Registration Dossier

Administrative data

Description of key information

Acute oral toxicity: a key study is available, indicating a LD50 of 324 mg/kg, thus justifying classification as Category 4.
Acute inhalation toxicity: Based on particle size considerations, incl. modelling on inhalability and fractional deposition in the respiratory tract, inhalation does not appear to be a relevant route of exposure for K2TiF6, and testing has been waived.
Acute dermal toxicity: The physicochemical and toxicological properties of K2TiF6 do not suggest potential for a significant rate of absorption through the skin. Therefore, testing for acute dermal toxicity is not required.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1994-08-01 to 1994-09-14 (addendum to study report: 1996-07-29 to 1996-09-05)
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: MAIN STUDY REPORT: GLP guideline study reliable with restrictions - the stability was missing in the study report. ADDENDUM STUDY REPORT: GLP guideline study reliable with restrictions -the purity and the stability were missing in the study report
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
, 1987-02-24
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
signed 1994-03-16 (addendum to study report: signed 1996-02-27)
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
MAIN STUDY REPORT:
TEST ANIMALS:
- Age at study initiation: approximately five to eight weeks old
- Weight at study initiation: males: 150 - 183 g; females: 136 - 155 g
- Fasting period before study: an overnight fast immediately before dosing and for approximately two hours after dosing
- Housing: the animals were housed in groups of up to five by sex in solid-floor polypropylene cages furnished with woodflakes.
- Diet (ad libitum, except for a fasting period as described above): Rat and Mouse Expanded Diet No. 1, Special Diets Services limited, Witham, Essex, U.K.
- Water (ad libitum, except for a fasting period as described above): mains drinking water
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature: 19 - 23°C
- Relative humidity: 49 - 68%
- Air exchanges: approximately 15 changes per hour
- Photoperiod (hrs dark / hrs light): 12/12

ADDENDUM STUDY REPORT:

TEST ANIMALS
- Age at study initiation: five to eight weeks old
- Weight at study initiation: males: 153 - 168 g; females: 124 - 171 g
- Fasting period before study: overnight fast immediately before dosing and for approximately two hours after dosing
- Housing: the animals were housed in groups of up to five by sex in solid-floor polypropylene cages furnished with woodflakes.
- Diet (ad libitum, except for a fasting period as described above): Rat and Mouse Expanded Diet No. 1, Special Diets Services limited, Witham, Essex, UK
- Water (ad libitum, except for a fasting period as described above): mains drinking water
- Acclimation period: minimum acclimatisation period of five days

ENVIRONMENTAL CONDITIONS
- Temperature: 20 to 23°C
- Relative humidity: 47 to 65%
- Air exchanges: approximately fifteen changes per hour
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
MAIN STUDY REPORT:
MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg; the volume administered to each animal was calculated according to its fasted bodyweight at the time of dosing.
DOSAGE PREPARATION: the test material was freshly prepared as a suspension at the appropriate concentration in arachis oil B.P. Homogeneity was assured by the use of a Silverson Homogeniser.

ADDENDUM STUDY REPORT:
MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg; the volume administered to each animal was calculated according to its fasted bodyweight at the time of dosing.
DOSAGE PREPARATION: the test material was freshly prepared as a suspension at the appropriate concentration in arachis oil B.P.



Doses:
MAIN STUDY REPORT:
250 mg/kg (males and females)
500 mg/kg (males only)
1000 mg/kg (males only)
(concentrations: 25, 50 and 100 mg/mL, respectively)
ADDENDUM STUDY REPORT:
125 mg/kg (males and females)
250 mg/kg (females only)
500 mg/kg (females only)
1000 mg/kg (females only)
(concentrations: 12.5 25, 50 and 100 mg/mL, respectively)
No. of animals per sex per dose:
MAIN STUDY REPORT:
5 male rats (doses: 250, 500 and 1000 mg/kg)
5 female rats (dose: 250 mg/kg)
ADDENDUM STUDY REPORT:
5 female rats (doses: 125, 250, 500 and 1000 mg/kg)
5 male rats (dose: 125 mg/kg)
Control animals:
no
Details on study design:
The following applies to the original study report and the addendum study report.
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: the animals were observed for deaths or overt signs of toxicity 0.5, 1, 2 and 4 hours after dosing and subsequently once daily for 14 days.
Individual bodyweights were recorded prior to dosing on Day 0 and on Days 7 and 14 or at death.
- Necropsy of survivors performed: yes
At the end of the study the surviving animals were killed by cervical dislocation. All animals, including those that died during the study, were subjected to gross pathological examination. This consisted of an external examination and opening the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
Statistics:
The data from the addendum to the study report was collected with data from the original study and the acute oral median lethal dose (LD50) and 95% confidence limits of the test material were calculated using a method of Thompson W R, Bact. Reviews, 11, 115 - 145 (1947).
Sex:
male
Dose descriptor:
LD50
Effect level:
297 mg/kg bw
Based on:
test mat.
95% CL:
155 - 572
Sex:
female
Dose descriptor:
LD50
Effect level:
354 mg/kg bw
Based on:
test mat.
95% CL:
129 - 971
Sex:
male/female
Dose descriptor:
LD50
Effect level:
324 mg/kg bw
Based on:
test mat.
95% CL:
185 - 569
Mortality:
MAIN STUDY:
Deaths were noted 1 hour after dosing at 1000 mg/kg bodyweight (all males), 1 hour to 1 day after dosing at 500 mg/kg bodyweight (4/5 males) and 4 hours after dosing at 250 mg/kg bodyweight (1/5 males) in the male animals .
Deaths were noted in the female group at 250 mg/kg bodyweight (4/5 females) 2 hours to 5 days after dosing.

ADDENDUM REPORT:
Deaths were noted two to four hours and one to three days after dosing.
The following numbers of animals died during the study:
125 mg/kg: 1/5 males
500 mg/kg: 2/5 females
1000 mg/kg: 4/5 females
Clinical signs:
MAIN STUDY:
Common signs of toxicity noted were hunched posture, lethargy, decreased respiratory rate, laboured respiration with additional signs of ataxia, pilo-erection, ptosis, diuresis, splayed gait and increased salivation. Isolated incidents of toxicity were noisy respiration in one male at 250 mg/kg, diarrhoea in one female at 250 mg/kg and tiptoe gait in one female at 250 mg/kg. All surviving animals recovered 2 to 6 days after dosing.

ADDENDUM REPORT:
Hunched posture was commonly noted in all animals on the day of dosing and up to eight days after dosing with additional signs of lethargy, decreased respiratory rate, laboured respiration and ataxia noted in animals dosed with 500 mg/kg or above. Lethargy, decreased respiratory rate and laboured respiration with incidents of ataxia and increased salivation were also noted in the animals dosed with 125 mg/kg. Isolated incidents of body tremors, diarrhoea, ptosis, occasional body tremors, pilo-erection and tiptoe gait were also noted. All surviving animals appeared normal eight days after dosing.
Body weight:
MAIN STUDY: Surviving animals showed expected gain in bodyweight throughout the study.

ADDEDNUM STUDY:
Surviving animals showed an expected gain in bodyweight during the study.
Gross pathology:
MAIN STUDY: Abnormalities noted at necropsy were haemorrhagic lungs, dark liver and kidneys, slight to severe haemorrhaging of the glandular region of the stomach, slight haemorrhaging of the non-glandular region of the stomach, haemorrhaging of small and large intestines and epithelial sloughing of the glandular and non-glandular region of the stomach. All animals surviving the study appeared normal at necropsy.

ADDDEDNUM STUDY:
No abnormalities were detected at necropsy of animals killed at the end of the study period.

Haemorrhagic lungs, dark liver, dark kidneys, haemorrhage of the gastric mucosa, sloughing of the non-glandular epithelium of the stomach, haemorrhage of the small intestines and haemorrhage of the large intestine were noted at necropsy of animals that died during the study. One male animals dosed with 125 mg/kg was found cannibalised, a necropsy was therefore not performed.
Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the original study report and the addendum to the study report the following LD50 values were calculated:
The LD50 for male rats only is 297 mg/kg bodyweight (95% confidence limit: 155 - 572).
The LD50 for female rats only is 354 mg/kg bodyweight (95% confidence limit: 129 - 971).
The LD50 for combined sexes is 324 mg/kg bodyweight (95% confidence limit: 185 - 569).
According to the EC Regulation No. 1272/2008 and subsequent regulations, dipotassium hexafluorotitanate is classified as Acute Toxic Category 4, based on the LD50 for combined sexes.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
324 mg/kg bw

Additional information

Justification for selection of acute toxicity – oral endpoint
Key study

Justification for classification or non-classification

Acute oral toxicity: a key study is available, indicating a LD50 of 324 mg/kg, thus justfying classification as Category 4.

Acute inhalation toxicity: Based on particle size considerations, incl. modelling on inhalability and fractional deposition in the respiratory tract, inhalation does not appear to be a relevant route of exposure for K2TiF6, and testing has been waived.

Acute dermal toxicity: The physicochemical and toxicological properties of K2TiF6 do not suggest potential for a significant rate of absorption through the skin. Therefore, testing for acute dermal toxicity is not required, and neither is classification.