Reaction mass of cerium dioxide and lanthanum oxide and lanthanum fluoride

Endpoint summary

Description of key information

- Parental NOEL oral, rat (37 to 45 days) > 1000 mg/kg bw (cerium dioxide)
- LOAEC inhalation, rat (90 days) = 50.5 mg/m3 (cerium dioxide)
- No data are available for repeated dose toxicity via the dermal route (for the reaction mass or the main constituents separately)

Additional information

• Animal data:

No repeated dose toxicity study is available for the reaction mass of Cerium dioxide and Lanthanum oxide and Lanthanum fluoride. However, available data on the main constituent cerium dioxide (around 65% of the reaction mass) are considered in a read-across approach to conclude on the repeated dose toxicity of the reaction mass of Cerium dioxide and Lanthanum oxide and Lanthanum fluoride for the oral and inhalation routes of exposure since the constituents of the reaction mass showed similar physicochemical, toxicological, ecotoxicological and environmental properties with the reaction mass itself. Studies on the repeated dose toxicity of the reaction mass of Cerium dioxide and Lanthanum oxide and Lanthanum fluoride via the dermal route are waived as reliable data on the majority constituent of the reaction mass are available for both the oral and inhalation routes.

Repeated dose toxicity: Oral

No test data are available on the repeated dose toxicity of the reaction mass of cerium dioxide and lanthanum oxide and lanthanum fluoride for the oral route. Although reliable data are available for Cerium dioxide, no data are available on the other constituents. Therefore testing of the reaction mass is waived based on the following justification: according to the REACH Regulation, only one route of exposure should be tested for repeated dose toxicity (column 2 adaptation, annex VIII, section 8.6.1). Therefore, it is not necessary to perform a repeated dose toxicity study via the oral route of exposure on the reaction mass of cerium dioxide and lanthanum oxide and lanthanum fluoride.

The general toxicity of cerium dioxide was tested in rats by the oral route in a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) and in accordance with GLP (Klimisch 2). This study was used as a key study for assessment of the reaction mass. Following daily oral administration for ~37 days (males) to 40 -45 days (females), no toxicologically meaningful sign of toxicity was observed up to the highest dose of 1000 mg/kg. Therefore, the unbounded NOAEL was 1000 mg/kg bw/day for the parents. In conclusion, the oral toxicity of cerium dioxide has been shown to be extremely low based on the absence of adverse effects in rats up to the limit-dose level of 1000 mg/kg bw/day.

Repeated dose toxicity: Inhalation

In an OECD TG 413 compliant study scored Klimisch 2, used as a key study for assessment of the reaction mass, the potential general toxicity of cerium dioxide was tested following repeated nose-only inhalation of a dry powder aerosol of cerium dioxide (mass median aerodynamic diameter = 1.8 -2.2 µm) to rats (15/sex) for 6 hours a day, 5 days a week, for 13 weeks, at the gravimetric concentrations of 0 (air), 0.005, 0.0505 or 0.5075 mg/L (0, 5, 50.5 or 507.5 mg/m³, respectively).

No treatment-related deaths or clinical signs occurred during the study. There were no effects on ophthalmology, clinical chemistry, urinalysis at any dose level. No behavioral changes following either acute or subchronic exposure and no significant differences in motor activity were observed in treated groups in the Functional Observational Battery assessment.

Treatment-related changes were observed in segmented neutrophil counts, lung and spleen weights, lung and lymph node gross appearance at necropsy and lung, respiratory tract and lymphoreticular system histopathology. Microscopically, pigmented material accumulation in the lungs, bronchial, mandibular and mediastinal or pancreatic lymph nodes, trachea, bronchi, larynx, nasal cavity, liver and spleen, as well as alveolar epithelial hyperplasia in the lungs, metaplasia in larynx, and lymphoid hyperplasia in lymph nodes and lungs, correlating with the presence of pigment in these tissues, were seen in treated groups with a clear dose-response relationship. No NOAEC was determined in the study report based on effects at the low concentration. This study identifed a LOAEC of 5 mg/m3 in rats, based on the increased incidence of lymphoid hyperplasia in the bronchial lymph nodes of male and female rats. However, considering that lymphoid hyperplasia in the bronchial lymph nodes may not represent a specific toxic effect, but rather a non-specific adaptive response to the overloading of the pulmonary alveolar macrophages by inorganic poorly soluble particles in rats, and considering that alveolar epithelial hyperplasia in the lungs represents a more sensitive indication of adverse effects, the concentration of 0.0505 mg/l (50.5 mg/m³) can be regarded as a LOAEC in rats based on the incidence and severity of alveolar epithelial hyperplasia in the lungs following exposure for 13 weeks.  

 

In the case of an inorganic particulate material such as cerium dioxide, a distinction has to be made between chemical-specific and inert particle-induced toxicity. Lung overload-related inflammatory response is commonly observed in rats following inhalation exposure to poorly soluble particles. The concept of overload applies specifically to poorly soluble particles with low cytotoxicity. The hallmark of particle overload is impaired alveolar clearance which, in rats exposed to poorly soluble particles, is associated with altered macrophage function, pulmonary inflammation, centri-acinar interstitial and alveolar accumulation of particles, and inflammation-induced epithelial cell proliferation (Ref. ILSI Risk Science Institute. The relevance of the rat lung response to particle overload for human risk assessment: A workshop consensus report. Inhalation Toxicology, 12: 1-17, 2000). In terms of risk assessment, lung overload conditions are not relevant to human health because of interspecies differences. The distribution of the retained particles within the lung compartments is different between species. It has been shown that during chronic inhalation exposure, particles are retained to a greater degree in interstitial locations in lungs of non-human primates and dogs than in lungs of rats, and that the interspecies differences in particle location might contribute to corresponding differences in tissue response (Ref. Snipes MB. Current information on lung overload in non-rodent mammals: contrast with rats. Inhalation Toxicology, 8(suppl): 91 -109, 1996). These differences combined with the fact that human macrophages have five times the volume of rat macrophages are considered to account for the tendency of rats to respond to poorly soluble particles with more chronic inflammation and epithelial responses compared to humans (Ref. Oberdörster G. Toxicokinetics and effects of fibrous and non-fibrous particles. Inhalation Toxicology, 14: 29-56, 2002).

 

In the case of the present 13-week inhalation rat study using cerium dioxide, initially no NOAEC was determined in the study report because of the occurrence of lymphoid hyperplasia in the bronchial lymph nodes at all test concentrations. The lymphoid hyperplasia likely reflects an inflammatory response due to the cerium dioxide particles delivered by dendritic cells from the tracheobronchial region to the bronchial lymph nodes. However from a chemical-specific toxicity standpoint, lymphoid hyperplasia is not known to be on the pathogenetic pathway for adverse effects resulting from continued inhalatory exposure to poorly soluble particles, or to represent an adverse effect in itself. Studies in rats exposed under overloading conditions have shown that enlarged lymph nodes can occur without functional impairment of the antibody-forming function of the lymphocytes (Ref. Bice DE et al. Effects of inhaled diesel exhaust on immune responses after lung immunization. Fundam Appl Toxicol, 5:1075-86, 1985). The negative results obtained with cerium dioxide in the Popliteal Lymph Node Assay conducted on Brown-Norway rats, a rat strain well known for its high sensitivity to immunotoxicants, on popliteal lymph node weights and tritiated thymidine incorporation, as well as on blood Ig E concentrations, further illustrate the absence of immunotoxicity of cerium dioxide. Clinically, a comprehensive review of human lung pathology indicates that bronchial lymph node hyperplasia is not regarded as a diagnostic marker of specific lung diseases (Ref. Travis WD et al. Non-neoplastic Disorders of the Lower Respiratory Tract. American Registry of Pathology & Armed Forces Institute of Pathology,Washington DC. pp. 277-281, 2002). Rather, lymph node hyperplasia appears to be a secondary response to other conditions. Therefore, lymph node hyperplasia should be considered as an adaptive response and alveolar epithelial hyperplasia in the lungs appears more clearly as an indication of adverse effects, and should therefore be considered for the NOAEC/LOAEC determination.

In conclusion, following inhalatory exposure, the observed toxic effects can be described as "portal-of-entry" effects. As an insoluble particle, the absorption of cerium dioxide or its translocation from the lung to blood circulation is expected to be minimal. The effects observed in rats in respiratory tract and lymphoreticular system appear to be due to the physical deposition of cerium dioxide particles in the lungs and the subsequent inflammatory reaction to the particles, and are not due to a chemical reaction of cerium dioxide with lung tissues. No systemic toxic effects specific to cerium dioxide as such were observed in the rat following 13 -week inhalatory exposure.

The study on the majority constituent cerium dioxide is used in a read-across approach and supports the fact that no systemic inhalation toxicity was observed after repeated exposure. Therefore, repeated dose toxicity study on the reaction mass of Cerium dioxide and Lanthanum oxide and Lanthanum fluoride is not regarded as scientifically necessary according to section 1 of Reach Annex XI and is not recommended under animal protection considerations.

Repeated dose toxicity dermal

No reliable studies are available on the repeated dose toxicity via the dermal route for the reaction mass, cerium dioxide, lanthanum oxide or lanthanum fluoride.

According to the REACH Regulation, only one route of exposure should be tested for repeated dose toxicity (column 2 adaptation, annex VIII, section 8.6.1). Two studies using cerium oxide by the oral and inhalation routes are already available. Therefore, it is not necessary to perform a repeated dose toxicity study via the dermal route of exposure on the reaction mass of cerium dioxide and lanthanum oxide and lanthanum fluoride.

Repeated toxicity – NOAEL/LOAEL	Reaction mass	Cerium dioxide	Lanthanum oxide	Lanthanum fluoride
Oral	-	NOAEL > 1000 mg/kg bw/d	-	-
Inhalation	-	LOAEC = 50.5 mg/m3	-	-
Dermal	-	-	-	-

• Human data:

Regarding the majority component of the reaction mass, cerium dioxide, some rare occurrences of cerium dioxide pneumoconiosis are described in the literature (see section 7.10.3 for details). However, these cases appear ancient (old procedures of industrial hygiene were in force), no information on the level of exposure to cerium dioxide are provided, the patients often did not use their protection equipment, and the imputability to cerium dioxide is doubtful due to the simultaneous exposure of the patients to other chemical agents in an occupational background. In one case report (Nappée et al., 1972), the pneumoconiosis did not result in any impairment of the respiratory function, but rather appeared as a pulmonary overload of cerium oxide which is opaque to X-rays. In another clinical case (Le Magrex et al., 1979; Sinico et al., 1982), the clinical evolution was favorable following withdrawal of the patient from exposure to dusts and initiation of a corticotherapy, resulting in the regression of the X-ray lesions and the improvement of the patient's general condition.

Justification for classification or non-classification

As no significant effect which could be relevant for human health were observed in the studies performed on the majority constituent of the reaction mass, cerium dioxide, it can be concluded that no classification is warranted for the reaction mass of Cerium dioxide and Lanthanum oxide and Lanthanum fluoride based on the classification criteria of Annex VI Directive 67/548/EEC or UN GHS/EU CLP.