reaction mass of neodymium carbonate and praseodymium carbonate

Endpoint summary

Description of key information

Weight-of-evidence approach based on dicerium tricarbonate, neodymium oxide and praseodymium(III,IV) oxide: 
NOAEL (oral, male/female rat) = 450 mg/kg bw/day (based on read-across for systemic toxicity)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

450 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Three OECD 422 studies conducted on analogues of the reaction mass of neodymium carbonate and praseodymium carbonate were available and used in a weight-of-evidence approach. These studies were awarded a reliability score of 2 (Klimisch, 1997), due to read-across (ECHA Practical Guide n°6), and were thus considered sufficient for assessment of repeated dose toxicity via oral route, therefore the overall quality of the dataset is considered to be good.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

There was no repeated dose toxicity study available on the reaction mass of neodymium carbonate and praseodymium carbonate. However, 3 studies were available on analogous substances of the reaction mass (i.e. dicerium tricarbonate, neodymium oxide and praseodymium(III,IV) oxide). The reaction mass of neodymium carbonate and praseodymium carbonate was a solid substance with a high melting point (> 450°C), a molecular weight of 926 - 940 g/mol, and a slight water solubility of 3.93 mg/L. As the substance was an inorganic, no partition coefficient (log Pow / Kow) could be determined. In addition, the reaction mass displayed a weak bioavailability and a low potential for toxicity. The physico-chemical and toxicological characteristics of the 3 analogues, dicerium tricarbonate, neodymium oxide and praseodymium(III,IV) oxide, were similar to the ones of the reaction mass: solid inorganic substances with a high melting point > 300°C, a relatively high molecular weight > 330 g/mol, a low water solubility ranging from 7.8 µg/L to 3.95 mg/L, weak bioavailability and a low potential for toxicity (see the justification document for read across attached in section 13 for a detailed argumentation). Therefore, the data from these analogues were considered all together in a weight-of-evidence approach to conclude on the repeated dose toxicity of the reaction mass of neodymium carbonate and praseodymium carbonate after exposure via oral route.

 

First, the general toxicity of dicerium tricarbonate was tested in rats by the oral route in a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (Davies R., 2008). Conducted in accordance with the OECD guideline 422 and in compliance with GLP, this study was scored as Klimisch 2 (due to read-across approach) and flagged as weight of evidence. Male and female Sprague-Dawley rats (10/sex and dose) were daily administered, by gavage, the test item at 0 (vehicle: 0.5% aqueous methylcellulose), 150, 450 or 1000 mg/kg bw/day for around 4 (male) to 8 weeks (female), i.e. 2 weeks before mating, throughout mating for both sexes, and during gestation and until day 5 post-partum for females. The following parameters and endpoints were evaluated in parental animals and pups: mortality, clinical signs, detailed functional tests and observations, bodyweights, food consumption, clinical pathology parameters (haematology, and blood biochemistry), gross necropsy findings, organ weights, and histopathological examinations, mating and pregnancy performance, fertility, maternal care and pup performance (litter size, pup number and weights, gross pathology).

 

No death occurred during the study. There were no adverse effects of treatment at any dose-level on the following parameters: mortality, clinical signs, body weight, food consumption, organ weights, gross necropsy, mating, fertility, delivery, mean numbers of corpora lutea, implantations, mean pup body weight, survival or sex. No microscopic treatment related changes were observed in the ovaries.

However, 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. Moreover, there were microscopic treatment related findings in the stomach that consisted in increased incidence and/or severity of submucosal eosinophil infiltration and pyloric gland hyperplasia in rats from both sexes treated at 1000 and 450 mg/kg bw/day. No test item-related microscopic findings were observed at 150 mg/kg bw/day. However, the 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.

 

Based on the hematology and biochemistry findings, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity in Sprague-Dawley rats was considered to be 450 mg/kg bw/day for both sexes. According to Annex I of CLP (section 3.9, paragraph 3.9.2.8) and REACh guidance on the application of the CLP criteria, no relevant sign of impairment was observed in any organ investigated in this study and thus there was no classification for specific target organ toxicity - repeated exposure (STOT-RE).

 

In a second study, the general toxicity of neodymium oxide was tested in rats by the oral route in a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test, as described above for dicerium tricarbonate (Laidlaw K., 2014). Conducted in accordance with the OECD guideline 422 and in compliance with GLP, this study was scored as Klimisch 2 (since used as read-across) and flagged as weight of evidence. Three groups of 10 male and 10 female Sprague-Dawley rats were dosed once daily, by gavage, with the test material at dose levels of 0 (vehicle: 1% w/v carboxymethylcellulose), 100, 300, or 1000 mg/kg bw/day. The males were treated for 2 weeks prior to mating, then through mating, until the day prior to necropsy (ca. 4 weeks of treatment). Females were treated for 2 weeks prior to mating, then through mating, gestation and until at least Day 4 of lactation (ca. 7 weeks of treatment). The following parameters and end points were evaluated: mortality, clinical signs, bodyweights, bodyweight changes, food consumption, ophthalmology, detailed functional tests and observations, clinical pathology parameters (haematology, coagulation and clinical chemistry), gross necropsy findings, organ weights, and histopathological examinations, mating and pregnancy performance, fertility, maternal care and pup performance (litter survival and pup weights).

 

No death occurred during the study. Mating performance, fertility indices, corpora lutea and implantation counts, duration of gestation, and the mean number of live pups born per litter were similar between control and treated animals. Litter survival, litter weights and mean pup weights were similar between litters derived from control and treated groups.

However, in males there was a slight decrease in red blood cell count and haematocrit and statistically significant decreases in total protein and albumin and an increase in phosphate at 1000 mg/kg/ bw/day during Week 4. Glucose was increased when compared to Controls at ≥ 300 mg/kg/day. There were no histological correlates for these changes and no other findings were noted.

In females at 1000 mg/kg bw/day there were a few instances of walking on tiptoes, irregular respiration and hunched posture during the treatment period, a decrease in bodyweight gain during lactation (also seen at 300 mg/kg bw/day), increases in the incidence of body held low, hunched posture and partial palpebral closure and a decrease in sectors crossed and number of rears noted in the arena during neurotoxicity assessments (also seen to a lesser extent at 300 mg/kg bw/day). There was a reduction in bodyweight gain during lactation for females at 300 mg/kg bw/day and above. There was a slight decrease in red blood cell count, haematocrit and haemoglobin at 300 mg/kg bw/day and above and an increase in alkaline phosphatase at 1000 mg/kg bw/day but there were no histological correlates for these findings.

There seemed a treatment associated finding in the kidney in females dosed at 1000 mg/kg bw/day, where marked bilateral cortical tubular necrosis and mild diffuse cortical basophilic tubules (bilateral), were recorded in one animal and mild diffuse cortical basophilic tubules (bilateral) were noted in another.

 

Under the conditions of this study in Sprague-Dawley rats, the NOAEL for systemic toxicity was considered to be 300 mg/kg bw/day for females and 1000 mg/kg bw/day for males. Neodymium oxide seemed to affect kidneys of only 2 females in the high-dose group (1000 mg/kg bw/day). Nevertheless, as the observation frequency of such effect was weak (2/10 females in only one group), it was not clear whether these adverse effects were truly related to the treatment. Moreover, repeated dose toxicity studies on other rare earth oxides did not show such adverse effects (e.g. dicerium tricarbonate, praseodymium(III,IV) oxide). As the significance of the kidney findings observed was unclear, and that these effects were of weak frequency and occurred only at 1000 mg/kg bw/day, the effects described in female rats cannot be taken into account in the weight-of-evidence approach used to conclude on the repeated dose toxicity of the reaction mass.

 

At last, the general toxicity of praseodymium (III,IV) oxide was tested in rats by the oral route in a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (Wallace I., 2012). Conducted in accordance with the OECD guideline 422 and in compliance with GLP, this study, scored as Klimisch 2 (due to weight-of-evidence approach), and flagged as weight of evidence. Male and female Sprague-Dawley rats (10/sex and dose) were daily administered, by gavage, the test item at 0, 100, 300, or 1000 mg/kg bw/day for around 4 (male) to 6 weeks (female),i.e. prior to mating, throughout mating for both sexes, and during gestation and the first 4 days of lactation for females. The following parameters and end points were evaluated in this study: mortality, clinical signs, bodyweights, food consumption, ophthalmology, detailed functional tests and observations, reproductive parameters (mating and pregnancy performance, fertility, maternal care and pup performance), clinical pathology parameters (haematology, coagulation and clinical chemistry), organ weights, and gross and microscopic pathological examinations.

 

Treatment at levels up to 1000 mg/kg bw/day was not associated with any unscheduled deaths, or any changes in clinical observations, body weight gain, food consumption, ophthalmoscopy findings, neurotoxicity findings, coagulation, organ weights, gross necropsy findings or histopathological findings.

At all dose levels in females during lactation, mean haemoglobin concentration, red blood cell counts and haematocrit were slightly lower than the concurrent control, whilst mean red cell distribution width values and reticulocyte counts were slightly higher. Mean lactate dehydrogenase activities were lower than the control at all dose levels in males at Week 4 of study and in females during lactation. Mean phosphate and calcium levels were also higher than the control during lactation in females receiving 300 or 1000 mg/kg bw/day. Given that these clinical pathology changes were without pathological correlates and that the changes did not manifest themselves clinically, they were considered not to be adverse.

 

Under the experimental conditions of this study, the NOAEL for systemic toxicity in male and female Sprague-Dawley rats was considered to be 1000 mg/kg bw /day. In conclusion, the oral toxicity of praseodymium (III,IV) oxide was found 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. Moreover, regarding the specific target organ toxicity - repeated exposure (STOT RE), no sign of impairment was observed in any organ investigated in this study.

 

Regarding repeated dose toxicity via inhalation and dermal routes, no study was available. Indeed, based on the available data and in accordance with column 2 adaptation of REACh Annex VIII (section 8.6), the repeated dose toxicity studies via inhalation and dermal routes do not need to be conducted if these studies do not appear to be scientifically necessary. The repeated oral toxicity studies conducted according to the OECD guideline 422 (weight of evidence from dicerium tricarbonate, neodymium oxide and praseodymium(III,IV) oxide) already sufficiently address the repeated dose toxicity data requirements for the reaction mass. Furthermore, as the substance is used as intermediate, exposure will be limited only to professionals using appropriate protection equipment. 

 

Taking into consideration all the data described above and because the reaction mass is under carbonate form, the NOAEL for the reaction mass of neodymium carbonate and praseodymium carbonate was set at 450 mg/kg bw/day. Indeed, the stomachal effects observed with dicerium tricarbonate seemed to be a common finding with rare-earth carbonates maybe due to the carbonate form of the substance. Indeed, similar effects were described in male and/or female rats orally exposed to dilanthanum tricarbonate for 104 weeks (Damment et al., 2003). Repeated oral administration of dilanthanum tricarbonate at 1500 mg/kg/day to rats caused increased adenomatous change in the gastric glandular epithelium of rodents. However, these effects were not observed in dogs repeatedly exposed to the same test item. Thus, such stomachal lesions seem to be specific to rodents and their particular stomach morphology. Damment et al. precisely considered that the changes observed in rats were an adaptive response to direct administration of dilanthanum tricarbonate into the stomach (gavage) without food. As there were no signs of functional impairment, no systemic toxicity associated with these stomachal effects in rats exposed to the different carbonates, and since these effects seemed specific to rodents and maybe not relevant for humans, these local effects were thus considered as irrelevant for classification according to the REACh guidance on the application of the CLP criteria and the classification criteria of UN GHS. Furthermore, the clinical signs observed in rats exposed to dicerium tricarbonate were transient and/or non-significant and were never associated to histopathological lesions. Therefore, these effects were considered as not adverse.

As a consequence, by analogy, the reaction mass of neodymium carbonate and praseodymium carbonate is therefore not considered as harmful following repeated oral exposure. Thus, the reaction mass does not need to be classified according to the classification criteria of Annex VI of Directive 67/548/EEC, Regulation (EC) No. 1272/2008 and UN GHS.

 

Repeated dose toxicity	Reaction mass of neodymium carbonate and praseodymium carbonate	Dineodymium tricarbonate	Dipraseodymium tricarbonate	Dicerium tricarbonate	Neodymium oxide	Praseodymium(III,IV) oxide
Oral route - rat	no data	no data	no data	NOAEL (systemic, both sexes) = 450 mg/kg bw/day (OECD 422, GLP)	NOAEL (systemic, female) = 300 mg/kg bw/day NOAEL (systemic, male)  = 1000 mg/kg bw/day (OECD 422, GLP)	NOAEL (systemic, both sexes) = 1000 mg/kg bw/day (OECD 422, GLP)
Inhalation route	no data	no data	no data	no data	no data	no data
Dermal route	no data	no data	no data	no data	no data	no data

 

 

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Three repeated dose toxicity studies done on analogous substances of the reaction mass were selected in a read-across strategy and considered together using a weight-of-evidence approach (i.e. dicerium tricarbonate, neodymium oxide and praseodymium(III,IV) oxide).
All studies were conducted in compliance with GLP and according to the OECD guideline 422. Well described and meeting the generally acceptable scientific principles, these studies were awarded a reliability score of 2 (Klimisch, 1997), since used as read-across (ECHA Practical Guide n°6), and were flagged as weight of evidence.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Based on the available data on oral route and in accordance with column 2 adaptation of REACh Annex VIII (section 8.6), the repeated dose toxicity study via the inhalation route does not need to be conducted if the study does not appear to be scientifically necessary. Three repeated oral toxicity studies conducted according to the OECD guideline 422 (weight of evidence from dicerium tricarbonate, neodymium oxide and praseodymium(III,IV)) already sufficiently address the repeated dose toxicity data requirements for the reaction mass. Moreover, as the substance is used as intermediate, exposure will be limited only to professionals using appropriate protection equipment.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Based on the available data on oral route and in accordance with column 2 adaptation of REACh Annex VIII (section 8.6), the repeated dose toxicity study via the inhalation route does not need to be conducted if the study does not appear to be scientifically necessary. Three repeated oral toxicity studies conducted according to the OECD guideline 422 (weight of evidence from dicerium tricarbonate, neodymium oxide and praseodymium(III,IV)) already sufficiently address the repeated dose toxicity data requirements for the reaction mass. Moreover, as the substance is used as intermediate, exposure will be limited only to professionals using appropriate protection equipment.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Based on the available data on oral route and in accordance with column 2 adaptation of REACh Annex VIII (section 8.6), the repeated dose toxicity study via the dermal route does not need to be conducted if the study does not appear to be scientifically necessary. Three repeated oral toxicity studies conducted according to the OECD guideline 422 (weight of evidence from dicerium tricarbonate, neodymium oxide and praseodymium(III,IV)) already sufficiently address the repeated dose toxicity data requirements for the reaction mass. Moreover, as the substance is used as intermediate, exposure will be limited only to professionals using appropriate protection equipment.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
Based on the available data on oral route and in accordance with column 2 adaptation of REACh Annex VIII (section 8.6), the repeated dose toxicity study via the dermal route does not need to be conducted if the study does not appear to be scientifically necessary. Three repeated oral toxicity studies conducted according to the OECD guideline 422 (weight of evidence from dicerium tricarbonate, neodymium oxide and praseodymium(III,IV)) already sufficiently address the repeated dose toxicity data requirements for the reaction mass. Moreover, as the substance is used as intermediate, exposure will be limited only to professionals using appropriate protection equipment.

Justification for classification or non-classification

The available data on the analogues (dicerium tricarbonate, neodymium oxide and praseodymium(III,IV) oxide) of the reaction mass were used in a weight-of-evidence approach to conclude on the repeated dose toxicity potential of the reaction mass of neodymium carbonate and praseodymium carbonate. The three studies showed no mortality and no clear systemic effects after repeated oral exposure at doses up to 450 mg/kg bw/day. Thus, a NOAEL ≥ 450 mg/kg bw/day in rats from both sexes was retained for the reaction mass of neodymium carbonate and praseodymium carbonate. Therefore, given the similar physico-chemical and toxicological characteristics between the three analogues and the reaction mass of neodymium carbonate and praseodymium carbonate, the reaction mass is not classified, by analogy, according to the classification criteria of Annex VI of Directive 67/548/EEC, Regulation (EC) No. 1272/2008 and UN GHS.