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Description of key information

No guideline study conducted. Information from two range-finding studies is included to support the justification for waiving the repeated dose toxicity endpoint.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

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

The repeated dose toxicity, and palatability, of the test material was investigated in a preliminary study in which groups of 3 rats per sex per dose were exposed to the test material over 7 consecutive days. Animals received treated diet at the following nominal dose levels; 0 (control), 140, 400, 1200 and 4000 ppm formulated in sunflower oil. Mortality, clinical signs, body weight, food consumption and water consumption were monitored during the study. Following the last day of treatment the animals were sacrificed and subjected to gross pathology.

None of the animals died. Decrease in body weight gain was observed in males and females, but this was not unequivocally dose-related. There was no negative effect recorded in food consumption, however, spillage of the diet was observed in all groups (including the control group). Calculation of food consumption (and test material intake) was therefore impaired. Gross pathology revealed significant effects on the stomach mucosa, most probably due to degradation of the test material in the stomach to Ta2O5, KF and HF. KF and HF are considered responsible for acute corrosive effects seen in the gastrointestinal tract.

Under the conditions of the study the No Observed Adverse Effect Level (NOAEL) was considered to be 140 ppm in diet.

To ensure that the animals received the required doses of test material, and to avoid the possibility of spilling diet formulations, a subsequent repeated dose toxicity study was conducted in which groups of 5 male and 5 female rats were administered test material orally, by gavage, over a period of 7 days. Animals received daily doses at 0 (control), 30, 100 and 300 mg/kg bw/day. Mortality, clinical signs, body weight, food consumption and water consumption were monitored during the study. Following the last day of treatment the animals were sacrificed and subjected to gross pathology.

One female dosed at 30 mg/kg bw/day died on day 3. Two males dosed at 300 mg/kg bw/day died, one on day 1 and one on day 2. Three females dosed at 300 mg/kg bw/day died on days 2, 3 and 5, respectively.

Animals of the control group and those dosed at 30 or 100 mg/kg bw/day gained weight during the study. Animals in dosed at 300 mg/kg lost weight during the study (by 18 % in males and 3 % in females).

Clinical signs observed in high dose (300 mg/kw bw/day) males included: decreased activity (3 animals), red skin on ears (3 animals), excessive licking to the nose (1 animal), piloerection (1 animal), and hunched back (2 animals). Clinical signs observed in high dose (300 mg/kw bw/day) females included: decreased activity (3 animals) and red skin on ears (3 animals).

At gross necropsy, two mid-dose, and all high dose, males revealed stomach effects. Some high dose males also revealed effects in the trachea, lungs, thymus, kidney, and heart. One low-dose female displayed effects to the lungs and stomach. One mid-dose female revealed effects in the stomach. All high dose females revealed effects on the stomach. Some high dose females also displayed effects to the lungs, mesenteric lymph nodes, thymus, and kidney.

In conclusion, under the conditions of the study marked mortality was observed in animals dosed at 300 mg/kg bw/day. Findings clearly demonstrate that the gastrointestinal tract is the main target organ of the test material. Gross pathology revealed significant effects on the stomach mucosa, most probably due to degradation of the test material in the stomach to Ta2O5, KF and HF. KF and HF are considered responsible for acute corrosive effects seen in the gastrointestinal tract. Stomach effects were even observed in the low dose group (1 female). The study revealed around 50% mortality at 300 mg/kg bw/day; this dose level is approximately equivalent to the single-dose LD50 of fluoride.

Both studies are non-GLP studies performed to sound scientific principles with a sufficient level of detail to assess the quality of the relevant results. Both studies were assigned a reliability score of 2 according to the criteria of Klimisch (1997) and substantiate overall findings that, in gastric juice (0.1 N HCl), the presence of hydrochloric acid promotes the degradation of K2TaF7to Ta2O5, KF and HF. 

While Ta2O5, is biologically inert, and considered toxicologically not relevant for human health risk assessment purposes, KF and HF are considered responsible for acute corrosive portal-of-entry effects seen in the gastro-intestinal tract in rats. The effects after repeat dosing in these two available range finding studies show effects that were reasonably attributable to liberated fluoride, such that all further in vivo testing are waived on the basis of corrosivity. 


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Two range-finding studies are available. Information from the studies is used to support the justification for waiving the repeated dose toxicity endpoint.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation 1272/2008, the test material does not meet the criteria for classification for repeated dose specific organ toxicity.