Dipotassium heptafluorotantalate

Repeated dose toxicity: oral

Administrative data

Endpoint:

repeated dose toxicity: oral

Remarks:

other: 7 day range-finding study

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

9 October 2012 to 01 November 2012

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: A non-GLP study performed to sound scientific principles with a sufficient level of detail to assess the quality of the relevant results.

Data source

Reference

Reference Type:

other: Study notes from range-finding test

Title:

Unnamed

Year:

2012

Report date:

2012

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Groups of 3 rats per sex per dose were exposed to the test material in a 7 day palatability test, designed to yield information to determine the dose range for an upcoming 14 day dietary dose range finding study. Animals received treated diet over a 7 day period at the following nominal dose levels; 0 (control), 140, 400, 1200 and 4000 ppm. 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.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Dipotassium heptafluorotantalate

EC Number:

240-986-1

EC Name:

Dipotassium heptafluorotantalate

Cas Number:

16924-00-8

Molecular formula:

F7Ta.2K

IUPAC Name:

Tantalate(2-), heptafluoro-, potassium (1:2)

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Name of test material (as cited in study report): dipotassium heptafluorotantalate
- Appearance: white crystalline powder
- Storage condition of test material: controlled room temperature (15 - 25 °C, below 70 RH%)

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain: Crl:WI
- Age at study initiation: at least 8 weeks.
- Weight at study initiation: 233 - 281 g (males); 191 - 215 g (females). Weights did not exceed ± 20 % of the mean weight for each sex at onset of treatment.
- Housing: animals were housed in groups of up to 3 animals per sex per goroup, in grid floor cages.
- Diet: Complete breeding and maintenance diet for rats and mice was provided, ad libitum.
- Water: tap water, ad libitum.
- Acclimation period: at least 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): 15 - 20 air changes per hour.
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light.

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: sunflower oil

Details on oral exposure:

DIET PREPARATION
4 g of test material was mixed with 50 g (approximately 60 mL) of sunflower oil. This formulation was then mixed into a diet premix with powdered diet before being mixed into a total weight of 1 kg of powder diet mix. This procedure was used to prepare the 4000 ppm diet, the maximum concentration used in the study.
Animals dosed at 0 ppm (control group) received powder diet mixed with 5 % w/w sunflower oil.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

At least three samples of test material treated diets were collected into plastic tubes (from the top, middle and bottom of the container) on day 0, (for homogeneity) and day 7. At least one sample will be similarly taken from the control diet on each occasion.
The level of test material in the diet was determined by ICP.

Duration of treatment / exposure:

7 days

Frequency of treatment:

Continuously (in diet)

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 140, 400, 1200, 4000 ppm
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0, 13, 39, 117, 350 mg/kg bw/day
Basis:
other: target dose levels, achieved dose levels dependent on food consumption.

No. of animals per sex per dose:

3 males and 3 females per dose

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: doses were selected, based on the results of previous investigations on the test material in attempt to obtain palatability information and identify toxicity associated with the test material under the conditions of this study and to permit the selection of the intended high dose level for use in a long term repeated dose toxicity study.
- Rationale for animal assignment: Animals were sorted according to body weight by computer and divided to weight ranges. There were an equal number of animals from each weight group randomly assigned to each dose group to ensure that animals of all test groups were of a uniform weight. The grouping was controlled by SPSS/PC software, according to the actual body weight verifying the homogeneity/variability between/within the groups and cages. Males and females will be randomised separately.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were inspected for signs of morbidity and mortality twice daily (at the beginning and end of each working day.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: At least twice daily, animals may be observed more frequently in cases that show signs of toxicity. The onset, degree and duration of all signs were recorded as applicable.
- Signs evaluated included: changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions, and autonomic activity (e.g. lachrymation, piloerection, pupil size, unusual respiratory pattern). Changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypies (e.g. excessive grooming, repetitive circling), and bizarre behaviour (e.g. self-mutilation, walking backwards). Special attention was directed towards the observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.

BODY WEIGHT: Yes
- Time schedule for examinations: The body weight of each animal was recorded on Day 0, 2, 4 and 6 (prior to necropsy).

FOOD CONSUMPTION: Yes
- Time schedule: Daily

WATER CONSUMPTION: Yes
- Time schedule for examinations: Daily, estimated by weighing the daily consumption by cage.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
Gross necropsy was performed on each animal irrespective of the date of death, including the animals found dead or euthanised pre-terminally in extremis. Surviving animals were euthanised under pentobarbital anaesthesia by exsanguination.
After exsanguination the external appearance was examined, cranium, thoracic and abdominal cavities were opened and the appearance of the tissues and organs were observed macroscopically. Any abnormality was recorded with details of the location, colour, shape and size, as appropriate. Special attention was paid to the gastrointestinal tract (stomach mucosa and full length of intestine).

On completion of the macroscopic examination, stomach, intestine, kidneys and any tissues showing macroscopic abnormality were preserved in 10 % buffered formaldehyde solution or in Bouin’s fixative solution (testes and epididymides) or Davidson’s fixative solution (eyes).

Statistics:

Statistical evaluation of data was performed with the program package SPSS PC+4.0 (SPSS Hungary Kft, Budapest). The homogeneity of variance between groups was checked by Bartlett`s homogeneity of variance test. Where no significant heterogeneity was detected a one-way analysis of variance (ANOVA) was made. If the obtained result was significant Duncan’s Multiple Range test was used to assess the significance of inter-group differences. Significant results with inter-group comparisons were further compared using Kruskal-Wallis and Mann-Whitney U-tests.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

See "Details on results" for information.

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

See "Details on results" for information.

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Details on results:

MORTALITY
None of the animals died during the study.

BODY WEIGHT AND WEIGHT GAIN
Decrease in body weight gain was observed in males and females, but this was not unequivocally dose-related.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
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 not possible.

GROSS PATHOLOGY
Gross pathology revealed significant effects on the stomach mucosa, as follows:
- Concentration 4000 ppm: ulcers, glandular mucosa, dark red focuses on mucosa
- Concentration 1200 ppm: ulcers, glandular mucosa, dark red focuses on mucosa
- Concentration 400 ppm: ulcers, glandular mucosa
- Concentration 140 ppm: no effect, NOAEL under the conditions of this study.

Effect levels

Dose descriptor:

NOAEL

Effect level:

140 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Based on significant effects observed in the stomach and mucosa.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table 1: Body Weight and Weight Gain

Concentration (mg/kg diet)	Sex	Individual body weights					Individual body weight gain from Day 0 to Day 7	Mean body weight gain Day 0 to Day 7
		Day 0	Day 2	Day 4	Day 6	Day 7
0	Male	251	264	265	282	286	35	50.33
		246	263	273	294	304	58
		250	276	281	303	308	58
	Female	200	198	206	216	223	23	27.00
		194	211	210	226	223	29
		201	215	217	231	230	29
140	Male	257	268	274	291	291	34	49.00
		259	278	288	308	318	59
		233	248	256	278	287	54
	Female	205	218	218	224	219	14	17.67
		203	209	217	219	222	19
		203	203	213	214	223	20
400	Male	254	268	281	301	315	61	57.67
		239	257	261	283	291	52
		264	278	290	311	324	60
	Female	202	218	224	235	236	34	23.67
		192	200	206	210	214	22
		200	197	211	208	215	15
1200	Male	253	262	271	290	298	45	54.00
		245	260	269	292	306	61
		273	287	297	317	329	56
	Female	193	208	209	218	211	18	22.00
		208	222	225	236	230	22
		191	206	202	212	217	26
4000	Male	281	268	281	185	298	17	0.67
		248	255	261	280	197	-51
		251	246	257	268	287	36
	Female	200	199	197	211	216	16	12.00
		215	212	211	223	230	15
		195	188	194	186	200	5

 

Table 2: Food Consumption

Concentration (mg/kg diet)	Sex	Food consumption (g/animal/day)*							Mean food consumption g/ animal/Day
		Day 0	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6
0	Male	28	29	27	30	27	26	28	27.86
	Female	23	22	12	24	23	21	23	21.14
140	Male	27	28	27	32	27	24	28	27.57
	Female	21	21	26	26	22	17	28	23.00
400	Male	30	29	26	31	30	27	31	29.14
	Female	26	26	20	29	21	21	25	24.00
1200	Male	27	28	28	31	38	28	31	30.14
	Female	26	33	22	35	24	28	21	27.00
4000	Male	19	22	25	39	25	32	41	29.00
	Female	23	27	27	39	23	25	42	29.43

* calculated data = cage level measured food consumption/number of animals in the cage (3)

Applicant's summary and conclusion

Conclusions:

Under the conditions of the study 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.

Executive summary:

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.