Dicerium tricarbonate

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

450 mg/kg bw/day

Study duration:

subacute

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Dose descriptor:

LOAEC

50.5 mg/m³

Study duration:

subchronic

Species:

rat

Additional information

There is one subacute toxicity study performed with dicerium tricarbonate administered by oral route (gavage) to rat. This study, a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422- GLP compliant study; Rhian D., 2008), is classified as validity 1 according to Klimisch criteria.

 

In this study, dicerium tricarbonate was administered daily by oral gavage to male and female Sprague-Dawley rats, for 2 weeks before mating, during mating, gestation and until day 5post-partum, at dose-levels of 150, 450 or 1000 mg/kg/day.

There were no adverse effects of treatment at any dose-level on mortality, clinical signs, body weight or food consumption. Animals treated at 1000 mg/kg/day had lower white blood cell counts and females in this group had lower chloride concentration and higher glucose, potassium, inorganic phosphorus and urea levels. There were no treatment-related organ weights and macroscopic changes in rats treated at all tested dose-levels. No microscopic treatment related changes were observed in the testes and ovaries. There were microscopic treatment related findings in the stomach that consisted of increased incidence and/or severity of submucosal eosinophil infiltration and pyloric gland hyperplasia in rats from both sexes treated at 1000 mg/kg/day and 450 mg/kg/kg. No test item-related microscopic findings were observed at 150 mg/kg/day.

Based on the experimental conditions of this study, the No Observed Adverse Effect Level (NOAEL) for parental toxicity was considered to be 450 mg/kg/day in female and male rats based onsystemic effects (laboratory investigations), considering thatthe microscopic findings in the stomach were likely to be related to portal-of-entry irritating effects, due to the high concentrations of the substance given as a bolus by gavage.

 

Furthermore a subchronic toxicity (90-day repeated inhalation study) is available on cerium oxide that could be considered as an analogous in a read across strategy based on similar physico-chemical, toxicological, ecotoxicological and environmental properties. Here below are reported the toxicological data on both cerium compounds for comparison.

 

Table

Toxicity Tests:	Cerium dioxide	Dicerium tricarbonate
7.2.1 Acute toxicity: oral (rat)	Oral LD50 Combined male/female > 5000 mg/kg bw (OECD 401)	Oral LD50 Combined male/female > 5000 mg/kg bw  (EPA guideline)
7.2.2 Acute toxicity Inhalation (rat)	Inhalation LC50 Combined male/female >mg/L (air)   (OECD 403, GLP)	-
7.2.3 Acute toxicity: dermal (rat)	Dermal LD50 > 2000 mg/kg bw (OECD 402)	Dermal LD50 > 2000 mg/kg bw  (OECD 402, GLP)
7.3.1 Skin Irritation / Corrosion (Rabbit)	Not irritating (OECD 404)	Not irritating  (EPA guideline)
7.3.2 Eye Irritation / Corrosion (rabbit)	Slightly irritating - Not Classified   (OECD 405,)	Slightly irritating - Not Classified   (EPA guideline)
7.4.1 Skin Sensitisation (Guinea pig, Maximisation test)	Not sensitizing (OECD 406,)	Not sensitizing (OECD 406, GLP)
7.4.1 Skin Sensitisation (PLNA assay in the rat combined with IgE determinations	Not sensitizing (GLP)	-
7.5.1 Repeated Dose Toxicity: Oral (Combined repeated dose toxicity study with the reproduction/ developmental toxicity screening test in the rat)	NOEL = 1000 mg/kg   (OECD 422, GLP)	NOAEL = 450 mg/kg   (OECD 422, GLP)
7.5.3 Repeated Dose Toxicity: Subchronic (90 day) Inhalation - rat	LOAEC = 50.5 mg/m3 (OECD 413, GLP)	-
7.6.1 Genotoxicity in vitro – Bacterial reverse muattion assay – Ames test)	No mutagenic effect+/- metabolic activation  (OECD 471, GLP)	No mutagenic effect +/- metabolic activation   (OECD 471, GLP)
7.6.1 Genotoxicity in vitro.  In vitro mammalian chromosome aberration test	-	No clastogenic effect +/- metabolic activation (OECD 473, GLP)
7.6.1 Genotoxicity in vitro –. In vitro mammalian cell gene mutation test.	No mutagenic effect+/- metabolic activation (OECD 476, GLP)	No mutagenic effect+/- metabolic activation  (OECD 476, GLP)
7.6.2 genetic toxicity in vivo  (Micronucleus test by oral route in mice	No clastogenic effect at 2000 mg/kg (OECD 474, GLP)	-
7.8.1 Toxicity to reproduction (Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in the rat)	NOEL parent = 1000 mg/kg/day NOEL progeny = 1000 mg/kg/day. (OECD 422, GLP)	NOEL parent = 1000 mg/kg/day NOEL progeny = 1000 mg/kg/day. (OECD 422, GLP)

 

The 90-day repeated dose toxicity study performed in the rat with the analogous cerium dioxide is summarized below. This study was performed according to OECD 413 guideline and in agreement with GLP (Viau A., 1994). Howevrn this study was classified as validity 2 according to Klimisch criteria because the study is used in a read-across strategy as indicated in the ECHA Practical Guide n° 6 : How to report Read-across and categories.

 

Following nose-only inhalation for 90 days (6 hours/day, 5 days/week) at 0, 5, 50.5 or 505.7 mg/m3, 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 behavioural 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 significant changes in segmented neutrophil counts, lung and spleen weights, lung and lymph node gross appearance at necropsy and lung, respiratory tract and lymphoreticular system histopathology, were noted in groups exposed to cerium dioxide. No NOAEC was determined in the study report based on effects at the low concentration. This study identified 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).

 

As a 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 inhalation exposure.

 

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: lung

Justification for classification or non-classification

Based on the classification criteria of Annex VI Directive 67/548/EEC or UN/EU GHS and considering the interspecies differences between rats and non-rodent mammals regarding location of the inhaled particles during chronic exposure, no significant effect of relevance to human health were observed in the repeated inhalation study study. No systemic toxic effects specific to cerium dioxide as such were observed. The observed effects were rather consistent with a species-specific phenomenon of "lung overload" inflammatory response in the rat following inhalation of poorly soluble particles of low toxicity and resulting "portal-of-entry" effects, with a limited relevance to the human occupational situation given the levels of exposure.

Furthermore, no important toxicological change was observed after exposure by oral route of male and female rats to cerium carbonate in acombined repeated dose toxicity study with the reproduction/developmental toxicity screening test.

 

Therefore no classification is warranted for this endpoint.