjustment factor SAR structure activity relationship DEN diethylnitrosamine SCE sister chromatid exchange DMSO dimethylsulfoxide SD standard deviation DNA deoxyribonucleic acid SDH sorbitol dehydrogenase EPA Environmental Protection Agency SE standard error ER estrogen receptor SGOT serum glutamic oxaloacetic FDA Food and Drug Administration transaminase, also known as AST FEVi forced expiratory volume of 1 second SGPT serum glutamic pyruvic transaminase, GD gestation day also known as ALT GDH glutamate dehydrogenase SSD systemic scleroderma GGT y-glutamyl transferase TCA trichloroacetic acid GSH glutathione TCE trichloroethylene GST glutathione-S-transferase TWA time-weighted average Hb/g-A animal blood-gas partition coefficient UF uncertainty factor Hb/g-H human blood-gas partition coefficient UFa interspecies uncertainty factor HEC human equivalent concentration UFc composite uncertainty factor HED human equivalent dose UFd database uncertainty factor i.p. intraperitoneal UFh intraspecies uncertainty factor IRIS Integrated Risk Information System UFl LOAEL-to-NOAEL uncertainty factor IVF in vitro fertilization UFs subchronic-to-chronic uncertainty factor LC50 median lethal concentration U.S. United States of America LD50 median lethal dose WBC white blood cell LOAEL lowest-observed-adverse-effect level Abbreviations and acronyms not listed on this page are defined upon first use in the PPRTV document. iv Soluble Lutetium ------- FINAL 08-16-2018 PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR LUTETIUM (CASRN 7439-94-3) BACKGROUND A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant scientific literature using established Agency guidance on human health toxicity value derivations. All PPRTV assessments receive internal review by at least two National Center for Environment Assessment (NCEA) scientists and an independent external peer review by at least three scientific experts. The purpose of this document is to provide support for the hazard and dose-response assessment pertaining to chronic and subchronic exposures to substances of concern, to present the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to characterize the overall confidence in these conclusions and toxicity values. It is not intended to be a comprehensive treatise on the chemical or toxicological nature of this substance. PPRTV assessments are eligible to be updated on a 5-year cycle to incorporate new data or methodologies that might impact the toxicity values or characterization of potential for adverse human-health effects and are revised as appropriate. Questions regarding nomination of chemicals for update can be sent to the appropriate U.S. Environmental Protection Agency (EPA) Superfund and Technology Liaison (https://www.epa.gov/research/fact-sheets-regional- science). DISCLAIMERS The PPRTV document provides toxicity values and information about the adverse effects of the chemical and the evidence on which the value is based, including the strengths and limitations of the data. All users are advised to review the information provided in this document to ensure that the PPRTV used is appropriate for the types of exposures and circumstances at the site in question and the risk management decision that would be supported by the risk assessment. Other U.S. EPA programs or external parties who may choose to use PPRTVs are advised that Superfund resources will not generally be used to respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program. This document has been reviewed in accordance with U.S. EPA policy and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. QUESTIONS REGARDING PPRTVS Questions regarding the content of this PPRTV assessment should be directed to the U.S. EPA Office of Research and Development's (ORD's) NCEA, Superfund Health Risk Technical Support Center (513-569-7300). 1 Soluble Lutetium ------- FINAL 08-16-2018 INTRODUCTION Lutetium (Lu), CASRN 7439-94-3, a member of the lanthanide series, is a metallic element with an atomic number of 71. One of the few commercial uses of lutetium is as a catalyst in cracking, alkylation, hydrogenation, and polymerization processes (Bunzli. 2013; Lewis and Hawlev. 2007). Radioactive lutetium (Lu-177) has been used in radiopharmaceuticals (Baneriee et al.. 2015). Occupational and public safety health risks associated with exposure to rare earth metals like lutetium may occur during mining, transportation, processing, commercial use, and waste disposal (TaekRim et al.. 2013). Lutetium is listed on U.S. EPA's Toxic Substances Control Act's public inventory (US EPA, 2018b); however, it is not registered with Europe's Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) program (ECHA, 2018). Lutetium occurs naturally in the earth's crust at a concentration of approximately 0.8 ppm (Bunzli. 2013). Lanthanides like lutetium are typically found as trivalent cations in insoluble compounds within rock-forming minerals such as carbonates, oxides, phosphates, and silicates (t'SGS, 2016). Lutetium occurs at a concentration of 0.003% in the mineral monazite, which is the element's commercial source. Monazite is digested using caustic soda to obtain the lanthanides as hydroxides. The hydroxides are then treated with hydrochloric or nitric acid to remove thorium and other elements, and further processed to recover the individual lanthanides (Bunzli. 2013). Lutetium is a soft, ductile, silvery-white metal that is difficult to isolate. It is relatively stable in air, reacts slowly with water, and is soluble in dilute acid (Havnes. 2014; Lewis and Hawlev. 2007). Table 1 summarizes the physicochemical properties of lutetium and two of its commonly occurring soluble salts. Like other lanthanides, lutetium forms mostly ionic compounds, has a high affinity to oxygen, and exists in its +3 oxidation state in compounds or in solution under most conditions. In general, lanthanide salts of chloride, nitrate, and perchlorate are soluble, while compounds of hydroxide, carbonate, phosphate, and fluoride are insoluble (Evans. 1990). 2 Soluble Lutetium ------- FINAL 08-16-2018 Table 1. Physicochemical Properties of Lutetium and Soluble Salts Property (unit) Lutetium Lutetium Chloride Lutetium Nitrate CASRN 7439-94-3 10099-66-8 10099-67-9 Formula Lu LuC13 Lu(N03)3 Physical state Solid Solid Solid Boiling point (°C) 3,402a >750 (sublimes)b NV Melting point (°C) l,663a 925a NV Density (g/cm3 at 25°C) 9.84a 3.98a NV pH at which precipitation starts (0.1 M Lu|NCh|3) 5.74 (ion)0 NV NV Vapor pressure (mm Hg at 25°C) NA NA NA Solubility in water (mg/L at 25°C) NV Soluble3 Soluble3 Atomic or formula weight (g/mol) 174.9673 281.3263 360.9823 Flash point (closed cup in °C) NA NV NV "Havnes (2014). bO'Neil (2013). cBimz1i (2.0131 NA = not applicable; NV = not available. Lutetium chloride (LuCb), CASRN 10099-66-8, is a hygroscopic, white, monoclinic crystalline solid that is water soluble (Havnes. 2014). Lutetium chloride is used in laser crystals and optical fibers and as an optical dopant (Metal 1 Rare Earth, 2015). Lutetium chloride also exists as the hexahydrate (LuCb*6H20; CASRN 15230-79-2) and the radiolabeled (177LuCb; CASRN 16434-14-3) forms. Lutetium nitrate (Lu[NC>3]3), CASRN 10099-67-9, is a soluble, hygroscopic, colorless solid (Havnes. 2014). Soluble lutetium salts (e.g., chloride and nitrate), once dissolved in aqueous solution or biological systems, would rapidly form Lu3+ ions with bound water molecules. The solubility of Lu3+ in aqueous solution is pH dependent. At pH below approximately 5.7, the Lu3+ ion is bound to water molecules as its soluble aqua ion (Lu[H20]63+), which would be the predominant lutetium species found in the stomach (pH 1-2), Above pH 5.7, as would be found in the small intestines and blood, lutetium will begin to precipitate out of solution as the bound water molecules are converted to hydroxide ions (Lu[0H]3[H20]3). In biological systems, Lu3+ ions may also bind to other oxygen donor molecules, such as carboxylic acids (proteins) and phosphates (nucleic acids) (Evans. 1990). A summary of available toxicity values for lutetium and lutetium compounds from U.S. EPA and other agencies/organizations is provided in Table 2. A 2007 PPRTV assessment from the U.S. EPA was previously available for "Stable Lutetium." The assessment herein provides an updated evaluation of soluble lutetium based on recent scientific literature and current PPRTV assessment practices. 3 Soluble Lutetium ------- FINAL 08-16-2018 Table 2. Summary of Available Toxicity Values for Lutetium (CASRN 7439-94-3) and Lutetium Compounds Source (parameter)3'b Value (applicability) Notes Reference Noncancer IRIS NV NA U.S. EPA (2018a) HEAST NV NA U.S. EPA (2011a) DWSHA NV NA U.S. EPA (2012) ATSDR NV NA ATSDR (2018) IPCS NV NA IPCS (2018): WHO (2018) CalEPA NV NA CalEPA (2016): CalEPA (2018a): CalEPA (2018b) OSHA NV NA OSHA (2017a): OSHA (2017b) NIOSH NV NA NIOSH (2016) ACGIH NV NA ACGIH (2018) DOE (PAC) PAC-3: 2,000 mg/m3; PAC-2: 330 mg/m3; PAC-1: 30 mg/m3 (for lutetium and lutetium oxide) PAC-3 and PAC-2 based on adjustments to 1-hr TEELs; documentation of the basis for TEEL values was not located. PAC-1 based on ACGIH TLV-TWA for insoluble or poorly soluble particles not otherwise specified. DOE (2015) USAPHC (air-MEG) 1-hr critical: 150 mg/m3; 1-hr marginal: 35 mg/m3; 1-hr negligible: 5 mg/m3 (for lutetium) Based on 1-hr TEELs. Documentation of the basis for TEEL values was not located. U.S. APHC (2013) USAPHC (air-MEG) 1-hr critical: 250 mg/m3; 1-hr marginal: 50 mg/m3; 1-hr negligible: 30 mg/m3 (for lutetium oxide) Based on 1-hr TEELs. Documentation of the basis for TEEL values was not located. U.S. APHC (2013) USAPHC (water-MEG) 1-yr negligible: 7 mg/L (for lutetium) Derived using 5 L intake rate and subchronic p-RfD from a previous/older PPRTV. U.S. APHC (2013) USAPHC (soil-MEG) 1-yr negligible: 1.06 x 105 mg/kg (for lutetium) Basis: noncancer, not further documented. U.S. APHC (2013) Cancer IRIS NV NA U.S. EPA (2018a) HEAST NV NA U.S. EPA (2011a) DWSHA NV NA U.S. EPA (2012) NTP NV NA NTP (2016) IARC NV NA IARC (2018) 4 Soluble Lutetium ------- FINAL 08-16-2018 Table 2. Summary of Available Toxicity Values for Lutetium (CASRN 7439-94-3) and Lutetium Compounds Source (parameter)3'b Value (applicability) Notes Reference CalFPA NV NA CalEPA (2011): CalEPA (2018a): CalEPA (2018b) ACGIH NV NA ACGIH (2018) aSources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic Substances and Disease Registry; CalEPA = California Environmental Protection Agency; DOE = Department of Energy; DWSHA = Drinking Water Standards and Health Advisories; HEAST = Health Effects Assessment Summary Tables; IARC = International Agency for Research on Cancer; IPCS = International Programme on Chemical Safety; IRIS = Integrated Risk Information System; NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program; OSHA = Occupational Safety and Health Administration; USAPHC = U.S. Army Public Health Command. Parameters: MEG = military exposure guideline; PAC = protective action criteria; p-RfD = provisional reference dose; TEEL = temporary emergency exposure limit; TLV = threshold limit value; TWA = time-weighted average. NA = not applicable; NV = not available; PPRTV = provisional peer-reviewed toxicity value. Non-date-limited literature searches were conducted in December 2015 and updated in July 2018 for studies relevant to the derivation of provisional toxicity values for soluble lutetium and primarily focused on commonly occurring forms of the compound as follows: lutetium (CASRN 7439-94-3), lutetium chloride (CASRN 10099-66-8), lutetium chloride hexahydrate (CASRN 15230-79-2), lutetium nitrate (CASRN 10099-67-9), lutetium bromide (CASRN 14456-53-2), and lutetium sulfide (CASRN 12163-20-1). Searches were conducted using U.S. EPA's Health and Environmental Research Online (HERO) database of scientific literature. HERO searches the following databases: PubMed, ToxLine (including TSCATS1), and Web of Science. The following databases were searched outside of HERO for health-related data: American Conference of Governmental Industrial Hygienists (ACGIH), Agency for Toxic Substances and Disease Registry (ATSDR), California Environmental Protection Agency (CalEPA), European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), Japan Existing Chemical Data Base (JECDB), European Chemicals Agency (ECHA), Organisation for Economic Co-operation and Development (OECD), Screening Information Data Sets (SIDS), OECD International Uniform Chemical Information Database (IUCLID), OECD High Production Volume (HPV), U.S. EPA Integrated Risk Information System (IRIS), U.S. EPA Health Effects Assessment Summary Tables (HEAST), U.S. EPA HPV, U.S. EPA Office of Water (OW), U.S. EPA TSCATS2/TSCATS8e, National Institute for Occupational Safety and Health (NIOSH), National Toxicology Program (NTP), Occupational Safety and Health Administration (OSHA), and Defense Technical Information Center (DTIC). Toxicological data were only located for lutetium chloride (CASRN 10099-66-8) and lutetium nitrate (CASRN 10099-67-9). 5 Soluble Lutetium ------- FINAL 08-16-2018 REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) Tables 3A and 3B provide overviews of the relevant noncancer and cancer databases, respectively, for lutetium and its soluble salts and include all potentially relevant repeated-dose short-term-, subchronic-, and chronic-duration studies as well as reproductive and developmental toxicity studies. Principal studies are identified in bold. The phrase "statistical significance," used throughout the document, indicates ap-value of < 0.05 unless otherwise specified. 6 Soluble Lutetium ------- FINAL 08-16-2018 Table 3A. Summary of Potentially Relevant Noncancer Data for Soluble Lutetium (CASRN 7439-94-3) Category3 Number of Male/Female, Strain, Species, Study Type, Reported Doses, Study Duration Dosimetryb Critical Effects NOAELb LOAELb Reference (comments) Notes0 Human 1. Oral (mg/kg-d) ND 2. Inhalation (mg/m3) ND Animal 1. Oral (mg/kg-d)b Subchronic 6 M/6 F, CRW rat; lutetium chloride in the diet; 0,0.01,0.1, or 1.0%; 90 d M: 0,5.56,55.6, or 555.8 (as lutetium); F: 0,6.11,61.1, or 611.2 (as lutetium) No effect on body weight, hematology, or gross or microscopic pathology of the heart, lung, liver, kidney, pancreas, spleen, adrenals, and small intestine. M: 555.8 (as lutetium) F: 611.2 (as lutetium) NDr Halcv et al. (1964). PR, PS 2. Inhalation (mg/m3) ND "Duration categories are defined as follows: Acute = exposure for <24 hours; short term = repeated exposure for 24 hours to <30 days; long term (subchronic) = repeated exposure for >30 days <10% lifespan for humans (>30 days up to approximately 90 days in typically used laboratory animal species); and chronic = repeated exposure for >10% lifespan for humans (>~90 days to 2 years in typically used laboratory animal species) (U.S. EPA. 20021. bDosimetry: Values are presented as ADD of lutetium (in mg Lu/kg-day) for oral noncancer effects. °Notes: PR = peer reviewed; PS = principal study. ADD = adjusted daily dose; F = female(s); LOAEL = lowest-observed-adverse-effect level; M = male(s); ND = no data; NDr = not determined; NOAEL = no-observed-adverse-effect level. 7 Soluble Lutetium ------- FINAL 08-16-2018 Table 3B. Summary of Potentially Relevant Cancer Data for Soluble Lutetium (CASRN 7439-94-3) Category Number of Male/Female, Strain, Species, Study Type, Reported Doses, Study Duration Dosimetry Critical Effects Reference (comments) Notes Human 1. Oral (mg/kg-d) ND 2. Inhalation (mg/m3) ND Animal 1. Oral (mg/kg-d) ND 2. Inhalation (mg/m3) ND ND = no data. 8 Soluble Lutetium ------- FINAL 08-16-2018 HUMAN STUDIES Oral Exposures No data regarding the toxicity of lutetium to humans following oral exposure have been located. Lutetium texaphyrin (Lu-Tex) has been used in the treatment of age-related macular degeneration. The reported effective dose range was 2-4 mg/kg-day of Lu-Tex (Pharmacvclics. 1999). The texaphyrin moiety is a large porphyrin structure with several side chains and is probably at least as important as the lutetium itself for the compound's biological action. Therefore, any dose-response information for Lu-Tex cannot be applied to the assessment of lutetium alone. Details of the responses encountered in clinical trials were not reported. In addition, even an approximate molecular weight for Lu-Tex cannot be estimated, so the dose range for the lutetium cannot be determined. Inhalation Exposures No studies of the toxicity of lutetium to humans exposed by inhalation have been located. The pulmonary toxicity of inhaled rare earth compounds, in general, is the subject of debate, especially with regard to the relative contributions of radioactive contaminants versus stable elements in the development of progressive pulmonary interstitial fibrosis (Beliles. 1994; Haley. 1991). In particular, although it is known that stable rare earth compounds can produce a static, foreign-body-type lesion consistent with benign pneumoconiosis, it is uncertain whether these compounds can also induce interstitial fibrosis that progresses after termination of exposure. Human inhalation toxicity data on stable rare earth elements mainly consist of case reports on workers exposed to multiple lanthanides (Dene et ai, 1991; Waring and Watling. 1990; Sulotto et ai, 1986; Vogt et aL 1986; Colombo et al.. 1983; Vocaturo et ai, 1983; Sabbioni et at., 1982; Husain et ai, 1980; Kappenberger and Buhl mann. 1975). ANIMAL STUDIES Oral Exposures Haley et al. (1964) Groups of six male and six female CRW rats were fed 0, 0.01, 0.1, or 1.0% lutetium chloride (purity not reported) in the diet for 90 days (Haley et ai. 1964). Although food intake was not reported, growth rates were the same in treated and untreated rats. Compound intake, as lutetium chloride (trichloride, LuCb), is estimated to have been 8.94, 89.4, or 893.6 mg LuCb/kg-day in males, and 9.83, 98.3, or 982.7 mg LuCb/kg-day in females based on reference body weights and food intake.2 The corresponding lutetium intakes are calculated to be 5.56, 55.6, and 555.8 mg Lu/kg-day for males and 6.11, 61.1, or 611.2 mg Lu/kg-day for females.3 Body weight and hematology (total erythrocytes, total leukocytes, differential cell count, platelets, hemoglobin [Hb], and hematocrit [Hct]) were measured biweekly, and gross and histological examinations (heart, lung, liver, kidney, pancreas, spleen, adrenal, and small intestine) were performed at the end of the study. No deaths or exposure-related changes were observed in any endpoint examined in either sex. No adverse effects were identified in this study; thus, a lowest-observed-adverse-effect level (LOAEL) could not be identified, and the high doses of 555.8 mg Lu/kg-day (males) and 611.2 mg Lu/kg-day (females) are identified as no-observed-adverse-effect levels (NOAELs). The 2Dose estimates for L11CI3 were calculated using the mean reference body weight and food consumption rate values for all rat strains in a subchronic-duration study (U.S. EPA. 19881. Mean reference body weight: 0.235 kg (male) and 0.173 kg (female). Mean reference food consumption: 0.021 kg/day (male) and 0.017 kg/day (female). Corresponding lutetium doses are calculated using the ratio of molecular weights (Lu:LuCl3 = 174.967:281.326). 9 Soluble Lutetium ------- FINAL 08-16-2018 lack of effects in this study is consistent with evidence for poor absorption of lutetium and other heavy lanthanide elements (see "Metabolism/Toxicokinetic Studies" section). Inhalation Exposures Animal inhalation toxicity data on stable rare earths consist mainly of a few inhalation or intratracheal instillation studies on some rare earth mixtures and some single compounds (Abel and Talbot. 1967; Mogilevskava and Raikhlin. 1967; Ball and Van Gelder. 1966; Scfaepers. 1955a. b; Schepers et ai. 1955). No lutetium-specific data have been found. A comprehensive assessment of the human and animal data by Haley (1991) concluded that the evidence suggests that inhalation exposure to high concentrations of stable rare earths can produce lesions compatible with pneumoconiosis and progressive pulmonary fibrosis, and that the potential for inducing these lesions is related to chemical type, physicochemical form, and dose and duration of exposure. OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) Supporting studies on lutetium include acute-duration oral and intraperitoneal (i.p.) lethality studies, an acute-duration study of intravenously (i.v.) injected lutetium, toxicokinetic data, and mechanistic studies. No genotoxicity data for stable lutetium have been located. These studies indicated the following: • Acute toxicity studies in mice (Haley et ai. 1964) suggest slightly greater sensitivity of guinea pigs to lutetium chloride-induced lethality, compared with mice (Graca et aL 1962). An acute toxicity study demonstrated that i.v.-administered lutetium chloride can impair blood clotting (Graca et ai, 1964). • Lutetium is expected to be poorly absorbed through the gastrointestinal (GI) tract [as reviewed by Leggett et ai (2014)1. Once absorbed, lutetium is primarily deposited in bone, where it may persist, and in the liver (Leggett et ai. 2014; Nakamura et ai. 1997; M tiller et ai. 1978; Durbin et ai. 1956). Data on the excretion of lutetium are not available, but other lanthanides are eliminated primarily via feces following oral exposure, likely due to poor absorption (Nakamura et ai. 1991). • Mechanistic data on lutetium are limited but show that lutetium can occupy calcium binding sites on calmodulin (Buccigross and Nelson. 1986). potentiate gam ma-am i nobuty ri c acid (GABA)-induced chloride channels in rat neurons (Ma and Narahashi. 1993). and stimulate fibroblast proliferation (Jenkins et ai. 2011). More detailed descriptions of these data are presented in the "Supporting Toxicity Studies" section below and in Table 4. Two acute studies (Graca et ai. 1964. 1962) assessed the toxicological effects of citrate and edetate complexes of lutetium. The data on these complexes are not discussed in this PPRTV assessment because the citrate and edetate chelating agents may, if dissociated from lutetium, perturb endogenous cation (e.g., calcium, copper, iron, or zinc) homeostasis, resulting in toxic effects that are not attributable to lutetium. Supporting Toxicity Studies Acute lethality data for lutetium chloride and lutetium nitrate are shown in Table 4. An oral median lethal dose (LD50) value of 4,441 mg Lu/kg and an i.p. LD50 of 197 mg Lu/kg were reported for lutetium chloride in male mice observed for 7 days (Haley et ai. 1964). Haley et ai (1964) reported symptoms and mortality information for both orally and i.p.-exposed animals, without 10 Soluble Lutetium ------- FINAL 08-16-2018 distinguishing by exposure route or dose level. Symptoms included ataxia, writhing, labored respiration, walking on toes with back arched, and sedation. The peak death rate was reached at 48 hours after exposure, but some deaths occurred at 24 hours. Acute i.p. LD50 values for lutetium nitrate were lower in female mice and rats (108 and 125 mg Lu/kg, respectively) observed for 30 days (Bruce et al.. 1963) than the value reported by Haley et al. (1964) for male mice exposed i.p. to lutetium chloride. Bruce et al. (1963) observed the mice and rats for a much longer duration and did observe several deaths after the first 8 days (see Table 4), suggesting that LD50 values obtained after only 7 days of observation may have underestimated lethality. Graca et al. (1964) investigated the effects of intravenously-administered chloride salts, citrate complexes, and edetate complexes of lanthanide elements on heart rate, blood pressure, respiration, and clinical hematology in male and female dogs (breed and number/sex not specified). Aqueous solutions of the chloride (equivalent to 5% of the chloride) and chelate complexes of 15 lanthanide elements were injected into a cannula inserted into the left femoral vein. Ten doses of 10 mg LuCb/kg (6 mg Lu/kg) per dose were injected under anesthesia at 10-minute intervals. For each lanthanide element, groups of three dogs were treated with the chloride. Three separate groups of control dogs were injected with sodium citrate (n = 6), ammonium versenate (n = 6), or Ringer's solution (n = 12) in the same manner as the treated animals. Blood samples were collected from the right femoral vein before treatment and 0, 10, 30, 60, 100, and 160 minutes after treatment for analysis of erythrocyte, leukocyte and differential cell counts, prothrombin and coagulation time, Hb, sedimentation, and Hct. After 160 minutes, the animals were necropsied and tissues were collected for histopathology (liver, spleen, kidney, lung, sternum, mesentery lymph nodes, heart, adrenal, and ovaries or testes). Heart rate, respiration, and blood pressure readings were made at the same intervals as blood samples. Results for the 15 elements were discussed generally and presented graphically as change over time after treatment (Graca et al.. 1964). Some animals died from treatment (14/45 treated with chlorides), but the mortality was not reported by element. Lutetium chloride treatment resulted in a transient spike in blood pressure (150% of pretreatment values) and heart rate (about 130% of pretreatment values) at 60 minutes post-treatment. Respiratory rates appeared to be within control values for lutetium chloride. Lutetium chloride resulted in increases in prothrombin time (to >100 seconds by 100 minutes after treatment, compared to a maximum of 10 seconds for control animals) and coagulation time (to >60 minutes by 1 hour after treatment, compared with a maximum of about 10 minutes for control animals). These effects on prothrombin and coagulation time were generally consistent for almost all the lanthanide elements tested. Visual observation of pooled blood at incision sites provided additional qualitative evidence of the effect of lanthanide elements on clotting parameters, but the study authors did not report the incidence or the specific treatment group(s) where this was observed. Gross and histopathological examinations revealed slight to moderate hyperemia of the lungs, but only in animals treated with chlorides of the lanthanide elements. 11 Soluble Lutetium ------- FINAL 08-16-2018 Table 4. Acute Lethality Studies Test Materials and Methods Results Conclusions References Acute oral lethality Lutetium chloride was administered orally to 50 male CF1 mice (doses not reported); the mice were observed for 7 d. No other details were provided. The peak death rate was reached at 48 hr after exposure, but some deaths occurred at 24 hr. Symptoms of acute lutetium chloride toxicity included ataxia, writhing, labored respiration, walking on toes with back arched, and sedation; the study authors did not specify the doses or exposure routes leading to these effects. Male mouse oral LD5o = 4,441 mg Lu/kg Halev et al. (1964) Acute i.p. lethality Lutetium chloride was administered i.p. to 60 male CF1 mice (doses not reported); the mice were observed for 7 d. No other details were provided. The peak death rate was reached at 48 hr after exposure, but some deaths occurred at 24 hr. Symptoms of acute lutetium chloride toxicity included ataxia, writhing, labored respiration, walking on toes with back arched, and sedation; the study authors did not specify the doses or exposure routes leading to these effects. Male mouse i.p. LD5o = 197 mg Lu/kg Halev et al. (1964) Acute i.p. lethality Lutetium nitrate was administered i.p. to 30 female CF1 mice (reported as single dose of 0.1% aqueous solution); the animals were observed for 30 d. For all the lanthanides tested, most mice died within the first 24 hr; however, 26% of the deaths occurred between D 8 and 30 of observation. Symptoms of toxicity were not reported. Gross necropsy of randomly selected survivors of all lanthanide exposure groups showed generalized peritonitis with adhesions and accumulation of ascitic fluid. Necropsy findings specific to lutetium were not reported. Female mouse i.p. LD5o = 108 mg Lu/kg Bruce et al. (1963) Acute i.p. lethality Lutetium nitrate was administered i.p. to 30 female S-D rats (reported as single dose of 0.5% aqueous solution); the animals were observed for 30 d. For all the lanthanides tested, very few rat deaths occurred within the first 8 d; most deaths occurred between D 10 and 25 of observation. Symptoms of toxicity were not reported. Gross necropsy findings in rats exposed to all the lanthanides included grossly distended abdomens, edema of the limbs, evidence for an inflammatory condition in the peritoneal cavity, with massive adhesions and accumulation of hemorrhagic ascitic fluid. Necropsy findings specific to lutetium were not reported. Female rat i.p. LD5o = 125 mg Lu/kg Bruce et al. (1963) Acute i.p. lethality Lutetium chloride was administered i.p. to CFW albino mice (sex and number not specified) at doses of 188 or 313 mg Lu/kg; the animals were observed for 7 d. 87 and 90% of mice died at 188 and 313 mg Lu/kg, respectively. Mean times to death were 39 and 37 hr, respectively. Mouse i.p. LD5o was not calculated; estimated to be <188 mg Lu/kg Graca et al. (1962) 12 Soluble Lutetium ------- FINAL 08-16-2018 Table 4. Acute Lethality Studies Test Materials and Methods Results Conclusions References Acute i.p. lethality Lutetium chloride was administered i.p. to guinea pigs (strain, sex, and number not specified) at doses of 31, 63, or 94 mg Lu/kg; the animals were observed for 7 d. 5, 28, and 44% of guinea pigs died at 31, 63, and 94 mg Lu/kg, respectively. Mean times to death were 95, 35, and 40 hr, respectively. Guinea pig i.p. LD5o = 101 mg Lu/kg Graca et al. (1962) Acute i.v. lethality 10 male and 10 female cats received i.v. doses of lutetium chloride (between 0.6-25 mg Lu/kg). Cardiovascular responses were examined 2 hr later. No effects occurred at doses up to 6 mg Lu/kg; 5 animals died at 13 mg Lu/kg and at 25 mg Lu/kg, all from complete cardiovascular collapse with respiratory paralysis. i.v. exposure to lutetium chloride is lethal to cats at a dose of 13 mg Lu/kg Halev et al. (1964) i.p. = intraperitoneal; i.v. = intravenous; LD5o = median lethal dose; Lu = lutetium; S-D = Sprague-Dawley. 13 Soluble Lutetium ------- FINAL 08-16-2018 No evidence of hepatotoxicity was noted in rats exposed to a single i.v. dose of lutetium chloride (Nakamura et ai, 1997). Doses of 0 or 10 nig Lu/kg (as lutetium chloride) were administered i.v. to 3-5 Wistar-KY rats, and the animals were sacrificed 1 or 3 days later for evaluation of serum chemistry (aspartate aminotransferase [AST], alanine aminotransferase [ALT], total cholesterol, phospholipids, triglycerides, total bile acids, and bilirubin) and hepatic lipids (phospholipids, triglycerides, and total cholesterol). Neither serum enzymes nor hepatic lipids were changed from control values in rats treated with lutetium chloride. Three studies showed that lutetium chloride injections may cause calcification of the injection site, but will not sensitize animals to calcification induced by a histamine liberator. In a very brief report, Haley and Upham (1963) described their finding that nodules of crystalline deposits, possibly containing calcium, occurred at the injection site in guinea pigs given intradermal injections of lutetium chloride. Doses were not specified other than to indicate that a range of 0.5-5 |ig was used for each of the lanthanide elements tested. Histopathological examination revealed histiocytes, foreign body giant cells, fibroblasts, and granulation in or surrounding the nodules (Haley and Upham. 1963). Garrett and YlcClure (1981) reported injection site calcification in groups of 20 male white mice given subcutaneous (s.c.) injections of 0.5 and 10 mg LuCb (0.3-6 mg Lu); lower doses did not result in calcification. Microscopic examination of the calcified areas showed mild fibrosis and accumulation of multinucleated giant cells around the calcifications (Garrett and VI cC lure. 1981). Lutetium chloride (3 mg, equivalent to 2 mg Lu) administered intravenously to groups of 10 Sprague-Dawley (S-D) rats (sex not specified) did not sensitize the animals to soft tissue calcification at the site of administration of polymyxin, a histamine liberator (Tuchweber and Savoie. 1968). Metabolism/Toxicokinetic Studies The oral absorption of lutetium and other lanthanide elements is very low, probably in part because many of these elements form insoluble hydroxides at neutral pH. While an estimate of the GI absorption of lutetium itself is not available, studies of other lanthanides in a wide variety of species suggested fractional absorption estimates in the range of 10 6 to 10 3 for all of the lanthanides [reviewed by Leggett et al. (2014)1. Little is known about the absorption of inhaled lanthanides; Leggett et al. (2014) noted that the ionic solutions of lanthanides are not stable at neutral pH, often forming colloidal or hydroxide complexes; such behavior may result in wide variations in lung clearance rates. The lanthanide elements are typically deposited in the bone, liver, and kidney, although deposition varies with route of exposure. Leggett et al. (2014) reported median molar concentrations of lutetium and other lanthanides in a number of tissues based on data obtained by Zhu et al. (2010) as cited in Leggett et al. (2014) from 68 adult males in China. The nature, magnitude, and routes of lanthanide exposures in this population were not described by Leggett et al. (2014). The highest lutetium concentration was in the rib (3.1 nmol/kg fresh weight), followed by lung (0.97 nmol/kg), thyroid (0.32 nmol/kg), thymus (0.16 nmol/kg), and liver, stomach, fat, skin, and adrenal gland (each at 0.11 nmol/kg); other tissues and blood had lower concentrations. Leggett et al. (2014) indicated that the data were very uncertain due to potential errors in measuring low concentrations and the high variability in the measured concentrations. Distribution of lutetium after oral exposure has not been studied. After exposure to radioactive lutetium oxides in citrate solution (to increase the speed of absorption from the injection site; 7.3-20 |iCi with 0.5-1.9 |ig unlabeled carrier) administered by intramuscular 14 Soluble Lutetium ------- FINAL 08-16-2018 (rats) and i.p. (mice) injection, the highest deposition was in the bone (65 and 35% of injected radioactivity, respectively, 1 day after dosing), with much less (<5%) in the liver (Muller et aL 1978; Durbin et aL, 1956). By contrast, 1 day after i.v. exposure of rats to lutetium chloride (10 or 20 mg Lu/kg), lutetium was primarily deposited in the liver (63.5-67% of administered dose) with lesser amounts in bone [11-15%; Nakamura et al. (1997)1. It is not clear whether the differences in distribution resulted from differences in species or strain of animal, route of administration, or form or dose of lutetium administered. Long-term retention of lutetium has not been studied; however, Miiller et al. (1978) estimated the half-lives for elimination of lutetium in female Naval Medical Research Institute (NMRI) mice given single i.p. injections of 177Lu (1-60 mCi/kg as lutetium oxide fused with potassium bisulfate, with 0.5 mg/kg stable lutetium carrier) and sacrificed 1, 7, or 15 days later. The estimated half-life for elimination of lutetium was 5 days for the liver, spleen, and kidneys and 50 days for the femur (Muller et al, 1978). Durbin et al. (1956) reported that the half-life for elimination from the skeleton of the heavier lanthanides (lutetium is the heaviest) was about 2.5 years in rats, based on data collected for 160terbium (Tb) and 170thulium (Tm) over 256 days. The skeletal half-life estimated for lutetium by Muller et al. (1978) is much lower than the skeletal half-life (2.5 years) estimated by Durbin et al. (1956) for heavy lanthanides, possibly because the lutetium estimate was based on a much shorter time frame. Muller et al. (1978) collected data on bone radioactivity over only 15 days, while Durbin et al. (1956) collected data on bone radioactivity for five lanthanides over 256 days. Graphical display of the bone radioactivity in the study by Durbin et al. (1956) indicated that some lanthanides (e.g., promethium [Pm], cerium [Ce]) exhibited an initial decline in skeletal radioactivity content followed by a plateau, so estimating a half-life using only data from the initial period after dosing could lead to underestimation. Data on the excretion of lutetium in humans or animals have not been located. After oral administration of other lanthanide elements (yttrium [Y], dysprosium [Dy], europium [Eu], and ytterbium [Yb], as their chloride hexahydrates) to male Wistar rats, none of these elements were detected in urine, and 92-98% of administered doses (100 and 1,000 mg lanthanide/kg) was eliminated in the feces within 7 days rNakamura et al. (1991); published in Japanese with English abstract and tables], likely reflecting poor absorption through the oral route of exposure. Elimination of lutetium is likely to follow a similar pattern. Mechanistic Studies Buccigross and Nelson (1986) assessed the binding of lanthanide elements to calmodulin in an electron paramagnetic resonance (EPR) study and observed that lutetium binds to calmodulin in a similar manner as calcium does, with preference for the two high-affinity binding sites on calmodulin. Calmodulin is a protein that plays an integral role in regulating a wide variety of physiological processes, including inflammation, metabolism, apoptosis, smooth muscle contraction, memory, and immune response via calcium-dependent signal transduction. Thus, interference with calmodulin function, and/or competition and displacement of calcium from binding to this protein could have pluripotent adverse impacts. Evidence for lutetium effects on calcium transport was seen in the study by Nakamura et al. (1997). who reported significantly increased concentrations of calcium in the liver, spleen, lungs, and kidneys in rats given lutetium chloride intravenously. In contrast, concentrations of phosphorus, zinc, copper, sodium, and potassium were not affected by lutetium administration (Nakamura et al.. 1997). 15 Soluble Lutetium ------- FINAL 08-16-2018 Ma and Narahashi (1993) tested a series of lanthanide elements, including lutetium, for the ability to potentiate GABA-induced chloride currents in rat dorsal ganglion neurons in vitro. Of the seven lanthanides tested (lanthanum [La], Ce, neodymium [Nd], Eu, Tb, erbium [Er], and Lu), lutetium induced the strongest increase in GABA-induced current (12.6-fold compared with control). Lutetium and the other lanthanides were also able to induce an inward chloride current in the absence of GAB A. In both assays, the strength of response declined monotonically with molecular weight (from Lu to La). Effects on GABA-induced currents suggest the possibility of neurological effects from lutetium exposure. Jenkins et al. (2011) tested chloride salts of 14 lanthanide elements, including lutetium, for the ability to stimulate proliferation of dermal fibroblasts. Concentrations of 10 and 50 |iM lutetium resulted in significantly increased proliferation of fibroblasts, but not of epidermal keratinocytes (Jenkins et al, 2011). Stimulation of fibroblast proliferation may play a role in localized fibrotic responses seen in guinea pigs and mice exposed to lutetium chloride by intradermal and s.c, injection, respectively (Garrett and YlcClure. 1981; Haley and Upham. 1963). 16 Soluble Lutetium ------- FINAL 08-16-2018 DERIVATION OF PROVISIONAL VALUES Tables 5 and 6 present summaries of noncancer and cancer references values, respectively, for soluble lutetium. Data were available to derive a subchronic provisional reference dose (p-RfD) for soluble lutetium, but no other reference values. Table 5. Summary of Noncancer Reference Values for Soluble Lutetium (CASRN 7439-94-3) Toxicity Type (units) Species/Sex Critical Effect p-Reference Value POD Method POD (HED) UFc Principal Study Subchronic p-RfD for soluble lutetium (mg Lu/kg-d) Rat/M None observed 4 x KT1 NOAEL 133.4 300 HaleYjet al. (1964) Chronic p-RfD (mg/kg-d) NDr Subchronic p-RfC (mg/m3) NDr Chronic p-RfC (mg/m3) NDr HED = human equivalent dose; Lu = lutetium; M = male(s); NDr = not determined; NOAEL = no-observed-adverse-effect level; p-RfC = provisional reference concentration; p-RfD = provisional reference dose; POD = point of departure; UFC = composite uncertainty factor. Table 6. Summary of Cancer Reference Values for Soluble Lutetium (CASRN 7439-94-3) Toxicity Type (units) Species/Sex Tumor Type Cancer Value Principal Study p-OSF (mg/kg-d) 1 NDr p-IUR (mg/m3)-1 NDr NDr = not determined; p-IUR = provisional inhalation unit risk; p-OSF = provisional oral slope factor. DERIVATION OF ORAL REFERENCE DOSES Derivation of a Subchronic Provisional Reference Dose Information on the toxicity of repeated oral exposure to lutetium is limited to a single subchroni c-durati on (90-day) dietary study of lutetium chloride in rats (Haley et al.. 1964). No deaths or exposure-related changes were observed in any endpoint examined in either sex (see study summary above); therefore, 555.8 mg Lu/kg-day and 611.2 Lu/kg-day are identified as NOAELs in male and female rats, respectively. No LOAELs could be identified. The only other information available on the oral toxicity of lutetium is an oral LD50 in male mice (4,416 mg Lu/kg). Since no LOAEL could be identified from the Haley et al. (1964) principal study or the soluble lutetium database, it is unknown where a true LOAEL may exist on the dose-response curve for male and female rats in Haley et al. (1964). and it is unknown how a true LOAEL for each sex would compare to each other, it is prudent in this case to select the more sensitive and health protective male rat NOAEL value of 555.8 mg Lu/kg-day reported by Haley et al. (1964) 17 Soluble Lutetium ------- FINAL 08-16-2018 as the point of departure (POD) to derive the subchronic p-RfD for soluble lutetium. The NOAEL is converted to a human equivalent dose (HED) according to current U.S. EPA (2011b) guidance. In Recommended Use of Body Weight4 as the Default Method in Derivation of the Oral Reference Dose (U.S. EPA, 201 lb), the U.S. EPA endorses body-weight scaling to the 3/4 power (i.e., BW3/4) as a default to extrapolate toxicologically equivalent doses of orally administered agents from all laboratory animals to humans for the purpose of deriving an oral reference dose (RfD) from effects that are not portal-of-entry effects. As the critical effect for lutetium is not known, it is assumed that body-weight scaling is appropriate. Following U.S. EPA (2011b) guidance, the POD is converted to a HED through the application of a dosimetric adjustment factor (DAF)4 derived as follows: DAF = (BWa1/4 - BWh1/4) where DAF = dosimetric adjustment factor BWa = animal body weight BWh = human body weight Using a reference BWa of 0.235 kg for rats and a reference BWh of 70 kg for humans, the resulting DAF is 0.24 (U.S. EPA, 201 lb). Applying this DAF to the NOAEL of 555.8 mg Lu/kg-day yields a POD (HED) as follows: POD (HED) = NOAEL (mg Lu/kg-day) x DAF = 555.8 mg Lu/kg-day x 0.24 = 13 3.4 mg Lu/kg-day The subchronic p-RfD for soluble lutetium was derived using the POD (HED) and a composite uncertainty factor (UFc) of 300 (reflecting an interspecies uncertainty factor [UFa] of 3, an intraspecies uncertainty factor [UFh] of 10, and a database uncertainty factor [UFd] of 10): Subchronic p-RfD for = POD (HED) UFc Soluble Lutetium = 133.4 mg Lu/kg-day ^ 300 = 4 x 10"1 mg Lu/kg-day Table 7 summarizes the uncertainty factors for the subchronic p-RfD for soluble lutetium. 4As described in detail in Recommended Use of Body Weight3/4 as the Default Method in Derivation of the Oral Reference Dose (U.S. EPA. 2011b'). rate-related processes scale across species in a manner related to both the direct (BWm) and allometric scaling (BW3/4) aspects such that BW3/4 ^ BW1 1 = B W1/4, converted to a DAF = BWa1'4 - BWh1'4. 18 Soluble Lutetium ------- FINAL 08-16-2018 Table 7. Uncertainty Factors for the Subchronic p-RfD for Soluble Lutetium UF Value Justification UFa 3 A UFa of 3 (10°5) is applied to account for uncertainty in characterizing the toxicokinetic or toxicodynamic differences between rats and humans following oral lutetium exposure. The toxicokinetic uncertainty has been accounted for by calculating a HED through application of a D AF as outlined in the U.S. EPA's Recommended Use of Body Weight4 as the Default Method in Derivation of the Oral Reference Dose (U.S. EPA, 2011b). UFd 10 A UFd of 10 is applied to account for the limited toxicity database for soluble lutetium, which consists of only a single subchronic-duration rat dietary study using LuCk. UFh 10 A UFh of 10 is applied for intraspecies variability to account for human-to-human variability in susceptibility in the absence of quantitative information to assess the toxicokinetics and toxicodynamics of lutetium in humans. UFl 1 A UFl of 1 is applied because the POD is a NOAEL. UFS 1 A UFS of 1 is applied because a subchronic-duration study was selected as the principal study. UFC 300 Composite UF = UFA x UFD x UFH x UFL x UFS. HED = human equivalent dose; LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; POD = point of departure; p-RfD = provisional reference dose; UF = uncertainty factor; UFA = interspecies uncertainty factor; UFC = composite uncertainty factor; UFd = database uncertainty factor; UFH = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty factor; UFS = subchronic-to-chronic uncertainty factor. The confidence in the subchronic p-RfD for soluble lutetium is low, as described in Table 8. 19 Soluble Lutetium ------- FINAL 08-16-2018 Table 8. Confidence Descriptors for the Subchronic p-RfD for Soluble Lutetium Confidence Categories Designation Discussion Confidence in principal study L Confidence in the principal study is low. While it is a peer-reviewed study using three dose groups plus a control group, group sizes were small (6/sex/group). The test material was administered in the diet, but food consumption was not measured, so the doses are estimated. Furthermore, the study did not evaluate clinical chemistry or organ weights, histopathology examinations were limited to major organs (heart, lung, liver, kidney, spleen, pancreas, adrenal glands, and small intestine), and a LOAEL was not identified. Confidence in database L Confidence in the database for lutetium is low. The relevant database consists of a single subchronic-duration rat study; the only other information on oral toxicity is an oral LD50 in mice. The available studv (TIalev et al.. 1964) did not examine the stomach for histopathology, and the stomach has been identified as a target organ for other lanthanide elements, including gadolinium and europium (Oeawa et al.. 1995; Oeawa et al.. 1992). In addition, the neurotoxicity and neurodevelopmental effects of lutetium have not been examined. Lutetium was shown to both potentiate GAB A-induced chloride currents and induce inward currents in rat neurons (Ma and Narahashi. 1993). sussestins potential for neurotoxic effects. Confidence in subchronic p-RfDa L The overall confidence in the subchronic p-RfD is low. aThe overall confidence cannot be greater than the lowest entry in the table (low). GABA = gamma-aminobutyric acid; L = low; LD5o = median lethal dose; LOAEL = lowest-observed-adverse-effect level; p-RfD = provisional reference dose. Toxicological data on other salts of lutetium are limited to i.p. LD50 studies of lutetium nitrate in mice and rats (Bruce et al.. 1963). Because the fundamental determinant of the toxicity of soluble lutetium compounds is expected to be due to lutetium metal itself, the toxicity of such soluble compounds is directly related to the relative molecular weight contribution from lutetium. Therefore, the subchronic p-RfD derived above for soluble lutetium is applicable to soluble lutetium compounds (e.g., salts) following application of a molecular-weight adjustment and appropriate stoichiometric calculations. Derivation of a Chronic Provisional Reference Dose A chronic p-RfD was not derived for soluble lutetium for several reasons. First, there are notable deficiencies in the database including (1) it is limited to a single subchronic-duration (90-day) dietary study of lutetium chloride in rats (Haley et al.. 19641 with no studies of chronic-duration exposure to soluble lutetium in any species, and (2) no LOAEL was able to be identified from this only available study. Additionally, although long-term retention of lutetium following oral exposure has not been examined, studies using injected radioactive lutetium oxide (chelated in a citrate solution to increase the speed of absorption from the site of injection) reported substantial deposition of 177Lu to bone (Milller et al., 1978; Durbin et al.. 1956). Durbin et al. (1956) estimated a half-life of 2.5 years for elimination of heavier lanthanides (lutetium is 20 Soluble Lutetium ------- FINAL 08-16-2018 the heaviest lanthanide) from the skeleton. Thus, the potential for prolonged retention of lutetium in the body bolsters the uncertainty surrounding the extrapolation of no observed toxicological effects after sub chronic-duration soluble lutetium exposure to potential effects following chronic-duration exposure. Taken together, these uncertainties collectively preclude the derivation of a chronic p-RfD for soluble lutetium. DERIVATION OF INHALATION REFERENCE CONCENTRATIONS No pertinent data regarding the toxicity of repeated inhalation exposure to soluble lutetium are found in the available literature. Derivation of a provisional reference concentration (p-RfC) for soluble lutetium is precluded by the lack of appropriate inhalation toxicity data. CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR No carcinogenicity or genotoxicity data have been located for soluble lutetium. The cancer weight-of-evidence (WOE) descriptor for soluble lutetium is presented in Table 9. Table 9. Cancer WOE Descriptor for Soluble Lutetium (CASRN 7439-94-3) Possible WOE Descriptor Designation Route of Entry (oral, inhalation, or both) Comments "Carcinogenic to Humans " NS NA There are no human data to support this. "Likely to Be Carcinogenic to Humans " NS NA There are no animal studies to support this. "Suggestive Evidence of Carcinogenic Potential" NS NA There are no animal studies to support this. "Inadequate Information to Assess Carcinogenic Potential" Selected Both No studies are available that evaluated carcinogenic effects in humans or animals exposed to lutetium. "Not Likely to Be Carcinogenic to Humans " NS NA No evidence of noncarcinogenicity is available. NA = not applicable; NS = not selected; WOE = weight of evidence. DERIVATION OF PROVISIONAL CANCER POTENCY VALUES Derivation of quantitative estimates of cancer risk for soluble lutetium is precluded by the lack of data demonstrating carcinogenicity associated with lutetium exposure. 21 Soluble Lutetium ------- FINAL 08-16-2018 APPENDIX A. REFERENCES Abel M; Talbot RB. (1967). Gadolinium oxide inhalation by guinea pigs: A correlative functional and histopathologic study. J Pharmacol Exp Ther 157: 207-213. ACGIH (American Conference of Governmental Industrial Hygienists). (2018). 2018 TLVs and BEIs. Based on documentation of the threshold limit values for chemical substances and physical agents and biological exposure indices. Cincinnati, OH. http://www.acgih.org/forms/store/ProductFormPublic/2018-tlvs-and-beis AT SDR (Agency for Toxic Substances and Disease Registry). (2018). Minimal risk levels (MRLs). June 2018. Atlanta, GA: Agency for Toxic Substances and Disease Registry (ATSDR). Retrieved from http://www.atsdr.cdc.gov/mrls/index.asp Ball. R A; Van Gelder. G. (1966). Chronic toxicity of gadolinium oxide for mice following exposure by inhalation. Arch Environ Health 13: 601-608. http://dx.doi.org/10.1080/00Q39896.1966.10664625 Baneriee. S: Pillai. MR: Knapp. PP. (2015). Lutetium-177 therapeutic radiopharmaceuticals: linking chemistry, radiochemistry, and practical applications [Review], Chem Rev 115: 2934-2974. http://dx.doi.org/10.1021/cr500171e Beliles. RP. (1994). The lanthanides. In GD Clayton; FE Clayton (Eds.), Patty's industrial hygiene and toxicology: Volume 2: Part C, toxicology (4th ed., pp. 2048-2065). New York, NY: John Wiley & Sons, Inc. Bruce. DW: Plietbrink. BE: DuBois. KP. (1963). The acute mammalian toxicity of rare earth nitrates and oxides. Toxicol Appl Pharmacol 5: 750-759. http://dx.doi.org/10.1016/0041 - 008X(63)90067-X Bucci gross. JM; Nelson. DJ. (1986). EPR studies show that all lanthanides do not have the same order of binding to calmodulin. Biochem Biophys Res Commun 138: 1243-1249. http ://dx. doi .org/10.1016/S0006-291 X(86)80416-8 Bun/1 i. JCG. (2013). Lanthanides. In RE Kirk; DF Othmer (Eds.), Kirk-Othmer Encyclopedia of Chemical Technology (4th ed.). New York, NY: John Wiley & Sons, Inc. http ://dx. doi .org/10.1002/047123 8961.1201142019010215. aO 1 ,pub3 CalEPA (California Environmental Protection Agency). (201 1). Hot spots unit risk and cancer potency values. Appendix A. 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