Development of Reference Doses

and

Reference Concentrations

for 

Lanthanides

Prepared for:

The Bureau of Land Management

National Applied Resource Sciences Center

Prepared by:

Toxicology Excellence for Risk Assessment

Amended Stage 2, November 1999

Views expressed in this text are those of Toxicology Excellence

for Risk Assessment (TERA) and do not necessarily reflect

the views and policies of the sponsor. Mention of trade

names or commercial products does not constitute

endorsement or recommendation for use.
Bureau of Land Management Amended Final

Toxicology Excellence for Risk Assessment 2 November 11, 1999

Development of Reference Doses

and

Reference Concentrations

for 

Lanthanides

Table of Contents Page

Table of Contents 2

List of Tables and Figures 3

1.0 Introduction 4

 1.1 Existing Reference Doses (RfDs) and Concentrations (RfCs) 4

 1.2 Purpose of This Document 4

 1.3 The Methods Used 4

2.0 Hazard Identification 9

 2.1 Review of Relevant Data Sources 9

2.2 Human Studies 9

 2.3 Inhalation Toxicity Data in Experimental Animals 10

 2.4 Oral Toxicity Data in Experimental Animals 12

2.4.1 Acute Studies 12

2.4.2 Short Term Studies 12

2.4.3 Subchronic Studies 14

2.4.4 Chronic Studies 15

3.0 Dose Response Assessment 16

3.1 Toxicokinetics 16

 3.2 Choice of Critical Studies 17

 3.3 Choice of Uncertainty and Modifying Factors 18

 3.4 Determination of RfD/RfCs 23

4.0 References 25

Appendix A Summary of Data

Table 1. Table of Toxicity Data for Rare Earth Elements

Table 2. Table of Pharmacokinetics Data for Rare Earth Elements

Appendix B Calculations for Various Human Equivalent Concentrations

Appendix C Mixtures Risk Assessment for Lanthanides
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List of Tables Page 

Table 1. Various Lanthanides and Their Recommended Uncertainty Factors 22

Table 2. Lanthanides and Their RfCs and RfDs 24

List of Appendices

Appendix A: Summary of Data

Appendix Table 1. Table of Toxicity Data for Rare Earth Elements

Appendix Table 2. Table of Pharmacokinetics Data for Rare Earth Elements

Appendix B: Calculations for Various Human Equivalent Concentrations

Appendix C: Mixtures Risk Assessment for the Lanthanides
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Toxicology Excellence for Risk Assessment 4 November 11, 1999

1.0 Introduction

1.1 Existing Reference Doses (RfDs) and Concentrations (RfCs)

This document addresses the development of an RfD and/or an RfC for the non-cancer, 

non-radiological risk assessments for the rare earth elements known as the Lanthanides. This 

mixture may include such rare earth elements as neodymium (Nd), cerium (Ce), scandium (Sc), 

yttrium (Y), dysprosium (Dy) and lanthanum (La). Currently, the U.S. EPA’s Integrated Risk 

Information System (IRIS) database does not list any risk assessment values for either the 

mixture known as the lanthanides or the individual rare earth metals including any of their 

respective salts. No EPA documentation for any of these elements characterized as lanthanides 

was located on IRIS or HEAST. This document presents the deve lopment of an RfD for the 

chlorides of lanthanum, europium, and yttrium and the oxides of lanthanum, europium and 

scandium and the development of an RfC for the oxides of cerium and gadolinium.

1.2 Purpose of This Document

The purpose of this project is to develop non-radiological, non-cancer risk assessment for 

the oral and/or inhalation routes of exposure on the rare earth mixture known as the lanthanides, 

and in particular a mixture composed primarily of lanthanum and cerium. This mixture is the 

primary material mined by Molycorp at the Mountain Pass Mine site, Mountain Pass, California. 

This document was preceded by an earlier text, where TERA conducted appropriate 

literature reviews to identify any studies that are likely to have had a bearing on the development 

of RfDs and RfCs for these lanthanides. This literature was reviewed, and TERA developed a 

brief summary of the database as it pertains to these noncancer risk assessments (TERA, 1999). 

We now show what are likely to be the definitive critical studies for the development of these 

RfDs and RfCs, and describe the areas of scientific uncertainty that require the use of uncertainty 

factors. Specific values for these lanthanides are proposed.

1.3 The Methods Used

The RfD/RfC methods of U.S. EPA were used to evaluate and quantify the non-cancer 

toxicity of the lanthanides. The determination of RfD/RfCs lies squarely in the area of hazard 

identification and dose response assessment as defined by the National Research Council of the 

National Academy of Sciences (NRC, 1983) report on risk assessment in the federal government. 

EPA defines the reference concentration (or reference dose) as an estimate (with uncertainty 

spanning perhaps an order of magnitude) of a continuous (or daily) exposure to the human 

population (including sensitive subgroups) that is likely to be without an appreciable risk of 

deleterious effects during a lifetime. (Barnes and Dourson, 1988; Dourson, 1994; Jarabek, 1994; 

U.S. EPA, 1994).
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Toxicology Excellence for Risk Assessment 5 November 11, 1999

For health effects that are not cancer, the EPA and others first identify the critical 

effect(s), which is the first adverse effect(s) or its known precursor that occurs in the dose scale. 

Human toxicity data adequate for use in the estimation of RfD/RfCs are seldom available, but if 

so, they are preferred in the selection of this critical effect. The use of human data has the 

advantage of avoiding the uncertainties inherent in interspecies extrapolation.

After the critical effect(s) has been identified, EPA generally selects an experimental 

exposure level from a study that represents the highest level tested at which the critical effect 

was not demonstrated. This level, the No Observed Adverse Effect Level (NOAEL), is the key 

datum gleaned from the toxicologist's review of the chemical's entire database and is the first 

component in the estimation of a RfC. If a NOAEL is not available, the use of a Low Observed 

Adverse Effect Level (LOAEL) is recommended. Alternatively, a benchmark concentration 

(BMC) (or benchmark dose, BMD) may be used in this part of the assessment. A BMC/BMD is 

a statistical lower confidence limit on the concentration that produces a predetermined level of 

change in adverse response compared with the response in untreated animals (called the 

benchmark response or BMR). Advantages and disadvantages of NOAELs and BMDs/BMCs 

are described elsewhere (U.S. EPA, 1995).

Presented with data from several animal studies, EPA first seeks to identify the animal 

model that is most relevant to humans, based on the most defensible biological rationale, for 

example using comparative pharmacokinetic data. In the absence of a clearly most relevant 

species, however, EPA generally chooses the critical study and species that shows an adverse 

effect at the lowest administered dose. This is based on the assumption that, in the absence of 

data to the contrary, humans may be as sensitive as the most sensitive experimental animal 

species.

The above discussion applies to both the development of RfDs and RfCs. For RfCs, 

there are several additional steps. Exposure levels in ppm are converted to mg/cu.m using the 

equation:

1 mg/cu.m = 1 ppm x MW/24.45 cu.m

The factor of 24.45 is the volume occupied by 1 mole of an ideal gas at 1 atmosphere of pressure 

and 25 degrees Celsius. 

In the next step, exposure levels are adjusted to account for the fact that the RfC is 

defined based on continuous exposure, but many inhalation toxicity studies in experimental 

animals are conducted using a discontinuous exposure regiment, such as 6 hours/day, 5

days/week. To account for this difference, exposures are normalized to account for 

discontinuous exposure. Mathematically:

NOAEL*[ADJ] (mg/cu.m) = E mg/cu.m x D (hours/24 hours) x W (days/7 days)
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Toxicology Excellence for Risk Assessment 6 November 11, 1999

where the NOAEL* is the NOAEL or analogous effect level, such as the benchmark concentration, 

E is the exposure level, D is the number of hours exposed per day, and W is the number of 

exposure days per week.

When extrapolating from occupational exposures, adjustments are made both for 

discontinuous exposure and for the higher ventilation rate under occupational conditions. Human 

equivalent concentrations for ambient exposure are calculated from occupational exposure levels 

by adjusting for the number of exposure days per week, as well as for the differences between 

the default human occupational minute volume (VEho, 10 m3 per 8 hour day) and the human 

ambient default minute volume (VEh, 20 m3 per 24 hour day):

NOAEL*[HEC] (mg/m3) = NOAEL (mg/m3) x (VEho/VEh) x 5 days/7 days

where NOAEL*[HEC] is the human equivalent concentration for the assumed ambient scenario or 

an analogous effect level, the NOAEL is the time-weighted-average (TWA) occupational 

exposure level, VEho is the human occupational default minute volume (10 m3 per 8 hour day), 

and VEh is the human ambient default minute volume (20 m3 per 24 hour day).

The final RfC-specific step is conducting dosimetric adjustments to calculate human 

equivalent concentrations. For gases, the dosimetric approach used is based on consideration of 

the target region (respiratory or extrarespiratory, and whether in the extrathoracic, 

tracheobronchial, or pulmonary region of the respiratory tract), as well as the chemical’s mode of 

action. Based on these considerations, the chemical is classified into one of three categories. 

Gases that do not penetrate to the blood are considered category 1. These gases are highly water 

soluble and/or rapidly reactive, and thus exert most of their toxic effects in the respiratory tract. 

HECs are calculated for category 1 gases based on animal and human minute volumes and 

surface areas of the respiratory tract, taking into account the “scrubbing” that occurs at higher 

levels of the respiratory tract and reduces penetration to lower levels. Category 3 gases are fairly 

insoluble in water, and are not chemically reactive. Thus, these chemicals do not deposit or react 

appreciably in the extrathoracic or tracheobronchial regions, and instead primarily cause 

extrarespiratory effects. HECs for category 3 gases, or extrarespiratory effects of category 1 

gases, are calculated based on the blood:air partition coefficient of the chemical in the 

experimental animal species of interest and in humans. Category 2 gases fall between categories 

1 and 3.

Inhalation exposures to the lanthanides in complex or individually are to the particulate 

form, for which a different dosimetric adjustment is used. For particles, human equivalent 

concentrations are calculated based on particle deposition in the respiratory tract region of 

interest, the ventilation rate, and the regional surface area. These calculations are conducted 

using EPA’s Regional Deposited Dose Ratio (RDDR) model (U.S. EPA 1994). Required inputs 

for the model are the mass median aerodynamic diameter (MMAD), and the geometric standard 

deviation (sigma g), which together describe the particle size distribution for the particle or 

aerosol of interest; as well as the animal species and body weight. The human equivalent 

concentration is calculated using the equation:

NOAEL*[HEC] (mg/m3) = NOAEL*[ADJ] (mg/m3) x RDDRr
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Toxicology Excellence for Risk Assessment 7 November 11, 1999

where the Regional Deposited Dose Ratio for region r is calculated by the RDDR model 

(U.S. EPA, 1994). The potential respiratory tract regions are the extrathoracic (ET), 

tracheobronchial (TB), or pulmonary (PU). Combined regions for which the RDDRr can 

also be calculated are the thoracic (TH) region (TB plus PU regions) and the total (TOT) 

respiratory tract (all three respiratory tract regions). The RDDR can also be calculated 

for extrarespiratory (ER) effects. For extrarespiratory (systemic) effects, total deposition 

(deposition summed for all three regions) is assumed to be available for transport to other 

organs.

In the absence of adequate human data EPA generally considers a "complete" database, 

that is, complete for the purpose of calculating a RfC for noncancer health effects, to be 

composed of:

• two adequate mammalian chronic inhalation toxicity studies in different species that included 

evaluation of the respiratory tract; 

• one adequate mammalian multi-generation reproductive toxicity study by an appropriate 

route; and 

• two adequate mammalian developmental toxicity studies by an appropriate route in different 

species. 

A “complete” database for the purposes of developing an RfD is similar. An adequate study is 

one that tests a sufficient number of animals of both sexes at two or more nonzero dose levels, 

and was adequately performed and documented. In addition, the study should ideally identify an 

effect level (i.e., a LOAEL). If no LOAEL is identified, the study can still be considered 

adequate if it tested doses well above the critical effect that forms the basis for the RfD or RfC. 

(For example, a developmental study in which the high concentration was10x the NOAEL for 

the principal study, but that found no effects, would be considered adequate.) The determination 

of study adequacy rests on professional judgment. A detailed discussion of the factors to be 

considered when evaluating the adequacy of a database and a study can be found in U.S. EPA 

(1994).

Uncertainty factors (UFs) are reductions in the dose rate or concentration to account for 

areas of scientific uncertainty inherent in most toxicity databases. The choice of appropriate 

uncertainty and modifying factors reflects a case-by-case judgment by experts and should 

account for each of the applicable areas of uncertainty and any nuances in the available data that 

might change the magnitude of any factor. 

Typically, EPA uses uncertainty factors to account for five areas of uncertainty. The UF 

for human variability (designated as H) is intended to account for the variation in sensitivity 

among the members of the human population. The UF for experimental animal-to-human 

extrapolation (designated as A) is intended to account for the extrapolation from animal data to 

the case of humans and is considered to have components of both toxicokinetics and 

toxicodynamics. The subchronic-to-chronic UF (designated as S) is intended to account for 

extrapolating from less than chronic levels to chronic levels. The UF for LOAEL-to-NOAEL 

extrapolation (designated as L) is applied when an appropriate NOAEL is not available to serve 

as the basis for a risk estimate, and extrapolation from an experimental LOAEL is necessary. 
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Toxicology Excellence for Risk Assessment 8 November 11, 1999

Database completeness (designated as D) is intended to account for the inability of any single 

study to adequately address all possible adverse outcomes. EPA currently uses an additional 

factor, referred to as a modifying factor (MF), as an occasional adjustment in the estimation of an 

RfD/RfC to account for areas of uncertainty not explicitly addressed by the usual factors. 

The traditional default value of 10 has been generally used for each of these UFs. EPA, 

however, through experience of calculating thousands of RfD/RfCs, has developed criteria for 

reducing UFs (generally to a half-log value of 3, or 1), when data warrant. EPA also recognizes 

the potential overlap between UFs and attempts to accommodate this. In particular, the standard 

practice is to use a factor of 3 for interspecies extrapolation when developing a RfC using the 

standard dosimetric adjustments (U.S. EPA, 1994). A recent publication discusses the use of 

factors other than default based on these criteria (Dourson et al., 1996).

The equation that EPA uses to determine the value of the RfC is:

RfC = NOAELHEC or LOAELHEC(mg/m3) ÷ (UF x MF) 

where: 

NOAELHEC = No Observed Adverse Effect Level or an equivalent value, such as a BMC, 

dosimetrically adjusted to an ambient human equivalent concentration

LOAELHEC = Lowest Observed Adverse Effect Level, dosimetrically adjusted to an ambient 

human equivalent concentration

HEC = Human Equivalent Concentration

UF = Uncertainty Factor 

MF = Modifying Factor.

The equation to develop a RfD is similar, where:

RfD = NOAEL or LOAEL (mg/kg-day) ÷ (UF x MF) 

NOAEL = No Observed Adverse Effect Level or an equivalent value, such as a BMD

LOAEL = Lowest Observed Adverse Effect Level

UF = Uncertainty Factor 

MF = Modifying Factor.

Finally, EPA provides a statement of confidence in their noncancer risk estimates (Barnes 

and Dourson, 1988; Dourson, 1994; U.S. EPA 1994). High confidence indicates a judgment that 

additional toxicity data are not likely to change the RfD/RfC. Low confidence indicates that at 

least a single, well-conducted, subchronic mammalian bioassay by the appropriate route is 

available. For such a minimum database, the likelihood that additional toxicity data may change 

the RfC is greater. Medium confidence indicates a judgment somewhere between high and low. 

Example of confidence statements for RfD/RfCs can be found on EPA's IRIS (U.S. EPA, 1999).
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Toxicology Excellence for Risk Assessment 9 November 11, 1999

2.0 Hazard Identification

2.1 Review of Relevant Data Sources

TERA obtained a literature search in December 1998, and reviewed the availability of 

toxicological studies related to the lanthanides in combination and individually. Specifically, 

each individual lanthanide and some lanthanide-like elements were searched for the following 

elements: lanthanum (CASRN 7439-91-0), cerium (CASRN 7440-45-11), praseodymium 

(CASRN 7440-10-0), promethium (CASRN 7440-12-2), samarium (CASRN 7440-19-9), 

europium (CASRN 7440-53-1), gadolinium (CASRN 7440-54-2), terbium (CASRN 7440-27-9), 

dysprosium (CASRN 7440-91-6), holmium (CASRN 7440-60-0), erbium (CASRN 7440-52-0), 

thulium (CASRN 7440-30-4), ytterbium (CASRN 7440-64-4), lutetium (CASRN 7440-94-3), 

neodymium (CASRN 7440-00-8), yttrium (CASRN 7440-65-5), thorium (CASRN 7440-29-1) 

and scandium (CASRN 7440-20-2) and their respective salts. The HSDB and TSCATS 

databases were searched by the CASRN of the chemicals of interest and their appropriate salts. 

All years of the MEDLINE and TOXLINE databases were searched (from when 

TOXLINE began in 1965 and MEDLINE began in 1966), using both CASRNs and name 

synonyms. The search strategy that we use for deriving RfDs/RfCs was employed in these 

databases. In MEDLINE, the appropriate MESH terms for the chemicals were used and 

metabolic and pharmacokinetic studies as well as toxicity studies and exposure studies were 

searched. In TOXLINE, CASRNs/synonyms were “ANDed” with an extensive list of search 

terms related to the oral and inhalation routes (e.g. nasal, ingest, etc.), some general health terms 

(e.g. chronic, neurotox, etc.) as well as an extensive list of reproductive developmental terms 

(e.g. fetal, sperm, etc.). The TOXLINE references from 1981-98 were downloaded in the search, 

using the chemical names/CASRNs in combination with our search strategy for finding health 

effects references. 

In selecting studies to review, TERA first examined human or animal toxicity studies that 

evaluated the dose-response relationship between the chemicals of interest and potential health 

effects. Second, we considered studies on absorption, distribution, metabolism, excretion, or 

toxicokinetics, which would have an impact on the choice of appropriate uncertainty factors for 

the lanthanide RfDs and RfCs and the potential for route-to-route extrapolation for the 

development of a RfC from oral data if there was insufficient data from the inhalation data set. 

A variety of studies were found. These are summarized in Appendix Tables 1 and 2. We 

discussed the more relevant studies below for the purposes of establishing RfDs and RfCs .

2.2 Human Studies

Longerich et al. (1990) conducted an analysis of the drinking water of mothers of neural 

tube defect (NTD) infants and of normal infants for 14 selected trace elements. The tested 

elements included: Y, Ce, Mg, Cu, Zn, Sr, Mo, Cd, Sn, Sb, I, Ba, Pb and U. Twenty-eight NTD 

mothers and 28 control mothers of age-matched infants living in the same geographic area were 

included in the study. The drinking water of these mothers was collected and tested for the 14 

trace elements by an inductively coupled plasma-mass spectrometry. The levels of Y (0.27±0.62 
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Toxicology Excellence for Risk Assessment 10 November 11, 1999

ug/L) and Ce (0.28±0.58 ug/L) in the drinking water of NTD mothers were higher than those in 

control groups (Y: 0.13±0.23 ug/L; Ce: 0.16±0.43 ug/L). However, the differences between the 

case group and the control were not statistically significant. Except Zn, all the other elements 

tested were found in higher, but not statistically significant, concentrations in the case group than 

in the control group. The result suggested a relationship of trace elements in drinking water with 

NTD, but a contribution of other factors to the NTD could not be excluded based on the available 

data. This study was limited by the limited exposure information. 

Arsenault et al. (1996) investigated systemic gadolinium toxicity in patients with 

impaired renal function. One hundred fifty-one patients with a serum creatinine value ≥2.0 

mg/dL during the 72-hour period immediately prior to a magnetic resonance imaging (MRI) 

examination were selected. These patients received gadolinium diethylenetriamine pentaacetic 

acid (DTPA) at dose of 0.1 mmol/kg as the contrast medium for the MRI examinations. A 

retrospective analysis was conducted of physician records, nursing records, radiology reports, 

laboratory data, and autopsy records during the 3 days before the MRI and for 30 days after the 

MRI. In addition, to assess any possible increase in mortality, 90-day mortality data from this 

group was compared to that in a control group of patients who had a MRI examination without 

using gadolinium DTPA as the contrast medium. Adverse events such as nausea (1.2%), rash 

(1.2%), seizure (0.6%) and headache (0.6%) were reported in patients received gadolinium 

DTPA, but the incidences were not significantly different from those in MRI patients with 

normal renal function in a previous study. Hematological and biochemical examinations showed 

no statistically significant change between pre-MRI and post-MRI examinations. A 14.6% 

mortality in the 90 days after MRI was found in gadolinium-exposed patients, but this value was 

comparable to that (13.8%) in the control group without exposure to gadolinium. Therefore, no 

significant adverse effect was observed after gadolinium DTPA exposure. 

No studies were located on the effects in humans exposed to lanthanides via the 

inhalation route.

2.3 Inhalation Toxicity Data in Experimental Animals

BioResearch Labs Ltd. (1995) for Rhone-Poulenc Inc. reported a subchronic study on 

ceric oxide toxicity following inhalation exposure. Fifteen male and fifteen female Sprague 

Dawley CD rats were exposed by nose-only inhalation to CeO2 aerosol at a concentration of 0, 5, 

50, or 500 mg CeO2/cu.m for 6 hours a day, 5 days a week for 13 weeks. This corresponded to a 

concentration of 0, 4.1, 41, or 407 mg Ce/cu.m. After adjustment for intermittent exposure, the 

exposures were to 0, 0.73, 7.3, or 73 mg Ce/cu.m. The mass median aerodynamic diameter 

(MMAD) was reported to be 2.00 microns, and the sigma g was 1.90 microns. Animals were 

examined daily for signs of toxicity, weekly for food consumption and body weight changes, and 

monthly for potential neurotoxic effects using a functional observation battery and motor activity 

testing. After 6 weeks of exposure and at study termination, hematology, clinical biochemistry, 

and urinalysis were performed. A gross pathological examination, assessment of organ weights, 

and a detailed histopathological evaluation were conducted at the end of the 13-week ceric oxide 

treatment. The histopathology examination included a thorough examination of the respiratory 

tract, including four levels of the nose. 
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The percentage of segmented (mature) neutrophils was significantly increased in highconcentration males; this parameter was also significantly increased in females at all 

concentrations, but the control group was unusually low, and the levels in exposed females were 

comparable to levels in control males. The toxicological significance of this effect is unclear. 

There was also a statistically significant increase in relative (but not absolute) spleen weight in 

males. Other significant effects due to ceric oxide exposure were confined to the respiratory 

tract. Concentration–related statistically significant increases in lung weight were seen in both 

male and female rats exposed to 50 and 500 mg/cu.m ceric oxide. The histopathological 

examination of the lung showed pigment accumulation at all exposure levels. We consider this 

pigment accumulation to be an indication of exposure, and not inherently adverse. Lymphoid 

hyperplasia in the bronchial lymph node was significantly increased in all exposed groups; the 

study authors considered this effect to be consistent with antigenic stimulation by the test 

material, and noted that this endpoint correlated with the volume of pigment. For the purpose of 

dosimetric conversions, we considered this endpoint to be a tracheobronchial effect, since the 

response is related to the dose to the bronchi. There was also a concentration-related incidence 

of larynx metaplasia that was statistically significant at mid and high concentrations. Alveolar 

epithelial hyperplasia was also statistically significant at mid and high concentrations in both 

sexes. For all of the respiratory tract endpoints, the low concentration was the NOAEL and mid 

concentration was the LOAEL. The corresponding NOAEL(HEC)s were 0.41 and 0.43 mg 

Ce/cu.m for alveolar epithelial hyperplasia in males and females, respectively, and 0.55 mg 

Ce/cu.m for increased lung weight in males and females. No NOAEL was identified for the 

bronchial lymph node hyperplasia; based on this minimal effect the LOAEL(HEC) is 0.85 or 

0.82 mg Ce/cu.m in males and females, respectively. In the absence of data showing genderspecific differences, the LOAEL(HEC), based on the average of the tracheobronchial effects in 

both male and female rats, for the study is 0.83 mg Ce/cu.m (1.0 mg CeO2/cu.m).

Abel and Talbot (1967) conducted a subchronic study on gadolinium oxide toxicity 

following inhalation exposure. Groups of six male and six female guinea pigs were exposed 

(whole body exposure) to 20 mg/cu.m Gd2O3 aerosol (particle sizes predominantly between 

MMAD of 0.1~1.0 μ) for 6 hours/day, 5 days/week for periods of 0, 40, 80, or 120 days. An 

equal number of animals exposed to atmosphere without gadolinium were used as controls. 

After exposure, the excised lungs were me asured for compliance and lung tissues were evaluated 

histologically. As measured by an increase in the slope of the elastance curve, lungs exposed to 

Gd2O3 had less elastance than lungs from unexposed control guinea pigs. An increase in the 

duration of exposure produced a significant linear decrease in the lung elastance. In addition, 

40-day exposure resulted in mild swelling and proliferation of septa cells and nodular 

lymphocytic hyperplasia. By 120 days after exposure, thickening of the alveolar wall, and 

numerous macrophages and nodular lymphocytic hyperplasia were observed in the lungs. The 

authors suggested the maximal permissible concentration should be less than 20 mg/cu.m of air. 

Limitations of this study include the use of only a single exposure concentration, the broad range 

of particle sizes in the exposure atmosphere, and the small number of animals per group. Since 

MMAD were not available in this study, and EPA (1994) does not provide default information 

for guinea pigs, no RDDR could be calculated. Thus, no HECs could be calculated.

Ball and van Gelder (1966) exposed mice (whole body exposure) to gadolinium oxide 

aerosol at an approximate concentration of 30 mg/cu.m of air for 6 hours/day, 5 days/week for 20 
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Toxicology Excellence for Risk Assessment 12 November 11, 1999

to 120 days, and monitored the surviving animals for the remaining duration of their lives. A 

total of 256 CFW mice, including both males and females, were used in the study, but the 

numbers of animals in each group were not given in the paper. The particle size was estimated 

to be between 0.1 and 0.5 micron diameter with a mean particle diameter of 0.312 ± 0.287 μ. 

Hematological examination was performed during the study on a randomized basis and at 12 and 

18 months postexposure on surviving mice. Histopathology and necropsy procedures were also 

performed on mice that died during the exposure period, and on surviving mice at the time of 

death. There were no differences in hematology and weight gain between exposed and control 

mice up to and including 120 days of exposure. The histology indicates that gadolinium oxide is 

a low-grade pulmonary irritant that resulted in the localized accumulation of metal-containing 

microphages within the lung and a minimal interstitial thickening. In addition, gadolinium oxide 

exposed mice had an unusual histological finding of pulmonary calcification in the region of the 

alveolar basement region. The study demonstrates histopathological changes in the lung, but did 

not adequately characterize corresponding deficits in lung function. The authors did suggest that 

there is a trend, though not statistically significant, towards shortened life span in exposed mice. 

Limitations of this study also result from the use of only a single exposure concentration 

although a large number of animals was used.

2.4 Oral Toxicity Data in Experimental Animals

2.4.1 Acute Studies

Haley et al. (1961, 1963, 1964a,b, 1965, 1966) conducted a series of acute oral toxicity 

studies on the rare earth elements each in form of the chloride salt. The elements tested included 

gadolinium, samarium, terbium, thulium, ytterbium, praseodymium, neodymium, lutetium, 

europium, dysprosium, holmium, and erbium. For gadolinium and samarium, oral doses up to 2 

g/kg were without lethality. Since it was impossible to obtain more concentrated solutions of 

these two compounds, no further tests of oral toxicity were conducted. The LD50 values for the 

other lanthanide elements were reported as: 5100 mg/kg for terbium chloride, 6250 mg/kg for 

thulium chloride, 6700 mg/kg for ytterbium, 4500 mg/kg praseodymium chloride, 5250 mg/kg 

for neodymium chloride, 5000 mg/kg for europium chloride, 7100 mg/kg for lutetium chloride, 

7650 mg/kg for dysprosium chloride, 7200 mg/kg for holmium chloride, and 6200 for erbium 

chloride. The common symptoms of acute toxicity included writhing, ataxia, slightly labored 

and depressed respiration, arched back, stretching of limbs on walking, and lacrimation. Some 

deaths occurred within 24 hours, but the peak in deaths was not reached until 48 hours after the 

exposure. 

2.4.2 Short Term Studies

Ogawa et al. (1992, 1994, and 1995) conducted a series of short term, subacute toxicity 

studies on several rare earth elements. The elements studied included lanthanum (La), yttrium 

(Y) and europium (Eu) in the form of hydrated chloride. In these studies, Wistar rats of both 

sexes received the compounds by gavage at doses of 0, 40, 200, or 1000 mg/kg for consecutive 

28 days. Body weight and food consumption were monitored during the exposure, and 

hematological, serum-biochemical and complete histopathological examinations were performed 
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Toxicology Excellence for Risk Assessment 13 November 11, 1999

at the end of exposure. In addition, the concentrations of the rare earth elements in organs were 

determined.

Lanthanum was tested in Wistar rats (5 animals/dose/sex) at doses of 0, 40, 200, or 1000 

mg/kg-day (as LaCl3

.

7H2O) for 28 consecutive days, which corresponds to 0, 15.0, 74.8 or 374 

mg La/kg-day (Ogawa et al. 1992). During lanthanum exposure, the body weight decreased (10-

15% compared to control) in both sexes at the doses ≥ 74.8 mg La/kg-day, but they were 

comparable to that in the pair feeding group, suggesting a food consumption related body weight 

gain change. Hematological examination indicated that the percentage of eosinocytes in blood 

increased in females at doses ≥ 15.0 mg La/kg, and in males at doses ≥ 74.8 mg La/kg-day. The 

significance of this change is unknown. At doses ≥74.8 mg La/kg-day, a significant decrease of 

serum cholinesterase activity was observed only in females. The serum transaminase activity 

increased in both sexes at a dose of 374 mg La/kg. This finding was suggestive of 

hepatotoxicity, although there were no corresponding histopathological changes of the liver 

reported. The histopathological data indicated significant increases in lung granulation and giant 

cell appearance at doses ≥ 74.8 mg La/kg. As discussed in another paper (Ogawa et al. 1995), 

the author suggested that these changes in the lungs might be caused by the inhalation of the test 

compound. In addition, 374 mg La/kg resulted in stomach lesions, including infiltration in the 

submucosa in both sexes, erosion and dilatation of the acinus in males and swelling in the 

epithelium of females. Based on several of these changes, but primarily the body weight 

decrease, caused by La exposure, the LOAEL in this study was judged to be 74.8 mg La/kg-day 

and the NOAEL was judged to be 15.0 mg La/kg-day.

Yttrium was tested in Wistar rats (5 animals/dose/sex) at doses of 0, 40, 200, or 1000 

mg/kg-day (as YCl3

.

6H2O) for 28 consecutive days, which corresponds to 0, 11.7, 58.6, or 293 

mg Y/kg-day (Ogawa et al. 1994). During yttrium exposure, decreased body weight compared 

to control occurred in males (25% lower) at the highest dose (293 mg Y/kg-day) and in females 

(10-15% lower) at doses ≥58.6 mg Y/kg-day. However, the decreases were comparable to that 

in pair feed controls, suggesting a food consumption related change. Hematological examination 

indicated that the percentage of eosinocytes in white blood cells increased in both males and 

females at doses ≥ 11.7 mg Y/kg. At doses ≥58.6 Y mg/kg-day, a significant decrease of the 

serum cholinesterase activity was observed only in females. In contrast to lanthanum exposure, 

no significant change in the serum transaminase activities was observed in yttrium exposed rats. 

The histopathological study indicated increases in lung granulation, giant cell appearance and 

eosinocyte infiltration in both sexes at doses ≥ 58.6 mg Y/kg-day, but the increases were dose 

independent and were not statistically significant from the control. Similar responses in the 

stomach following exposure to lanthanum were also observed following exposure to high dose of 

yttrium (293 mg Y/kg-day), including eosinocyte infiltration in submucosa in both sexes, and 

hyperkerotosis of forestomach and swelling epithelium of glandular stomach in females. Based 

primarily on the decreased body weight effect in female rats, the LOAEL in this study was 

judged to be 58.6 mg Y/kg-day and the NOAEL was judged to be 11.7 mg Y/kg-day.

Europium was tested in Wistar rats (10 animals/dose/sex) at doses of 0, 40, 200, or 1000 

mg/kg-day (as EuCl3

.

6H2O) for 28 consecutive days, which corresponds to 0, 16.6, 82.9, or 415 

mg Eu/kg-day (Ogawa et al. 1995). Following europium exposure, decreased body weight 

(17%) compared to the control was only observed in females at the highest dose 415 mg Eu/kg-
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Toxicology Excellence for Risk Assessment 14 November 11, 1999

day, while there was no difference in food consumption between the tested groups. No pair 

feeding control was included in this study. All the hematological changes observed were within 

the historical control data ranges in the testing laboratory. At doses ≥415 mg Eu/kg-day, a 

significant decrease of the serum cholinesterase activity was observed only in females. In 

contrast to lanthanum exposure, no significant change in the serum transaminase activities was 

observed in europium exposed rats. The histopathological study indicated dose independent 

increases in lung granulation, giant cell appearance and eosinocyte infiltration in both sexes. The 

authors suggested that these changes might be due to the inhalation of rare earth elements. 

Similar responses in the stomach following exposure to lanthanum were also observed following 

exposure to high dose of europium (415 mg Eu/kg-day), including hyperkeratosis of the 

forestomach and eosinocyte infiltration in the submucosa of both sexes. Based primarily on the 

decreased body weight in females and the stomach lesions in both sexes, the LOAEL in this 

study was 415 mg Eu/kg-day and the NOAEL was 82.9 mg Eu/kg-day.

2.4.3 Subchronic Studies

Haley et al. conducted a series of subchronic toxicity studies for rare earth elements each 

in the form of the chloride salt. The tested elements included gadolinium, samarium, terbium, 

thulium, ytterbium, praseodymium, neodymium, lutetium, europium, dysprosium, holmium, and 

erbium (Haley et al. 1961, 1963, 1964a,b, 1965, 1966). Groups of 6 rats/sex (CFN or CRW 

strain) received the test compounds in the form of chloride through diet at doses of 0, 0.01%, 0.1 

%, or 1% of the diet for 12 weeks. Based on commonly used default values for body weights 

and food intake (0.05 kg food/kg body weight for rats), the corresponding doses were 0, 5, 50, 

and 500 mg/kg-day (of testing compound). During the exposure period, hematological changes, 

including erythrocytes, total leukocytes, differential cell count, platelets, hemoglobin, 

hematocrit, and body weight were examined periodically. At the end of the study, a complete 

histological examination was conducted. 

Most of the tested rare earth chlorides had no effect on growth, hematology, and 

histopathology on exposed animals. Specifically for gadolinium exposure (Haley et al. 1961), 

the only significant exposure related changes were perinuclear vacuolization of the parenchymal 

cells of the liver and a coarse granularity of the their cytoplasm in male rats exposed to 500 

mg/kg-day gadolinium chloride. Similar effects were not observed in females. For ytterbium 

chloride exposure (Haley et al. 1963), rats exposed to 500 mg/kg-day had gastric hemorrhages 

predominantly in the females (the number of animals responding was not reported). However, 

histopathological examination of these stomachs and of the esophagus revealed no tissue damage 

that would account for the gastric hemorrhages found at autopsy. An apparent dose dependent 

perinuclear vacuolization in the liver were observed in rats, mainly in males, exposed to terbium 

(≥5 mg/kg-day), thulium (50 mg/kg-day) and ytterbium (5 mg/kg-day) chlorides (control values 

were not provided, however). Since the observed perinuclear vacuolization of the liver cell is 

abnormal but the significance of this effect is not known and control values were not given, these 

changes should not necessarily be considered as an adverse effect caused by the exposure to rare 

earth elements. Based on the gastric hemorrhages in females, however, the LOAEL for 

ytterbium chloride was determined at 500 mg/kg-day, and the NOAEL would be 50 mg/kg-day. 

For the other tested rare earth compounds, gadolinium, samarium, terbium, thulium, 
Bureau of Land Management Amended Final

Toxicology Excellence for Risk Assessment 15 November 11, 1999

praseodymium, neodymium, lutetium, europium, dysprosium, holmium and erbium, equivocal, 

free standing NOAELs of 500 mg/kg-day were identified.

2.4.4 Chronic Studies

Schroeder and Mitchener (1971) fed yttrium nitrate at 5 ppm of the metal in drinking 

water to mice for up to 18 months. Groups of 54 CD mice of each sex were given yttrium nitrate 

in drinking water from weaning until natural death. Based on EPA default mouse water intake 

value of 0.19 L/kg-day (U.S. EPA, 1987), the calculated exposure dose was 0.95 mg Y/kg-day. 

Body weight was measured at monthly intervals up to 6 months, at 1 year and at 18 months of 

age. Dead animals were weighted and autopsied. Histopathological examinations were made on 

the heart, lung, liver, kidney, and spleen. Decreases in body weight were observed in males 

within first 6 months of exposure with 5% decreased at end of 6 months. In contrast, body 

weight decreases in females maintained in the whole exposure period with 17% decrease at the 

end of 18 months. However, survival curves were not affected following life long exposure. 

Yttrium was suggested to exert some carcinogenic activity, but the data were incomplete to 

definitively show this affect. No other toxicological end points were evaluated, making the 

adverse significance of the decreased body weight gain difficult to interpret. Additionally, the 

use of a single dose of yttrium does not allow for the development of a dose response curve and 

therefore the use of this data for risk assessment purposes is severely restricted.

Hutcheson et al. (1975) fed a diet that contained 10 heavy metals to CF-1 mice for three 

generations in this less-than-chronic study. Sixteen females and eight males were used in each 

dose group. All metals were fed in combination at 0, 1, 10, 100, and 1,000 times use-amount. 

For the lanthanides (as oxides) included in this diet, the use amount was (in ppm): dysprosium 

(1.2), europium (0.036), 1anthanum (0.40), samarium (0.80), scandium (0.12), terbium (1.20), 

ytterbium (0.12) and thulium (0.08). The mice were weighed periodically during the experiment. 

Hematological examinations of the blood sample from five 3-month-old dams in the 100-X 

group and control in each generation were conducted. In addition, gross necropsy observations 

were made on five adult third-generation mice from the 100-X group and five from the control 

group. There were no treatment effects reported among the treatment groups on survival, 

hematology, morphological development, maturation, reproduction or lactational performance. 

Although there were some significant differences in body weight between the tested groups, the 

differences were not consistent with levels of mineral added to the diet. Measurements of 

mineral content in carcasses from 100-X and control groups of the second-generation animals 

indicated a negligible gastrointestinal absorption of lanthanide compounds due to their poor 

solubility at tissue pH. These data provided a freestanding NOAEL for reproductive effects for 

each of the lanthanides listed above for up to 1000 times the use-amounts listed. Based on the 

EPA default values for food factor of 0.13 kg food/kg body weight (U.S. EPA, 1987), the 

calculated exposure doses of each lanthanide in the 1000-X group are: 156 mg Dy/kg-day, 5 mg 

Eu/kg-day, 52 mg La/kg-day, 104 mg Sm/kg-day, 16 mg Sc/kg-day, 156 mg Tb/kg-day, 16 mg 

Yb/kg-day, and 10 mg Tm/kg-day.
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Toxicology Excellence for Risk Assessment 16 November 11, 1999

3. Dose Response Assessment

3.1 Toxicokinetics

Different forms of lanthanide may present different toxicity. There are three forms of 

lanthanide: soluble, insoluble and chelated compounds. The soluble salts include chloride or 

nitrate; insoluble compounds include oxide or hydroxide; and chelated compounds include 

citrate, diethylenetriaminepentaacetic acid (DTPA) or ethylenediamine-N,N,N',N'-tetraacetic 

acid (EDTA) containing compounds. The toxicity of lanthanide after oral or inhalation exposure 

depends on its absorption, distribution, and its portal of entry effect. 

Absorption of the form of a given lanthanide may determine its toxicity to the body. So 

far, all the available information on lanthanide absorption after oral exposure comes from studies 

on soluble lanthanide salts (see Appendix A, Table 2). No data on insoluble or chelated 

lanthanide absorption were identified. Therefore, a direct comparison of absorption rate between 

three forms of lanthanide could not be conducted. However, available data from soluble 

lanthanide indicate that DTPA (a well known chelator) treatment 1 or 2 days after oral 

administration of CeCl3 (with milk) significantly decreased whole body retention of soluble 

cerium from 40% to 2% (Kostial et al. 1989). Whether the decreased cerium retention was 

caused by decrease in cerium absorption or by increase in its excretion is not known. However, 

these data suggested that different forms of lanthanide (soluble versus chelated for example) 

might lead to different systemic effects due to different bioavailabilities. 

Different forms of lanthanides have different organ distribution and excretion rates once 

the portal of entry is bypassed and it is available systemically. Intravenous injected chelated 

lanthanide is transiently accumulated in the kidney and most of the injected dose is excreted in 

urine. Only small portion of the injected dose remained in other organs. In contrast, intravenous 

injected soluble salt is taken up by reticuloendothelial cells, and most of the dose is accumulated 

in the liver and spleen. As the result, intravenous injection of soluble lanthanide causes necrosis 

in the liver (Hirano and Suzuki 1996). Thus, different forms of lanthanide are expected to have a 

different systemic effect after it is absorbed into the body.

Toxicity data do not exist to judge which form of a given lanthanide is more toxic. For 

example, a three generation study (Hutcheson et al. 1975) on the toxicity of insoluble 

lanthanides, lanthanum and europium oxides, indicated that doses up to 52 mg La/kg or 4.7 mg 

Eu/kg mixed in the diet resulted in no consistent significant toxic effect in mice. Similarly, 

soluble lanthanum and europium, in the same dose range, had no adverse effect in 28-day studies 

when given by gavage (Ogawa et al. 1992, 1995). Nevertheless, a portal of entry effect did 

occur at the higher dose of soluble lanthanide gavage treatment, suggesting that the risk value for 

a specific route and method of administration should be derived from a toxicity study following 

the corresponding route or method of exposure.

Based on possible differences in absorption, distribution, and portal of entry effects, we 

recommended that the risk assessment of lanthanides should focus on specific forms to which the 
Bureau of Land Management Amended Final

Toxicology Excellence for Risk Assessment 17 November 11, 1999

toxicity data are available for deriving risk values. In the case of oral exposures, most of the 

available toxicity information comes from studies on soluble lanthanide. Therefore, a 

development of the RfD for soluble lanthanide is recommended. Inhalation risk assessment 

values should be conducted on chemicals with respiratory exposure and not be calculated from 

route-to-route extrapolations from other modes of administration. 

3.2 Choice of Critical Studies

The available human data are not sufficient as a basis of either an RfC or an RfD. 

The primary source of scientific uncertainty at this point in the development of the 

lanthanide RfC is the interpretation and paucity of the toxicological data, and the resulting 

implications for the choice of principal study and critical effect. 

 For ceric oxide, only one adequate toxicity study exists from which to determine an 

RfC: Bio-Research Labs (1995). We judged that bronchial lymph node hyperplasia was the 

critical effect, and that it is minimal at the lowest concentration. Thus, the LOAEL[HEC] for ceric 

oxide would be 1.0 mg/cu.m. (0.83 mg Ce/cu.m).

Of the two available inhalation studies for gadolinium oxide (i.e., Abel and Talbot, 1967; 

Ball and van Gelder, 1966), we consider the latter as a better basis for the development of an 

RfC. This is because toxicity was monitored over several exposure times and a large number of 

mice were used. Although only one concentration was evident from this study, the other study 

(Abel and Talbot 1967) gave some minimal support in another species. The critical effect of the 

Ball and van Gelder, (1966) study was calcification in the alveolar region and accumulation of 

macrophages in the lungs. The effect was not judged to be minimal. The resulting LOAEL[HEC]

was 5.5 mg Gd2O3 (4.8 as mg Gd/cu.m.)

The oral data for subchronic or chronic exposure to lanthanides is likewise sparse and 

difficult to interpret for risk assessment purposes. The data of Ogawa (1992, 1994 and 1995) 

demonstrate dose-response effects for lanthanum, yttrium and europium as chlorides. The 

authors measured a number of parameters in pair-fed animals and determined both NOAELs and 

LOAELs. However, these studies were only for 28 days of exposure, which is shorter than the 

usually required length of study for development of an RfD. The Hutcheson et al. (1975) data 

provide multigenerational database testing of reproductive endpoints for the seven rare earth 

metals tested as oxides (i.e., dysprosium, europium, lanthanum, samarium, scandium, terbium, 

and thulium). These authors tested a series of doses (up to 1000-fold the normal use amount), 

but did not test high enough to demonstrate toxicity. The Schroeder and Mitchener (1971) study 

likewise did not test high enough doses to be used as a basis of an RfD. The Haley et al. data 

(1961, 1965, and 1966) provide additional subchronic dose response information on other rare 

earth elements as chlorides (gadolinium, samarium, dysprosium, europium, holmium and 

erbium). These authors tested for multiple endpoints and determined dose response for several 

parameters. 
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Toxicology Excellence for Risk Assessment 18 November 11, 1999

After reviewing all of this information, we recommend that the short term studies of 

Ogawa (1992, 1994 and 1995) be used to determine RfDs for the chlorides of lanthanum, yttrium 

and europium with corresponding NOAELs of 15.0, 11.7, and 82.9 mg/kg-day, respectively. 

The primary critical effect for each of these lanthanides is decrease body weight. Although these 

studies are only 28 days in duration, they measured portal of entry effects and established a doseresponse. The other available subchronic data of Haley et al. (1961, 1965, and 1966) along with 

the multi-generation study of Hutcheson et al. (1975) can be used to support the derivation of 

these oral RfDs. The Hutcheson et al. (1975) study can also be used to derive preliminary RfDs 

for the oxides of dysprosium, europium, lanthanum, samarium, scandium, terbium, thulium, and 

ytterbium, however, only the derivations for lanthanum, europium, and scandium are presented 

here.

3.3 Choice of Uncertainty and Modifying Factors

The choice of uncertainty factors to be used with the appropriate critical effect of the 

various lanthanides depends on the areas of uncertainty that exist given the quality of the 

database. The available toxicity data for lanthanides in general necessitates the use of a larger 

composite uncertainty factors when compared to some other chemicals on EPA’s IRIS (U.S. 

EPA, 1999). In addition, the toxicokinetic data on lanthanides are not sufficiently clear as to 

affect the value of individual uncertainty factors. The following discussion describes our choice 

of uncertainty factors for the determination of Reference Concentration (RfC) and Reference 

Dose (RfD) for the lanthanides. Table 1 summarizes these factors.

Human Variability (UFH) 

Do existing data account for sensitive individuals? 

If yes, this suggests an uncertainty factor other than a default value of 10, as low as a 

value of 1 in some instances [see for example, the description of the uncertainty factor for 

nitrates on U.S. EPA’s IRIS database (1999), where a NOAEL of a sensitive population was 

used as the basis of the RfD]. Scientists familiar with this area have considered this default 

factor to be composed of roughly equal parts for toxicodynamic and toxicokinetic differences 

among humans. Some recent work has attempted to quantify these distinctions (Renwick, 1993). 

The available data in humans are insufficient to change the use of the default value of 10 

for this area of scientific uncertainty for any RfDs or RfCs calculated here. 

Inter-Species Variability (UFA)

Do existing data allow for a quantifiable extrapolation of animal dose to the expected 

human equivalent dose for effects of similar magnitude? Or as is more likely the case, is a 

quantifiable extrapolation possible for NOAELs?

If yes, this suggests an uncertainty factor other than a default value of 10---with RfCs for 

example, a value of 3 is used when dosimetric adjustments are used in the determination of 
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Toxicology Excellence for Risk Assessment 19 November 11, 1999

Human Equivalent Concentration (HEC) [see U.S. EPA’s IRIS (1999) for numerous examples]. 

Scientists familiar with this area have also considered this default factor to be composed of 

roughly equal parts for toxicodynamic and toxicokinetic differences between experimental 

animals and humans, but also recognize that some overlap with the uncertainty factor for intraspecies variability exists. Some recent work has also attempted to quantify these distinctions in 

general (Renwick, 1993). 

The RfCs for ceric oxide and gadolinium oxide should have an UF of 3-fold for this area 

of uncertainty, because dosimetric adjustments are used to extrapolate from animals to humans. 

This is standard practice within EPA (EPA, 1994).

Currently there are no dosimetric adjustments used in oral risk assessment values nor do 

sufficient toxicokinetic or toxicodynamic data exist to modify this area of uncertainty. Thus, the 

RfDs for the chlorides of europium, lanthanum, and yttrium would each have an uncertainty 

factor of 10-fold for this area. Likewise, a similar value would be applied to the oxides of 

europium, lanthanum and scandium. This is also standard practice within EPA (Dourson, 1994).

Subchronic-to-Chronic Extrapolation (UFS) 

Do existing data allow for a quantifiable extrapolation of the critical effect after 

subchronic exposure to the effect after chronic exposure? If different critical effects are 

identified after subchronic and chronic exposure, do they differ quantitatively?

U.S. EPA has occasionally used values less than 10 (nearly always 3-fold) with less than 

chronic exposures when data were available to support such a reduction [for example, see the 

RfD for arsine on U.S. EPA’s IRIS (1999)]. Scientists familiar with this area also recognize that 

some overlap with this factor occurs with the database uncertainty factor (see following 

discussion).

The RfC for ceric oxide and gadolinium oxide would be expected to have an UF of 10-

fold for this area of uncertainty because subchronic data was used to extrapolate to chronic 

exposure. Moreover, available toxicity data indicate an increasing severity in toxic response 

over duration to either of these chemicals. This increasing severity supports the use of the 

standard default value of 10-fold.

For the RfDs of the chlorides of europium, lanthanum, and yttrium, we also 

recommend the use of an UF of 10-fold. This is especially true for an RfD derivation that is 

predicated on an exposure period of something less than subchronic, in this case a 28-day study. 

The use of this short term study is supported somewhat, however, by the available information 

from multi-generation study which suggests no toxicity at lower doses and by the sub-chronic 

data reported by the Haley studies. 

For the Hutchenson et al. (1975) study that is used to support the derivation of 

preliminary RfDs for the lanthanide oxides, an uncertainty factor of 10 would still be employed 

even in this three generation study. The parameters that were measured were conducted in 

animals that had exposure to the oxides for periods of time that were less than chronic and more 
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Toxicology Excellence for Risk Assessment 20 November 11, 1999

like sub-chronic intervals. There is no data that might justify using a factor less than the default 

value of 10.

LOAEL to NOAEL Extrapolation (UFL) 

Do existing data allow for the use of a NOAEL, rather than a LOAEL for the estimation 

of a RfD?

 If a well-defined NOAEL does not exist, a factor of 10 is often used. However, U.S. 

EPA has often used values less than 10 (nearly always 3-fold) when data suggest that the 

LOAEL is for a minimally adverse effect, since the hypothesized NOAEL would likely be closer 

to this LOAEL then to a LOAEL with greater severity. For example, compare the RfDs for 

acrylonitrile and 1,2 epoxybutane on U.S. EPA’s IRIS (U.S. EPA, 1999). The former RfD uses a 

3-fold factor with degeneration and inflammation of nasal respiratory epithelium; the later RfD 

uses a 10-fold factor with more severe degenerative lesions of the epithelium. 

The RfCs for both ceric oxide and gadolinium oxide have a LOAEL identified at the 

lowest concentration. For gadolinium oxide, the severity of response at the LOAEL (i.e., 

calcification in the alveolar region and accumulations of macrophages in the lung) suggests that 

the standard default uncertainty factor of 10-fold should be used for this area of uncertainty. 

However, we consider that the LOAEL for ceric oxide (i.e., bronchial lymph node hyperplasia) is 

minimal and should be reduced to a 3-fold factor. 

For the chlorides of europium, lanthanum, and yttrium and the oxides of europium, 

lanthanum and scandium, an UF of 1-fold would be applied to the respective identified NOAELs 

for the RfD derivation.

Insufficient Database (UFD) 

Do existing data allow for a reasoned judgment of likely critical effect, given that any one 

toxicity study is unable to adequately address all possible outcomes? 

If data exist from at least five studies (two chronic standard toxicity bioassays in different 

species, one two-generation reproductive bioassay and two developmental toxicity studies in 

different species), an uncertainty factor of 1 is applied. U.S. EPA has occasionally used values 

less than 10 (nearly always 3-fold) when data were available on several, but not all 5 studies [for 

example, see the RfD for acetaldehyde on U.S. EPA’s IRIS (1999)], and factors of 10 (generally) 

when data were only available from a single study. Scientists familiar with this area also 

recognize that some overlap occurs with the subchronic to chronic uncertainty factor (discussed 

previously). The general solution to this problem when subchronic studies are available in two 

species, is to assign the uncertainty for lack of a chronic study to the subchronic to chronic 

factor, and not to the database factor.

The RfCs for ceric oxide and gadolinium chloride are based on the only studies 

identified that can be reasonably used to derive a risk assessment value. For ceric oxide, only 

one study is available in only one species. Thus, the standard default uncertainty factor of 10-
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Toxicology Excellence for Risk Assessment 21 November 11, 1999

fold is considered reasonable. For gadolinium chloride, however, two bioassays in two different 

species are available. Although both of these studies are weak (from the point of view of an RfC 

derivation), they nonetheless are mutually supportive. Thus, the database is more than bare 

minimum and an intermediate factor of 3-fold factor is considered appropriate. This latter 

judgment is borderline, however, and might change with additional data.

The chlorides of europium, lanthanum, and yttrium have somewhat better than 

minimal data sets as compared to the RfCs. Each has information from two species and each has 

been tested in a multigeneration reproductive study, although the latter study was conducted with 

oxides of lanthanides and the principal studies on which the RfDs are based on the chloride salts. 

The usual 10-fold uncertainty factor for this area of uncertainty can be reduced. We suggest the 

use of a 3-fold factor. 

Likewise, the uncertainty factor for the oxides of europium, lanthanum and scandium 

may be reduced from the default value of 10 to 3 if the data of the chloride salts are used to 

support the total data base. It has been previously argued that based on solubility, the chloride 

salts are likely to be more soluble and bioavailable than the oxide salts.

Modifying Factor (MF) 

A modifying factor is not considered necessary with these chemicals. This is because the 

outstanding uncertainties can be adequately addressed with the standard factors. U.S. EPA only 

occasionally uses a modifying factor; for example, see the RfD for methyl ethyl ketone on U.S. 

EPA’s IRIS (1999). The default value of 1 is appropriate for these lanthanides.

Composite Uncertainty and Modifying Factors 

The composite uncertainty factor to use with a given database for developing RfDs and 

RfCs is a case-by-case judgment by experts, and should be flexible enough to account for each of 

the applicable five areas of uncertainty and any nuances in the available data that might change 

the magnitude of any factor. U.S. EPA describes its choice of composite UF and subcomponents 

for individual assessments on its IRIS database (U.S. EPA, 1999). The Table 1 discusses the 

recommended uncertainty factors for the various lanthanides:
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Toxicology Excellence for Risk Assessment 22 November 11, 1999

Table 1. Various Lanthanides and Their Recommended Uncertainty Factors 

Lanthanide UFH UFA UFS UFL UFD MF Total Factor

Ceric oxide (RfC) 10 3 10 3 10 1 3000a

Gadolinium oxide 

(RfC)

10 3 10 10 3 1 3000a

Europium chloride 

(RfD)

10 10 10 1 3 1 3000b

Lanthanum chloride 

(RfD)

10 10 10 1 3 1 3000b

Yttrium chloride 

(RfD)

10 10 10 1 3 1 3000b

Lanthanum oxide 

(preliminary RfD)

10 10 10 1 3 1 3000b

Europium oxide 

(preliminary RfD)

10 10 10 1 3 1 3000b

Scandium oxide 

(preliminary RfD)

10 10 10 1 3 1 3000b

a

 As a general default procedure, EPA combines four 10-fold factors to 3000. This includes 

consideration of several partial areas of uncertainty as well. Thus, three 10-fold factors and two 

3-fold factors would also warrant a 3000-fold composite factor.

b

 As a general procedure in EPA, the data base uncertainty factor could be lower to 1-fold, if a 

credible argument is made that developmental toxicity, or other issues associated with the 

toxicity in younger animals, is not likely to be found based on an overall understanding of the 

chemical under study. We do not make this argument here, but are open to input.
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Toxicology Excellence for Risk Assessment 23 November 11, 1999

3.4 Determination of RfD/RfCs

RfDs and RfCs are determined based on the choice of the most appropriate or most 

sensitive species, the choice of NOAEL, LOAEL or benchmark dose/concentration for the 

critical effect, and the judgment of the appropriate composite uncertainty factor. Usually, 

chemicals are looked at individually on the merits of their underlying toxicity data; occasionally, 

the toxicity of several chemicals are studied together, and data base gaps can be filled or 

enhanced by information from related chemicals. 

Confidence in the estimated RfCs is considered low. For ceric oxide, only 1 adequate 

toxicity study exists from which to determine an RfC. Gadolinium oxide only has two available 

inhalation studies. Although toxicity was monitored over several exposure times for gadolinium 

oxide and a large number of animals was used, only one concentration was tested.

Confidence in the estimated RfDs for the lanthanide soluble salts is considered medium 

to low. This is because the oral data for subchronic or less-than-chronic exposure to lanthanides 

is somewhat less limited than that for the RfCs. For example, the data of Ogawa (1992, 1994 and 

1995) which form the basis of RfDs for the chlorides of lanthanum, yttrium and europium 

demonstrate dose-response effects. The authors measured a number of parameters and 

determined both NOAELs and LOAELs. The brief length of these studies was offset in part by 

other work. Hutcheson et al. (1975) provided multigenerational testing of reproductive 

endpoints and additional supporting data of Haley et al. (1961, 1965, and 1966) also show no 

toxicity at lower doses. However, the Hutcheson et al. (1975) study reported limited 

reproductive data for the doses and a minimum of toxicological endpoints for only a single dose 

(100X). Therefore the confidence in the estimated RfDs for the oxides of lanthanides based on 

this study is considered low.

The resulting RfDs shown above are not necessarily internally consistent. For example, the RfD 

for Europium oxide is 2E-3 mg/kg-day, whereas the RfD for Europium chloride is 3E-2 mg/kgday. This suggests that the oxide is more toxic than the chloride, whereas the toxicity of the 

soluble form of Europium would be expected to be greater than its oxide form. Unfortunately, 

the data supporting the development of these RfDs are not sufficiently strong to rule out such 

seeming inconsistencies. 

We encourage the development of additional toxicity data in order to more confidently 

estimate RfDs and RfCs for these compounds. New data would be expected to raise the levels of 

these risk values for various lanthanides as shown in Table 2.
Bureau of Land Management Amended Final

Toxicology Excellence for Risk Assessment 24 November 11, 1999

Table 2. Lanthanides and Their RfCs and RfDs

Lanthanide Choice of Effect Level UF RfD/RfC 

Ceric oxide as Ce/kgday (RfC) 0.83 mg/cu.m (Bio-Research Labs, 

1995)

3000 3E-4 mg/cu.m 

Gadolinium as Gd/kgday oxide (RfC)4.8 mg/cu.m (Ball and van Gelder, 

1966)

3000 2E-3 mg/cu.m

Europium oxide as 

Eu/kg-day 

(preliminary RfD)

5 mg/kg-day (Hutcheson et al., 1975) 3000 2E-3 mg/kg-day

Lanthanum oxide as 

La/kg-day 

(preliminary RfD)

52 mg/kg-day (Hutcheson et al., 1975) 3000 2E-2 mg/kg-day

Scandium oxide as 

Sc/kg-day 

(preliminary RfD)

16 mg/kg-day (Hutcheson et al., 1975) 3000 5E-3 mg/kg-day

Europium chloride as 

Eu/kg-day (RfD)

82.9 mg/kg-day (Ogawa et al., 1995) 3000 3E-2 mg/kg-day

Lanthanum chloride 

as La/kg-day (RfD)

15.0 mg/kg-day (Ogawa, 1992) 3000 5E-3 mg/kg-day

Yttrium chloride as 

Yt/kg-day (RfD)

11.7 mg/kg-day (Ogawa et al., 1994) 3000 4E-3 mg/kg-day
Bureau of Land Management Amended Final

Toxicology Excellence for Risk Assessment 25 November 11, 1999

4.0 References

Abel, M. and R.B. Talbot. 1967. Gadolinium oxide inhalation by guinea pigs: A correlative 

functional and histopathologic study. J. Pharmacol. Exper. Thera. 157: 207-213.

Arsenault T.M., B.F. King, J.W. Marsh Jr. 1996. Systemic gadolinium toxicity in patients with 

renal insufficiency and renal failure: retrospective analysis of an initial experience. Mayo Clin. 

Proc. 71(12):1150-4. 

Ball, R.A. and G. van Gelder. 1966. Chronic toxicity of gadolinium oxide for mice following 

exposure by inhalation. Arch. Environ. Health 13:601-608.

Barnes, D.G., and M.L. Dourson. 1988. Reference Dose (RfD): Description and Use in Health 

Risk Assessments. Reg Toxicol Pharmacol 8: 471-486.

Bio-Research Labs. 1995. Final report for a 90-day inhalation neurotoxicity and toxicity study 

by exposure to a dry powder aerosol of ceric oxide in the albino rat with cover letter dated 

013095. Document ID 89-950000107. Prepared for Rhone-Poulenc Inc.

D’Agostino, R.B., B.A. Lown, J.B. Morganti, et al. 1982. Effects of in utero or suckling 

exposure to cerium (citrate) on the postnatal development of the mouse. J. Toxicol. Environ. 

Health. 10: 449-458.

Dourson, M.L. 1994. Methodology for establishing oral reference doses (RfDs). In: Risk 

Assessment of Essential Elements. W. Mertz, C.O. Abernathy, and S.S. Olin Eds. ILSI Press 

Washington, D.C., pages 51-61.

Dourson, M.L., S.P. Felter, and D. Robinson. 1996. Evolution of science-based uncertainty 

factors in noncancer risk assessment. Reg Toxicol Pharmacol 24: 108-120.

Eisele, G.R., F.R. Mraz, and M.C. Woody. 1980. Gastrointestinal uptake of 441Ce in the 

neonatal mouse, rat and pig. Health Physics. 39: 185-192.

Haley, T.J., K. Raymond, N. Komesu and H.C. Upham. 1961. Toxicological and 

pharmacological effects of gadolinium and samarium chlorides. Brit. J. Pharmacol. 17:526-532.

Haley, T.J. 1963. Pharmacology and toxicology of the rare earth elements. Jour. of Pharma. 

Sci. 54: 663-670.

Haley, T.J., N. Komesu, M. Efros, et al. 1964(a). Pharmacology and toxicology of lutetium 

chloride. J. Pharmaceut. Sci. 53(10): 1186-1188.

Haley, T.J., N. Komesu, M. Efros, et al. 1964(b). Pharmacology and toxicology of 

praseodymium and neodymium chlorides. Toxicol. Appl. Pharmacol. 6: 614-620.
Bureau of Land Management Amended Final

Toxicology Excellence for Risk Assessment 26 November 11, 1999

Haley, T.J. 1965. Pharmacology and toxicology of the rare earth elements. J. Pharmaceut. Sci. 

54(5): 663-670.

Haley, T.J., L. Koste, N. Komesu, M. Efros and H.C. Upham. 1966. Pharmacology and 

toxicology of dysprosium, holmium, and erbium chlorides. Toxicol. Appl. Pharm. 8:37-43.

Hirano, S. and K.T. Suzuki. 1996. Exposure, metabolism, and toxicity of rare earths and related 

compounds. Environ. Health Perspec. 104:85-95.

Hutcheson, D.P., D.H. Gray, B. Venugopal and T.D. Luckey. 1975. Studies of nutritional safety 

of some heavy metals in mice. J. Nutr. 105: 670-675.

Jarabek, A.M. 1994. Inhalation RfC methodology: dosimetric adjustments and dose-response 

estimation of noncancer toxicity in the upper respiratory tract. Inhal Toxicol 6(suppl): 301-325.

Kostial, K., B. Kargacin, and M. Landeka. 1987. Reduction of 141Ce absorption in suckling rats. 

Int. J. Radiat. Biol. 51(1): 139-145.

Kostial, K., B. Kargacin and M. Landeka. 1989. Gut retention of metals in rats. Biol. Trace 

Elem. Res. 21:213-218.

Longerich, H.P., J.K. Friel, C. Fraser. 1990. Analysis of the drinking water of mothers of 

Neural Tube Defect infants and of normal infants for 14 selected trace elements by inductively 

coupled plasma-mass spectrometry (ICP-MS). Canadian Journal of Applied Spectroscopy. 35: 

15-21.

McClellan, R.O., L.K. Bustad, and R.F. Keough. 1965. Metabolism of some SNAP 

radionuclides in miniature swine. Aerospace Med. 36: 16-20.

NRC (National Research Council). 1983. Risk assessment in the federal government: managing 

the process. Washington, DC: National Academy Press.

Ogawa, Y. 1992. Studies on the biological effects of lanthanum: effects of repeated oral 

administration tests in rats. Jpn. J. Toxicol. Environ. Health. 38(6): 545-553.

Ogawa, Y., S. Suzuki, K. Naito, et al. 1994. Studies on the biological effects of yttrium: effects 

of repeated oral administration tests in rats. Jpn. J. Toxicol. Environ. Health. 40(4): 374-382.

Ogawa Y., S. Suzuki, K. Naito, et al. 1995. Toxicity study of europium chloride in rats. J 

Environ Pathol Toxicol Oncol. 14(1): 1-9.

Renwick, A.G. 1993. Data derived safety factors for the evaluation of food additives and 

environmental contaminants. Food Add Contam 10(3): 275-305.
Bureau of Land Management Amended Final

Toxicology Excellence for Risk Assessment 27 November 11, 1999

Rhoads, K. and C.L. Sanders. 1985. Lung clearance, translocation, and acute toxicity of arsenic, 

beryllium, cadmium, cobalt, lead, selenium, vanadium, and ytterbium oxides following 

deposition in rat lung. Environ. Res. 36: 359-378.

Sagan, C.E. and F.W. Lengemann. 1973. The retention and movement of cerium-141 in the 

gastrointestinal tract of adult rats irradiated with 800 R and fed grain-based or milk diets. Radiat. 

Res. 53: 480-487.

Sturbaum, B., A.L. Brooks, and R.O. McClellan. 1970. Tissue distribution and dosimetry of 

144Ce in Chinese hamsters. Radiat. Res. 44: 359-367.

Schroeder, H.A. and M. Mitchener. 1971. Scandium, chromium (VI), gallium, yttrium, 

rhodium, palladium, indium in mice: Effects on growth and life span. J. Nutr. 101:1431-1438. 

Sullivan, M.F., B.M. Miller, and J.C. Goebel. 1984. Gastrointestinal absorption of metals (51Cr, 

65Zn, 95mTc, 109Cd, 113Sn, 147Pm, and 238Pu. Environ. Res. 35: 439-453.

Sullivan, M.F., P.S. Ruemmler, J.L. Ryan, et al. 1986. Influence of oxidizing or reducing agents 

on gastrointestinal absorption of U, Pu, Am, Cm and Pm by rats. Health Physics. 50(2): 223-

232.

TERA (Toxicology Excellence for Risk Assessment). April 1999. Development of Reference 

Doses and Reference Concentrations for Lanthanides. Stage 1.

Thomas, R.L., J.K. Scott, and T.L. Chiffelle. 1972. Metabolism and toxicity of inhaled 144Ce in 

rats. Radiat. Res. 49:580-610.

U.S. EPA. 1987. Recommendation for and documentation of biological values for use in risk 

assessment. ECAO-CIN-554, Cincinnati, Ohio. 

U.S. EPA. 1994. Methods for derivation of inhalation reference concentrations and application 

of inhalation dosimetry. Office of Research and Development, Washington, DC. EPA/600/8-

90/066F. 

U.S. EPA. 1995. The use of the benchmark dose approach in health risk assessment. 

EPA/630/R-94/007. Risk Assessment Forum. Office of Research and Development. 

Washington, D.C.

U.S. EPA. 1999. Integrated Risk Information System (IRIS). National Center for 

Environmental Assessment. Online: http://www.epa.gov/iris. Washington, DC. 
Bureau of Land Management Final

Toxicology Excellence for Risk Assessment A-1 July 30, 1999

Appendix A

Summary of Data

Appendix Table 1: Table of Toxicity Data for Rare Earth Elements

Appendix Table 2: Table of Pharmacokinetics Data for Rare Earth Elements
Appendix Table 1. Table of Toxicity Data for Rare Earth Elements

Acute toxicity - Summary

Chemical Name Study Type Route Species Duration Exposure levels Number Response Comments Reference

Trace elements Case-control 

study

Oral by 

drinking 

water

Human Continuous 

with drinking 

water

28 /group High levels of Y 

and Ce in the 

drinking water of 

neural tube defect 

(NTD) infants' 

mothers than that in 

control, but the 

difference is not 

statistically 

significant. 

Twelve other trace 

elements were 

measured in

addition to the 

lanthanide, and 

13/14 tested 

elements were 

higher in case 

group. None of 

the differences 

were significant.

Longerich et 

al. 1990 

(Canadian J. 

Appl Spectroscopy )

Gadolinium Retrospective 

analysis

Intravenous

(i.v.)

Patients 

with 

renal 

insufficiency 

(serum 

creatinine >2.0 

mg/dL

Once 0.1 mmol/kg 151 patients No significant 

changes in adverse 

effects, 

hematological 

values, and 90-day 

mortality. 

Hematological 

values include: 

hemoglobin, 

hematocrit, platelet 

count, aspartate 

transaminase, 

bilirubin, alkaline 

phosphatase, 

calcium and 

phosphorus. 

Adverse effects 

include: nausea, 

rash, seizure and 

headache.

Arsenault et 

al. 1996 

(Mayo Clin. 

Proc. 71: 

1150-1154)
Appendix Table 1 (continued)

Page 2 of 16

Acute toxicity – Summary Continued

Chemical Name Study Type Route Species Duration Exposure levels Number Response Comments Reference

Yttrium chloride Acute 

toxicity

Intratracheal 

instillation 

in 0.4 ml

Male 

rats

One dose 0, 10, 20, 50, 

100, or 200 μg 

Y/rat

3 rats/group ≥10 μg/rat:

increased bglucuronidase,

≥20 μg/rat:

increased LDH in 

BALF,

≥50 μg/rat:

increased BAL 

protein,

≥100 μg/rat:

increased AM and 

PMN in BALF.

Maximal increases 

in PMN, LDH, βglucuronidase, and 

BAL protein was 

observed on day 1-

2. Maximal 

increase of AM 

occurred on day 3. 

t1/2 of Y in the 

lungs was 168 

days. 40% of the 

initial dose still 

remained in the 

lungs after 162 

days.

Hirano et al. 

1990 

(Toxicol. 

Appl. 

Pharmacol. 

104:301-311)

Lanthanum 

chloride

Acute 

toxicity

Intratracheal 

instillation 

in 0.4 ml

Male 

rats

One dose 0, 0.5, 1, 10, 20, 

50, 100 or 200 

μg La/rat. 

4 rats/group ≥1.0 μg/rat: 

increased LDH, βglucuronidase, Ca, 

P in BALF,

≥50 μg/rat:

increased protein, S 

and PMN in BALF,

≥100 μg/rat:

increased AM in 

BALF, 

200 μg/rat:

increased BAL 

eosinophils.

The study also 

examined time 

course of the 

cellular and 

biochemical 

changes and La 

distribution in the 

lung and other 

organs. 

La half-life in the 

lung was 244 days.

Suzuki et al. 

1992 

(Toxicol. 

76:141-152)
Appendix Table 1 (continued)

Page 3 of 16

Acute toxicity – Summary Continued

Chemical Name Study Type Route Species Duration Exposure levels Number Response Comments Reference

Gadolinium 

chloride

Acute 

toxicity 

Intratracheal 

instillation 

in 0.4 ml 

saline

Male 

rats

One dose 0, 10, 20, 50 

and 100 μg 

Gd/rat

4 rats/group >= 10 μg/rat:

increase LDH, and 

protein in BALF;

>= 20 μg/rat:

increase in 

epithelial lining 

fluid volume;

>=50 μg/rat:

increased PMN in 

BALF;

100 μg/rat:

increased 

eosinophil in 

BALF.

The study also 

examined time 

course of the 

cellular and 

biochemical 

changes and Gd 

distribution in the 

lung.

Gd half-life in the

lung was 136 days.

Yoneda et al. 

1995 (Fund. 

Appl. Toxicol. 

28:65-70)

Rare earth nitrate Acute 

toxicity

Oral by 

stomach 

tube in 50% 

water

Female 

rats

One dose Not reported 30-35 LD50 mice 

(mg/kg):

Didymium: 4100,

Cerium: 4200,

Praseodymium: 

3500,

Neodymium: 2750,

Samarium: 2900,

Europium: >5000,

Gadolinium: 

>5000,

Terbium: >5000,

Dysprosium: 3100,

Holmium: 3000,

Ytterbium: 3100.

All chemicals 

tested are nitrates. 

Didymium nitrate 

contains 45-46% 

lanthanum, 32-

33% neodymium, 

9-10% 

praesodymium, 5-

6% samarium, 3-

4% gadolinium, 

etc.

Bruce et al. 

1963 

(Toxicol. 

Appl. 

Pharmacol. 

5:750-759) 

Cerium chloride Acute 

toxicity

Intragastric 

gavage 

(i.g.) and 

subcutaneous (s.c.) 

administration.

Male 

mice

One dose 10/group LD50 (i.g.)=1291 

Ce/kg;

LD50 (s.c.)=205 

mg Ce/kg.

Stineman et 

al. 1978 (J. 

Environ. 

Pathol. 

Toxicol. 

2:553-570)
Appendix Table 1 (continued)

Page 4 of 16

Acute toxicity – Summary Continued

Chemical Name Study Type Route Species Duration Exposure levels Number Response Comments Reference

Cerium chloride Acute 

toxicity

Oral 

Intragastric 

gavage 

(i.g.) and 

subcutaneous (s.c.) 

administration.

Male 

mice

One dose i.g. 1000 or 

1163 mg Ce/kg;

s.c. 136 or 173 

mg Ce/kg.

10/group i.g. and s.c.: 

hypertrophy, 

reticuloendothelial 

hyperplasia and 

hyperactive 

ymphoid follicles in 

the spleens after 

i.g. ≥1000 mg/kg 

caused gastritis and 

enteritis;

s.c. ≥136 mg/kg 

caused focal 

midzonal necrosis 

in the livers. 

The effect in 

spleen after i.g. 

and s.c. exposure 

was not explained 

clearly in the 

paper.

Stineman et 

al. 1978 (J. 

Environ. 

Pathol. 

Toxicol. 

2:553-570)

Gadolinium and 

samarium 

chloride

Acute 

toxicity

Oral Mice Up to 2 g/kg No lethality up to 

oral 2 g/kg. 

i.p. LD50 (mg/kg)

gadolinium: 550,

samarium: 585.

i.p. symptoms 

include decreased 

respiration, 

lethargy, 

abdominal cramps 

and diarrhea.

Haley et al. 

1961 (Brit. J. 

Pharmacol. 

17:526-532)

Dysprosium, 

holmium and 

erbium chlorides

Acute 

toxicity

Oral gavage 

or 

intraperiton

-eal (i.p.) 

administration

Mice 50-90 

mice/study

LD50 (mg/kg)

Dysprosium: 585 

(i.p.) and 7650 

(oral),

Holmium: 560 (i.p.) 

and 7200 (oral),

Erbium: 535 (i.p.) 

and 6200 (oral). 

Symptoms: 

writhing, ataxia, 

slightly labored 

and depressed 

respiration, arched 

back, stretching of 

limbs on walking 

and lacrimation. 

Haley et al. 

1966 

(Toxicol. 

Appl. 

Pharmacol. 

8:37-43)
Appendix Table 1 (continued)

Page 5 of 16

Acute toxicity – Summary Continued

Chemical Name Study Type Route Species Duration Exposure levels Number Response Comments Reference

Rare earth nitrate Acute 

toxicity

Intraperiton

-eal 

administration in 

water

Female 

rats

One dose Not reported 30-40 LD50 mice 

(mg/kg):

Didymium: 270,

Cerium: 190,

Praseodymium: 

245,

Neodymium: 270,

Samarium: 285,

Europium: 210,

Gadolinium: 230,

Terbium: 260,

Dysprosium: 295,

Holmium: 270,

Erbium: 230,

Thulium: 285,

Ytterbium: 255,

Lutetium: 335.

All chemicals 

tested are nitrates. 

Didymium nitrate 

contains 45-46% 

lanthanum, 32-

33% neodymium, 

9-10% 

praesodymium, 5-

6% samarium, 3-

4% gadolinium, 

etc. 

Bruce et al. 

1963 

(Toxicol. 

Appl. 

Pharmacol. 

5:750-759) 

Rare earth nitrate Acute 

toxicity

Intraperiton

-eal 

administration in 

water

Female 

mice

one dose Not reported 35-55 LD50 mice 

(mg/kg):

Didymium: 330,

Lanthanum: 410,

Cerium: 470,

Praseodymium: 

290,

Neodymium: 270,

Samarium: 315,

Europium: 320,

Gadolinium: 300,

Terbium: 480,

Dysprosium: 310,

Holmium: 320,

Erbium: 225,

Thulium: 255,

Ytterbium: 250,

Lutetium: 290.

All chemicals 

tested are nitrates. 

Didymium nitrate 

contains 45-46% 

lanthanum, 32-

33% neodymium, 

9-10% 

praesodymium, 5-

6% samarium, 3-

4% gadolinium, 

etc.

Bruce et al. 

1963 

(Toxicol. 

Appl. 

Pharmacol. 

5:750-759) 
Appendix Table 1 (continued)

Page 6 of 16

Acute toxicity – Summary Continued

Chemical Name Study Type Route Species Duration Exposure levels Number Response Comments Reference

Rare earth nitrate Acute

toxicity

i.v. Female 

rats

Single dose Not reported 25-40 LD50 mice 

(mg/kg):

Cerium: 1.3 (F) and 

49.6 (M),

Praseodymium: 7.4 

((F) and 77.2 (M),

Neodymium: 6.4 

(F) and 66.8 (M),

Samarium: 8.9 (F) 

and 59.1 (M),

Erbium: 35.8 (F) 

and 52.4 (M).

All chemicals 

tested are nitrates. 

Didymium nitrate 

contains 45-46% 

lanthanum, 32-

33% neodymium, 

9-10% 

praesodymium, 5-

6% samarium, 3-

4% gadolinium, 

etc.

Bruce et al. 

1963 

(Toxicol. 

Appl. 

Pharmacol. 

5:750-759) 

Cerium fluoride Acute 

toxicity

Gavage Male 

and 

Female 

SD rats

Single Dose 5.0 g/kg (50% 

w/w in distilled 

water

5/sex LD50 > 5.0 g/kg

No signs of dermal 

irritation; 

Minimally irritating 

to eyes

Lambert et 

al., 1993 (J. 

Amer. Col. 

of Tox. 12: )

Cerium 

concentrate

Acute 

toxicity

Gavage Male 

and 

Female 

SD rats

Single Dose 5.0 g/kg (50% 

w/w in distilled 

water

5/sex LD50 > 5.0 g/kg

No signs of dermal 

irritation; 

Moderately 

irritating to eyes

Lambert et 

al., 1993 (J. 

Amer. Col. 

of Tox. 12: )

Cerium carbonate Acute 

toxicity

Gavage Male 

and 

Female 

SD rats

Single Dose 5.0 g/kg (50% 

w/w in distilled 

water

5/sex LD50 > 5.0 g/kg

No signs of dermal 

irritation; 

Minimally irritating 

to eyes

Lambert et 

al., 1993 (J. 

Amer. Col. 

of Tox. 12: )

Cerium oxide Acute 

toxicity

Gavage Male 

and 

Female 

SD rats

Single Dose 5.0 g/kg (50% 

w/w in distilled 

water

5/sex LD50 > 5.0 g/kg

No signs of dermal 

irritation; 

Minimally irritating 

to eyes

Lambert et 

al., 1993 (J. 

Amer. Col. 

of Tox. 12: )

Cerium chloride Acute 

toxicity

Gavage Male 

and 

Female 

SD rats

Single Dose 5.0 g/kg (50% 

w/w in distilled 

water

5/sex LD50 < 5.0 g/kg

Severe skin irritant; 

100% mortality by 

day one.

Lambert et 

al., 1993 (J. 

Amer. Col. 

of Tox. 12: )
Appendix Table 1 (continued)

Page 7 of 16

Acute toxicity – Summary Continued

Chemical Name Study Type Route Species Duration Exposure levels Number Response Comments Reference

Cerium nitrate Acute 

toxicity

Gavage Male 

and 

Female 

SD rats

Single Dose 5.0 g/kg (50% 

w/w in distilled 

water

5/sex LD50 , < 5.0 g/kg

Mild primary skin 

irritant; Severely to 

moderately 

irritating to eyes

100% mortality by 

day two.

Lambert et 

al., 1993 (J. 

Amer. Col. 

of Tox. 12: )

Cerium acetate Acute 

toxicity

Gavage Male 

and 

Female 

SD rats

Single Dose 5.0 g/kg (50% 

w/w in distilled 

water

5/sex LD50 > 5.0 g/kg

Non-primary skin 

irritant; Severely to 

moderately 

irritating to eyes

Lambert et 

al., 1993 (J. 

Amer. Col. 

of Tox. 12: )

Yttrium oxide Acute 

toxicity

Gavage Male 

and 

Female 

SD rats

Single Dose 5.0 g/kg (50% 

w/w in distilled 

water

5/sex LD50 > 5.0 g/kg

No signs of dermal 

irritation; Mildly 

and minimally 

irritating to eyes

Lambert et 

al., 1993 (J. 

Amer. Col. 

of Tox. 12: )

Yttrium nitrate Acute 

toxicity

Gavage Male 

and 

Female 

SD rats

Single Dose 5.0 g/kg (50% 

w/w in distilled 

water

5/sex LD50 < 5.0 g/kg

Moderate primary 

skin irritant; 

Severely irritating 

to eyes

100% mortality by 

day three

Lambert et 

al., 1993 (J. 

Amer. Col. 

of Tox. 12: )

Neodymium 

carbonate

Acute 

toxicity

Gavage Male 

and 

Female 

SD rats

Single Dose 5.0 g/kg (50% 

w/w in distilled 

water

5/sex LD50 > 5.0 g/kg

No signs of dermal 

irritation; Mildly 

irritating to eyes

Lambert et 

al., 1993 (J. 

Amer. Col. 

of Tox. 12: )

Neodymium 

fluoride

Acute 

toxicity

Gavage Male 

and 

Female 

SD rats

Single Dose 5.0 g/kg (50% 

w/w in distilled 

water

5/sex LD50 > 5.0 g/kg

No signs of dermal 

irritation; 

Minimally irritating 

to eyes

Lambert et 

al., 1993 (J. 

Amer. Col. 

of Tox. 12: )

Neodymium 

oxide

Acute 

toxicity

Gavage Male 

and 

Female 

SD rats

Single Dose 5.0 g/kg (50% 

w/w in distilled 

water

5/sex LD50 > 5.0 g/kg

No signs of dermal 

irritation; Mildly 

irritating to eyes

Lambert et 

al., 1993 (J. 

Amer. Col. 

of Tox. 12: )
Appendix Table 1 (continued)

Page 8 of 16

Acute toxicity – Summary Continued

Chemical Name Study Type Route Species Duration Exposure levels Number Response Comments Reference

Lanthanum 

concentrate

Acute 

toxicity

Gavage Male 

and 

Female 

SD rats

Single Dose 5.0 g/kg (50% 

w/w in distilled 

water

5/sex LD50 > 5.0 g/kg

No signs of dermal 

irritation; 

Minimally irritating 

to eyes

Lambert et 

al., 1993 (J. 

Amer. Col. 

of Tox. 12: )

Lanthanum oxide Acute 

toxicity

Gavage Male 

and 

Female 

SD rats

Single Dose 5.0 g/kg (50% 

w/w in distilled 

water

5/sex LD50 > 5.0 g/kg

No signs of dermal 

irritation; Mildly 

and minimally 

irritating to eyes

Lambert et 

al., 1993 (J. 

Amer. Col. 

of Tox. 12: )

Bastnasite 

concentrate

Acute 

toxicity

Gavage Male 

and 

Female 

SD rats

Single Dose 5.0 g/kg (50% 

w/w in distilled 

water

5/sex LD50 > 5.0 g/kg

No signs of dermal 

irritation; 

Minimally irritating 

to eyes

Lambert et 

al., 1993 (J. 

Amer. Col. 

of Tox. 12: )

Dysprosium 

oxide

Acute 

toxicity

Gavage Male 

and 

Female 

SD rats

Single Dose 5.0 g/kg (50% 

w/w in distilled 

water

5/sex LD50 > 5.0 g/kg

No signs of dermal 

irritation; 

Minimally irritating 

to eyes

Lambert et 

al., 1993 (J. 

Amer. Col. 

of Tox. 12: )

Erbium oxide Acute 

toxicity

Gavage Male 

and 

Female 

SD rats

Single Dose 5.0 g/kg (50% 

w/w in distilled 

water

5/sex LD50 > 5.0 g/kg

No signs of dermal 

irritation; Mildly 

and minimally 

irritating to eyes

Lambert et 

al., 1993 (J. 

Amer. Col. 

of Tox. 12: )

Europium oxide Acute 

toxicity

Gavage Male 

and 

Female 

SD rats

Single Dose 5.0 g/kg (50% 

w/w in distilled 

water

5/sex LD50 > 5.0 g/kg

No signs of dermal 

irritation; 

Minimally irritating 

to eyes

Lambert et 

al., 1993 (J. 

Amer. Col. 

of Tox. 12: )

Gadolinium 

oxide

Acute 

toxicity

Gavage Male 

and 

Female 

SD rats

Single Dose 5.0 g/kg (50% 

w/w in distilled 

water

5/sex LD50 > 5.0 g/kg

No signs of dermal 

irritation; Mildly 

and minimally 

irritating to eyes

Lambert et 

al., 1993 (J. 

Amer. Col. 

of Tox. 12: )
Appendix Table 1 (continued)

Page 9 of 16

Acute toxicity – Summary Continued

Chemical Name Study Type Route Species Duration Exposure levels Number Response Comments Reference

Praseodymium 

oxide

Acute 

toxicity

Gavage Male 

and 

Female 

SD rats

Single Dose 5.0 g/kg (50% 

w/w in distilled 

water

5/sex LD50 > 5.0 g/kg

No signs of dermal 

irritation; 

Minimally irritating 

to eyes

Lambert et 

al., 1993 (J.

Amer. Col. 

of Tox. 12: )

Samarium oxide Acute 

toxicity

Gavage Male 

and 

Female 

SD rats

Single Dose 5.0 g/kg (50% 

w/w in distilled 

water

5/sex LD50 > 5.0 g/kg

No signs of dermal 

irritation; 

Minimally irritating 

to eyes

Lambert et 

al., 1993 (J. 

Amer. Col.

of Tox. 12: )

Cerium chloride

Acute 

toxicity

Oral 

Intragastric 

(i.g.) and by 

subcutaneous (s.c.)

Male 

mice

One dose i.g. 1000 or 

1163 mg Ce/kg;

s.c. 136 or 173 

mg Ce/kg.

10/group No effect after i.g. 

exposure.

s.c. 173 mg Ce/kg 

caused significantly 

depressed behavior 

at 4 hours after 

exposure. 

Stineman et 

al. 1978 (J. 

Environ. 

Pathol. 

Toxicol. 

2:553-570)

Terbium oxide Acute 

toxicity

Gavage Male 

and 

Female 

SD rats

Single Dose 5.0 g/kg (50% 

w/w in distilled 

water

5/sex LD50 > 5.0 g/kg

No signs of dermal 

irritation; 

Minimally irritating 

to eyes

Lambert et 

al., 1993 (J. 

Amer. Col. 

of Tox. 12: )
Appendix Table 1 (continued)

Page 10 of 16

Subchronic toxicity – Summary

Gadolinium 

oxide

Subchronic 

toxicity 

Inhalation 

by aerosol

Mice 6 h/day, 5 

days/week 

for 20-120 

days

30 mg 

Gd2O3/cu.m.

20-30

mice/group/sex

≥1-2 week 

exposure increased 

mortality from 

pneumonia,

≥20-day exposure 

lead to a trend of 

decreased life span, 

There was only 

one exposure dose.

Ball et al. 

1966 (Arch 

Environ. 

Health 

13:601-608)

Gadolinium 

oxide

Subchronic 

toxicity 

Inhalation 

by aerosol, 

92% or the 

mass was 

smaller than 

0.563 ±

0.531 μm.

Whole body 

exposure.

Guinea 

pigs

6 h/day, 5 

days/week, 

for 40, 80, or 

120 days

20 mg 

Gd2O3/cu.m.

6 

animals/group/s

ex

Gd2O3 caused:

less elastance in the 

lungs;

alveolar cell 

hypertrophy, septal 

wall thickening, 

lymphoid 

hyperplasia and 

macrophage 

proliferation.

There was only 

one exposure dose.

Abel and 

Talbot 1967 

(J. 

Pharmacol. 

Exp. Therap. 

157:207-213)

Ceric oxide Subchronic 

toxicity

Inhalation 

aerosol 

MMAD=2.

0±1.9 μm,

Nose only 

exposure.

Rats 6 h/day, 5 

days/week 

for 13 weeks

0, 5, 50, or 500 

mg CeO2/cu-m.

15 

rats/group/sex

≥ 5 mg/cu-m:

pigment 

accumulation in 

nasal cavity, 

bronchi, trachea, 

and in the bronchial 

and other lymph 

nodes in both 

sexes;

≥ 50 mg/cu-m:

alveolar hyperplasia 

in both sexes.

Examined: body 

weight, food 

consumption, 

neurotoxic effects, 

hematology, 

clinical 

biochemistry, 

urinalysis, 

complete 

histopathology. 

Besides the 

pathological 

observations, no 

other adverse 

effect was noted. 

Authors concluded 

that NOAEL was 

not established in 

this study.

Bio-Research 

Labs, 1995 
Appendix Table 1 (continued)

Page 11 of 16

Subchronic toxicity – Summary Continued

Chemical Name Study Type Route Species Duration Exposure levels Number Response Comments Reference

Lanthanum 

Chloride

Subacute 

toxicity

Oral gavage Rats 

both 

sexes

Daily for 28 

days

0, 40, 200 or 

1000 mg LaCl3

7H2O/kg/day

(0, 15.0, 74.8, 

or 374.0 mg 

La/kg)

4-5/group Body weight:

≥200 mg/kg-day:

decreased body 

weight gain.

Blood:

Increased blood 

eosinocyte in male 

rats at 40 mg/kg, 

and in both sexes at 

200 mg/kg;

increased serum 

transaminase 

activity in both 

sexes at 1000 

mg/kg.

Lung: 

Granulation and 

giant cell at ≥200 

mg/kg in both 

sexes, 

Glandular 

stomach:

1000 mg/kg caused

eosinophil 

infiltration in the 

submucosa in both 

sexes, erosion and 

dilatation of acinus 

in males, and 

swelling epithelium 

in females, 

Small sample size

Monitored: body 

weight, food 

consumption, and 

examinations on 

hematology, 

serumbiochemistry and 

histopathological 

examinations. 

La was 

accumulated in the 

liver, kidneys, 

spleen and femur 

in a dosedependent manner 

with the highest 

accumulation in 

the liver.

Ogawa 1992 

(Jpn J. 

Toxicol. 

Environ. 

Health 

38:545-553)
Appendix Table 1 (continued)

Page 12 of 16

Subchronic toxicity – Summary Continued

Chemical Name Study Type Route Species Duration Exposure levels Number Response Comments Reference

Yttrium Chloride Subacute 

toxicity

Oral gavage Rats 

both 

sexes

Daily for 28 

days

0, 40, 200 or 

1000 mg YCl3

6H2O/kg/day

(0, 11.7, 58.6, 

or 293.1 mg 

Y/kg)

10 

rats/group/sex

Body weight:

decreased body 

weight gains in 

males at ≥200 

mg/kg -day, and in 

females at 1000 

mg/kg -day:

Blood:

Increased blood 

eosinocyte in both 

sexes at 40 mg/kg;

Lung: 

No significant 

change; 

Glandular 

stomach:

1000 mg/kg caused

hyperkeratosis in 

forestomach;

the same dose also 

caused eosinophile 

infiltration in the 

submucosa in both 

sexes. 

Small sample size.

Monitored: body 

weight, food 

consumption, and 

examinations on 

hematology, 

serumbiochemistry and 

complete 

histopathological 

examinations. 

Y was 

accumulated in the 

kidney, femur, 

liver and spleen in 

dose-dependent 

manner with the 

highest 

accumulation in 

the kidney.

Ogawa 1994 

(Jpn J. 

Toxicol. 

Environ. 

Health 

40:374-382)
Appendix Table 1 (continued)

Page 13 of 16

Subchronic toxicity – Summary Continued

Chemical Name Study Type Route Species Duration Exposure levels Number Response Comments Reference

Europium 

chloride

Subchronic 

toxicity

Oral gavage 

5 ml of 

EuCl3⋅6H2O 

in 5% 

glucose 

solution.

Rats 

both 

sexes

Daily for 28 

days

0, 40, 200 or 

1000 mg EuCl3

6H2O/kg/day

(0, 16.6, 82.9, 

or 414.7 mg 

Eu/kg/day)

10/group/sex Body weight:

≥200 mg/kg-day:

decreased body 

weight.

Blood:

At 1000 mg/kgday, decreased 

mean cell 

hemoglobin, cell 

volume in both 

sexes, and 

decreases in WBC 

in recovery males, 

and in activated 

thromboplastin 

time in recovery 

females. 

Lung: 

Granulomatous 

lesions in 100% 

and 40% male rats 

at 40 and 200 

mg/kg, and 60% 

females at 200 

mg/kg. 

Forestomach:

1000 mg/kg caused

basal cell 

hyperplasia and 

eosinophile 

infiltration in the 

submucosa in both 

sexes.

Authors concluded 

that the NOAEL is 

200 mg/kg-day.

Monitored: body

weight, food 

consumption, and 

examinations on 

hematology, 

serumbiochemistry and 

histopathological 

examinations. 

Eu was 

accumulated in the 

liver, kidneys, 

spleen and femurs. 

The accumulation 

of Eu in these 

organs account for 

1/100,000 of the 

total dose.

Ogawa et al. 

1995 (J. 

Environ. 

Pathol. 

Toxicol. 

Oncol. 14:

1-9)
Appendix Table 1 (continued)

Page 14 of 16

Subchronic toxicity – Summary Continued

Chemical Name Study Type Route Species Duration Exposure levels Number Response Comments Reference

Gadolinium and 

samarium 

chloride

Subchronic 

toxicity

Oral by diet Rats 12 weeks 0, 0.01, 0.1, or 

1% in diet

(5, 50 and 500 

mg/kg -day)

6 rats/group/sex 1% Gadolinium 

chloride resulted in 

perinuclear 

vacuolization of the 

parenchymal cells 

of the liver and a 

coarse granularity 

of their cytoplasm 

in male rats. 

No effect after 

exposure to 

samarium chloride.

Examined: 

hematology, 

growth rate, 

complete 

histopathology. 

Haley et al. 

1961 (Brit. J. 

Pharmacol. 

17:526-532)

Europium 

chloride

Subchronic 

toxicity

Oral by diet Rats 12 weeks 0, 0.01, 0.1, or 

1% in diet

(5, 50 and 500 

mg/kg -day)

6 rats/group/sex No effect in terms 

of growth, 

histopathology and 

hematology. 

Haley et al. 

1965 (J. 

Pharmaceut. 

Sci. 54:643-

645)

Dysprosium, 

holmium and 

erbium chlorides

Subchronic 

toxicity

Oral by diet Rats 12 weeks 0, 0.01, 0.1, or 

1% in diet

(5, 50 and 500 

mg/kg -day)

6 rats/group/sex No effect in terms 

of growth, 

histopathology and 

hematology. 

Examined: 

hematology, 

growth rate, and 

complete 

histopathology 

except the 

stomach. 

Haley et al. 

1966 

(Toxicol. 

Appl. 

Pharmacol. 

8:37-43)
Appendix Table 1 (continued)

Page 15 of 16

Subchronic toxicity – Summary Continued

Chemical Name Study Type Route Species Duration Exposure levels Number Response Comments Reference

Yttrium nitrate Chronic 

toxicity

Oral in 

drinking 

water

Mice From 

weaning until 

natural death

5 ppm Y (mg/L) 

in drinking 

water 

(1mg/kg-day, 

based on default 

mouse water 

intake 0.19 

L/kg-day)

54 mice/sex Decreased growth 

and body weights 

were observed in 

12 out of 16 time 

intervals. 

Survival curve of 

yttrium did not 

differ from those of 

the control group, 

however, males fed 

yttrium lived even 

longer than their 

controls. 

Yttrium is 

somewhat 

tumorigenic and 

carcinogenic, 

although the data 

were not 

statistically 

significant. 

Schroeder 

and 

Mitchener 

1971 (J. 

Nutr. 

101:1431-

1438)
Appendix Table 1 (continued)

Page 16 of 16

Reproductive and Developmental toxicity - Summary

Chemical Name Study Type Route Species Duration Exposure levels Number Response Comments Reference

Cerium chloride Developmental 

toxicity

Intrascapular subcutaneous. 

Dissolved 

in Na 

citrate 1:3

Female 

mice

On 7, or 12 

of gestation 

or on day 2 

after 

parturition

80 mg Ce/kg 10-22 

mice/group

1. in utero Ce 

exposure on day 12 

and mother Ce 

exposure on 

lactation day 2 

decrease offspring 

body weight;

2. in utero Ce 

exposure decreases 

pups retrieval time;

3. in utero Ce 

exposure increases 

frequency of 

rearings.

Body weight 

conclusion was 

not supported by 

provided data.

D'Agostino 

et al. 1982. 

(J. Toxicol. 

Environ. 

Health 

10:449-458)

Rare earth oxides Development

al toxocity

Oral by diet Female 

mice

3 generations Each dose 

contained 0, 1, 

10, 100, or 

1000x the 

amount of 

chemicals listed 

below:

 La 0.40 ppm 

(0.052 mg/kg-d)

Sm 0.80 ppm 

(0.104 mg/kg-d)

Eu 0.036 ppm 

(0.005 mg/kg-d)

Tb 1.20 ppm 

(0.156 mg/kg-d)

Dy 1.20 ppm 

(0.156 mg/kg-d)

Tm 0.08 ppm 

(0.010 mg/kg-d)

Yb 0.12 ppm 

(0.016 mg/kg-d) 

16 

females/group

Different groups 

showed different 

growth rats during 

different 

generations. 

No other significant 

changes were 

observed. 

The examinations 

included: 

mortality, 

morbidity, survival 

rate, growth rate, 

hematology, 

morphological 

development, 

maturation, 

reproduction, and 

lactational 

performance.

Hutcheson et 

al. 1975 (J. 

Nutr. 

105:670-675)
Appendix Table 2. Table of Pharmacokinetics Data for Rare Earth Elements

Pharmacokinetics - Summary

Chemical Name Study Type Route Species Duration Exposure levels Number Response Comments Reference

Cerium 

Hydroxide

Acute Inhalation, 

Aerosol 

(1.4 μm ±

2.0)

Rats Inhalation 10 

min.

3.0 or 170 

μCi/kg (0.45 or 

175 μCi/L)

34 rats either 

sexes

Skeleton T1/2=230 

days.

Lung T1/2=2

130 days. 

Skeletal accumula -

tion as high as 

66% of whole 

body burden.

Liver could be 

44%. Lung could 

be 30%. The 

maximal accumulation in these 

organs does not 

present at the same 

time 

Thomas et al. 

1972 (Radiat. 

Res. 49:580-

610)

Cerium chloride Acute Nose-only 

inhalation 

Aerosol 

(MMAD=

0.83 μm ±

1.7)

Hamste

rs

Once for 20 

min.

4.2 μCi/L 40 hamsters Day 2: 50% 144Ce 

was associated with 

the lung, 7% with 

the liver and 

skeleton. The rest 

with pelt and GI 

tract. 

Sturbaum et 

al. 1970 

(Radiat. Res. 

44:359-367)

Ytterbium Oxide Acute Intratracheal 

instillation

Female 

rats

One dose 0.026 μg YbO3 4-5 rats/group Lung clearance T1/2 

= 21 days.

Whole body 

clearance = 22 day.

The highest body 

burden is on day 

0.042 and has 11% 

dose. Chemical 

form in the body is 

unknown.

Rhoads and 

Sanders 1985 

(Environ. 

Res. 36:359-

378)

Cerium chloride Acute Oral gavage 0-6 or 

6-24 h 

old 

mice or 

rats, 6-

24 h old 

piglets

One dose 1 μCi (141Ce144Pr chloride or 

141Ce144Pr 

citrate) for mice 

or rats, 200 μCi 

141Ce144Pr 

chloride for 

piglets

20 mice/group,

7-12 rats/group,

1-4 pigs/group.

Absorption (0-21 

days):

31% in 0-6 h old 

mice,

24% in 6-24 h 

mice,

13% in 6-24 h rats,

10% in 6-24 h 

piglets,

Skeleton accumu -

lates the most 

followed by the 

liver.

Absorption =body 

retention – GI tract

Eisele et al. 

1980 (Health 

Physics 

39:185-192)
Appendix Table 2 (continued)

Page 2 of 3

Pharmacokinetics – Summary Continued

Chemical Name Study Type Route Species Duration Exposure levels Number Response Comments Reference

Cerium nitrate Acute Oral by 

gavage

Male 

rats

One dose 105 cpm/rat 5-7 rats/group 

fed or fasted.

Fasted rats have 

more whole body 

retention on day 6 

(0.15%) than fed 

rats (0.03%), but

not before day 3. 

Milk increased 

retention in day 1 

(53.9%) than grain 

(3.6%).

Sagan et al. 

1973 (Radiat. 

Res. 53:480-

487)

Cerium chloride Acute Oral as 

144CeCl3

with food

Miniatu

re 

swine

Once Not reported 4 animals In 10 days, 0.001% 

144Ce was excreted 

in urine, <0.01% 

present as body 

burden.

Authors concluded 

that absorption was 

<0.01%. 

McClellan et 

al. 1965 

(Aerosp. 

Med. 36:16-

20)

Cerium chloride Acute Oral in milk 6-day 

old rats

Take milk for 

8 h

6.7 MBq 

141Ce/kg bw,

Zn-DTPA is 

given on day 1-

2 or day 2-3.

10-12 

rats/group

Control whole body 

retention is 40.19%. 

DTPA on day 1-2 

results in retention 

of 2.03%. DTPA 

on day 2-3 results 

in retention of 

1.89%

Chelate decreases 

Ce retention, but 

the mechanism is 

unknown. It could 

be: decrease in 

absorption in GI 

tract, or increased 

absorption and 

excretion in urine. 

Kostial et al. 

1989 (Biol. 

Trace. Elem. 

Res. 21:213-

218)

Cerium chloride Acute Oral as 

141CeCl3

with milk, 

food or 

food 

ingredients

6-day 

old 

Rats

8 h in milk, 

food or food 

ingredients

0.026 mg Ce 

with 4 uCi 141Ce 

(specific 

activity = 0.15 

mCi/mg Ce)

6 rats/group Whole body 

retention in rats fed 

with milk is 3x 

activity in rats fed 

with food, and 7.5x 

activity in rats fed 

with ingredients. 

92%-98% activity 

is in gut. Main 

difference comes 

from gut activity. 

Internal organs 

have 2-2.8 fold 

difference.

Kostial et al. 

1987 (Int. J. 

Radiat. Biol. 

51:139-145)
Appendix Table 2 (continued)

Page 3 of 3

Pharmacokinetics – Summary Continued

Chemical Name Study Type Route Species Duration Exposure levels Number Response Comments Reference

Promethium Acute Oral. 147Pm, 

chemical 

form not 

reported

Rats One gavage 3.5 

μCi/neonatal,

10.7 μ/Ci /adult

8-9 rats/group Day 7-9 after 

gavage: total 

absorption rate is 

5.4% in neonatal 

and 0.007% in 

adult.

Sullivan et 

al. 1984 

(Environ. 

Res. 35:439-

453)

Promethium Acute Oral 147Pm, 

chemical 

form not 

reported

Swine One gavage 6.5 μCi/animal 5-9 

swine/group

Day 5-9 after 

gavage: total 

retention is 1.77% 

in neonatal and 

3.4% in adult. 

Sullivan et 

al. 1984 

(Environ. 

Res. 35:439-

453)

Promethium 

chloride

Acute Oral by 

gavage

Rats One dose 10 μCi/rat 8 fed rats and 6 

fasted rats

Over 7 days, total 

absorption is 

0.013% in fed rats 

(most in the 

carcass) and 

0.072% in fasted 

rats (most in the 

liver).

Sullivan et 

al. 1986 

(Health 

Physics 

50:223-232)

Yttrium Chloride Subacute 

toxicity

Oral by 

gavage

Rats 

both 

sexes

Daily for 28 

days

0, 40, 200 or 

1000 mg YCl3

6H2O/kg/day

10 

rats/group/sex

Total accumulation 

of Y in rats was 

about 50 times as 

much as that of La. 

The highest 

accumulation of Y 

was found in the 

kidney.

Monitored: body 

weight, food 

consumption, and 

examinations on 

hematology, 

serumbiochemistry and 

complete 

histopathological 

examinations. 

Ogawa 1994 

(Jpn J. 

Toxicol. 

Environ. 

Health 

40:374-382)
Bureau of Land Management Final

Toxicology Excellence for Risk Assessment B-1 July 30, 1999

Appendix B 

Calculations for Various Human Equivalent Concentrations

BioResearch Labs Ltd. (1995):

The exposure concentrations were 5, 50, or 500 mg CeO2/cu.m (0, 4.1, 41, or 407 Ce/cu.m) for 6 h/day, 5 

days/week. Particle size, MMAD, was reported to be 2.00 microns, and the sigma g was 1.90 microns. Based on 

EPA’s default Sprague Dawley rat body weight for subchronic assay, 0.267 kg for male and 0.204 kg for female, 

RDDRs were calculated and listed in the following table. In addition, the table also includes all the calculation 

results for HECs. The concentration unit listed is mg Ce/cu.m.

Effect NOAEL NOAEL(adj) LOAEL LOAEL (adj) RDDR NOAEL(HEC)

PU-M 4.1 0.73 41 7.3 0.564 0.41

PU-F 4.1 0.73 41 7.3 0.588 0.43

TH-M 4.1 0.73 41 7.3 0.755 0.55

TH-F 4.1 0.73 41 7.3 0.76 0.55

TB-M 4.1 0.73 1.167 0.85 

(LOAEL)

TB-F 4.1 0.73 1.122 0.82

(LOAEL)

NOAEL (adj) = NOAEL x 6/24 x 5/7

LOAEL (adj) = LOAEL x 6/24 x 5/7

NOAEL (HEC) = NOAEL (adj) x RDDR

LOAEL (adj) = LOAEL (adj) x RDDR

Abel and Talbot (1967):

The exposure concentration was 20 mg Gd 2O3/cu.m for 6 h/day, 5 days/week. Particle size ranged from 0.1 to 1.0 

micron with 92% of the mass smaller than 0.563 ± 0.531 micron. Based on particle size information, it is assumed 

that 0% mass is at size ≤ 0.1 micron and 92% mass is ≤ 0.563 micron. By using two points, (0.1, 0%) and (0.563, 

92%) to make a log-probability line, the expected 50% mass was calculated at 0.2558 micron; 84.1% of the mass 

was at 0.4853 micron, and 15.9% at 0.1348 micron. Thus, the MMAD was 0.2558 micron. The log concentration 

difference between either 84.1% and 50% mass or 50% and 15.9% mass is 0.2781. Thus sigma g is 10x(0.2781), or 

1.8971. Since the MMAD < 0.5 micron and guinea pig data were used, the RDDR could not be determined based 

on the RDDR software (EPA RfC guideline 1994) or the rat RDDR table (EPA RfC guideline 1990). Because the 

RDDR could not be determined, HECs could not be calculated.

Ball and van Gelder (1966):

The exposure concentration was 30 mg Gd 2O3/cu.m for 6 h/day, 5 days/week. Particle size was ≥ 0.1 micron with 

70% of the mass smaller than 1.0 micron. By using two points, (0.1, 0%) and (1.0, 70%), to make a log-probability

line, the expected 50% mass was calculated at 0.5179 micron and 15.9% at 0.1687 micron. Thus the MMAD was 

0.5179 micron. The log difference between 15.9% and 50% is 0.4872. Thus, the sigma g is 10x(0.4872) or 3.07.

Mouse body weights were calculated based on EPA default values for subchronic assay in BAF1 and B6C3F1 mice, 

which resulted in 0.0269 kg for male mice and 0.0225 kg for female mice. By using the RDDR software (EPA RfC 

guideline 1994), the RDDR for the thoracic region was calculated:

RDDR (TH) = 1.191 for male and 1.041 for female. The following HEC was then derived.
Bureau of Land Management Final

Toxicology Excellence for Risk Assessment B-2 July 30, 1999

LOAEL = 30 mg Gd 2O3/cu.m

LOAEL (adj) = 30 x 6/24 x 5/7 = 5.36 mg Gd2O3/cu.m

LOAEL (HEC) = 5.36 x 1.191 = 6.38 mg Gd 2O3/cu.m (males) or 5.36 x 1.041 = 5.58 mg Gd2O3/cu.m 

(females).

The corresponding LOAEL (HEC) in mg Gd/cu.m = 5.53 for males or 4.84 for females.
Bureau of Land Management Amended Final

Toxicology Excellence for Risk Assessment C-1 July 30, 1999

Appendix C

Mixtures Risk Assessment for the Lanthanides

Introduction:

Conducting environmental risk assessments very often requires evaluating the significance of 

exposures to chemical mixtures. In 1986, the U.S. Environmental Protection Agency’s Risk 

Assessment Forum (RAF) published Guidelines for the Health Risk Assessment of Chemical 

Mixtures (U.S. EPA, 1986). This was followed by a Technical Support Document on Health 

Risk Assessment of Chemical Mixtures (U.S. EPA, 1990). These guidelines represent the 

current Agency’s science policy on chemical mixtures and serve as procedural guides. 

However, because the science in the area of mixtures risk assessment continues to evolve, EPA 

has continued to evolve its guidelines. Recently, a document developed by EPA entitled 

“Guidance for Conducting Health Risk Assessment of Chemical Mixtures” was reviewed by 

experts in toxicology, mechanistic and pharmacokinetic modeling, statistics, and risk assessment 

(EPA, 1999). 

The experts agreed that a tiered approach to risk assessment is a good idea, similar to what EPA 

uses in its current guidelines. This approach should be supported by a tiered approach to mixture 

toxicity testing, noting a need to look at multiple endpoints and screening assays. 

For noncancer toxicity, the reviewers agreed that the hazard index (HI) is an acceptable default 

method to handle risk characterization of mixtures of chemicals for which dose additivity of 

components is considered appropriate. Here, “appropriate” requires that the components act by 

the same mechanism and do not interact with each other. If enough data are not available to 

know for sure whether the components act by the same mechanism, acting on the same target 

organ will suffice. Several other approaches, such as a Weight-of-Evidence (WOE) interactions 

index, were discussed and were considered as useful as the HI.

Any risk assessment should outline the assumptions and criteria associated with the model 

choice and then describe how well the particular mixture or situation being assessed agrees with 

that choice. The extent to which the model is not a perfect match should also be described at 

least qualitatively, if not quantitatively.

Toxicity of Lanthanides:

As discussed above for the lanthanides, the available human data are not sufficient as a basis for 

the development of either an RfC or an RfD. Moreover, the available animal toxicity data are 

limited to only a few studies for each of the several lanthanides, and even fewer studies from 

which to estimate various risk values (see section 3.2, Choice of Critical Studies). 

For example, ceric oxide has only one adequate toxicity study from which to determine an RfC. 

The critical effect is limited to the respiratory system. For gadolinium oxide, Ball and van 
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Toxicology Excellence for Risk Assessment C-2 July 30, 1999

Gelder (1966) also show toxicity in the lung as the critical effect. The resulting RfCs for these 

two chemicals are 3-fold apart.

The oral toxicity data used to determine the RfDs for the lanthanides are likewise sparse and 

difficult to interpret. For example, the data of Ogawa (1992, 1994 and 1995) demonstrate doseresponse effects for chlorides of lanthanum, yttrium and europium. The authors measured a 

number of parameters in pair-fed animals and determined both NOAELs and LOAELs. 

Decreases in body weight and stomach lesions appeared to be the critical effect for each of these 

lanthanides. Although, these studies were only for 28 days of exposure, which is shorter than the 

usually required length of study for development of an RfD, they measured portal of entry effects 

and established a dose-response. The other available subchronic data of Haley et al. (1961, 

1965, and 1966) along with the multigeneration study of Hutcheson et al. (1975) supports the 

critical effects found and the derivation of these oral RfDs. The resulting RfDs for these 3 

lanthanides lie within a range of 7-fold of each other.

Preliminary RfDs were also developed for oxides of europium, lanthanum and scandium based 

on the study of Hutcheson et al. (1975). Numerous difficulties exist with the interpretation of 

this study making the resulting RfDs only preliminary in nature. Values for these RfDs lie 

within 10-fold of each other. 

Mixtures Risk Assessment:

Several options exist to conduct risk assessments for the mixture of lanthanides found at the 

Mountain Pass mine site. First, mixtures of specific lanthanides could be tested for toxicity. 

Studies of 90 days duration would be ideal, but studies of shorter duration would still be helpful. 

The RfDs for chorides of lanthanum, yttrium, and europium, for example, are based on 28-day 

studies (as above). Such testing is essentially Tier 1 of EPA’s (1986) chemical mixtures 

guidelines and draft update (U.S. EPA, 1999).

A second option would be to base a risk assessment for any particular mixture of lanthanides on 

a sufficiently similar mixture. This approach is basically Tier 2 of EPA’s (1986) guidelines and 

draft update (U.S. EPA, 1999). Unfortunately, no mixture of lanthanides has been tested as 

evidenced in the appendix tables to this document.

A third option would be to base a risk assessment for any particular mixture of lanthanides on the 

toxicity of individual lanthanides. This approach is basically Tier 3 of EPA’s (1986) guidelines 

and draft update (U.S. EPA, 1999). RfCs (for cerium and gadolinium) and RfDs (for chlorides 

of lanthanum, yttrium and europium and oxides of europium, lanthanum and scandium) exist for 

the lanthanides as developed in this document. The use of these values to determine the likely 

Hazard Index for mixtures of these specific lanthanides is supported and recommended by EPA 

(1986) guidelines.

However, it may be that several lanthanides exist in the mixture that do not have an RfD or RfC 

value. In such cases, the risk assessment scientist must make a judgment regarding whether the 

existing RfCs and RfDs might be useful as a surrogate for the missing information. Based on 

possible differences in absorption, distribution, and portal of entry effects, we recommended that 
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Toxicology Excellence for Risk Assessment C-3 July 30, 1999

this judgment focus on specific forms to which the toxicity data are available for deriving risk 

values. In the case of oral exposures, most of the available toxicity information comes from 

studies on soluble lanthanide. Therefore, development of RfDs for different soluble lanthanides 

based on the existing soluble RfDs calculated in this text seems appropriate. Likewise, 

development of RfDs for different insoluble forms, based on preliminary insoluble RfDs 

calculated in this text seems appropriate. Similarly, the development of RfCs for different lesssoluble lanthanides based on the existing RfCs calculated in this text also seems appropriate. For 

soluble forms, however, such development of RfCs may not be appropriate.

Regardless of how these judgments are made, the risk assessor should proceed with caution. At 

the very least, one should find any comparative toxicity or toxicokinetic data on the compounds

to be compared. For example, one can look in the appendix to determine the similarities (or 

differences) in the acute toxicity data of different lanthanides in the mixture. (In general, the 

acute toxicities of this class of chemicals are similar.) Afterwards, a judgment based on 

sufficient similarity should be carefully described, noting appropriate caveats.

References:

U.S. EPA. 1986. Guidance for Conducting Health Risk Assessment of Chemical Mixtures. 

51 FR 34014. September 24.

U.S. EPA. 1990. Technical Support Document for Guidance for Conducting Health Risk 

Assessment of Chemical Mixtures. EPA/600/8-90/064.

U.S. EPA. 1999. Guidance for Conducting Health Risk Assessment of Chemical Mixtures. 

Risk Assessment Forum. U.S. Environmental Protection Agency, Washington, DC., NCEA-C0148, April.