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Description of key information

ACUTE ORAL TOXICITY: The oral LD50 in rats was determined to be 178 mg/kg bw of Nickel fluoride anhydrous in a key study contucted according to OECD guideline 425 (K1; Eurofins, 2008).


 


ACUTE INHALATION TOXICITY: Data generated with the related substance NiSO4 is used for endpoint coverage. The LC50 for acute inhalation toxicity in rats was determined to be 2.48 mg NiSO4.6H2O/L air for males and females, corresponding to 0.91 mg/L of Nickel Fluoride (i.e. 910 mg/m³) in a key study conducted according to OECD guideline 403 (K1; EPSL, 2009).


 


ACUTE DERMAL TOXICITY: No reliable data via dermal exposure are available. However, this endpoint is waived for the dermal route as reliable data are available for the oral and inhalation route.

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:
July 16,2008 to October 13,2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
up-and-down procedure
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Ace Animals Inc, Boyertown PA USA
- Age at study initiation: young-adult
- Weight at study initiation:182-230
- Fasting period before study: overnight prior to each dosing
- Housing:singly housed in suspended stainless caging with mesh floors
- Diet (ad libitum): Purina Rodent Chow #5012
- Water (ad libitum): filtered tap water
- Acclimation period: 10-23 days
-other: the female rats are nulliparous and non pregnant.
Contaminants: THere were no known contaminants reasonably to be expected to be found in th efood or water at level which would have interfered with the results of this study. Analyses of the food and water are conducted regularly and the records are kept on file at Eurofin

ENVIRONMENTAL CONDITIONS
- Temperature (°C):19-21°C
- Humidity (%):63-86%. The humidity was above targeted upper limit of 70% during the study due to exceptionally high seasonal humidity. Portable dehumidifiers were used to lower the humidity levels during this time
- Photoperiod (hrs dark / hrs light):12 h light/dark cycle

IN-LIFE DATES: From: To:8/8/2008 to 10/10/2008

-CHOISE:
-choise of sex: Females were selected for the test because they are frequently more sensitive to the toxicity of test compounds than males.
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 55% w/w
Doses:
The test substance was administered as a 55% w/w mixture in distilled water using a stainless steel ball-tipped gavage attached to an appropriate sysinge.Following administration, each animal was returned to its designed cage.Feed was replaced approximately 3-4 hours after dosing.
No. of animals per sex per dose:
6 in total, 1 per step
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Prior to administration and again after 7 and 14 days
- Necropsy of survivors performed: yes. Tissue and organs of the thoracic and abdominal cavities were examined on both decedents and euthanised animals
Statistics:
The Acute Oral Toxicity (Guideline 425) Statistical program (Westat, version 1.0, May 2001) was used for all data analyses including: dose progression selections, stopping criteria determination and/or LD50 and confidence limit calculations.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
ca. 310.2 mg/kg bw
Based on:
test mat.
95% CL:
> 175 - < 550
Remarks on result:
other: corresponding to 178 mg/kg bw nickel fluoride anhydrous
Clinical signs:
other: The animals were observed for mortality, signs of gross toxicity, and behavioral changes during the first several hours post-dosing and at least once daily thereafter for 14 days dosing or until death occured.Observations included gross evaluation of skin
Gross pathology:
The animals were observed for mortality, signs of gross toxicity, and behavioral changes during the first several hours post-dosing and at least once daily thereafter for 14 days after dosing or until death occured. Observations included gross evaluatuion of skin and fur, eyes and mucous, membranes, respiratory, circulatory, autonomic and central nervous systems, somatomotor activity and behavior pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhea, coma.

Animal N. Sex Dose Level (mg/kg)  Body weight (g)   DOSE Mortality  
    Initial Day 7 Day 14 mL Day Weight (g)
3101 F  175 193 212 252 0.044 E  
3103 F 175 215 259 271 0.049 E  
3105 F  175 207 224 256 0.048 E  
3102 F  550 222     0.16 3 201
3104 F 550 182     0.13 0 176
3106 F  550 230     0.17 2  

E= eutanized via CO2 inhalation after weighing on day 14

Animal Number Finding Day of Occurrence
175 mg/kg Dose level    
3101 active and healthy  0 -14
3103 active and healthy 0 - 14
3105  active and healthy  0 - 14
550 mg/kg Dose level    
 3102 active and healthy 0(1-5 Hrs)
  Ano-genital stainig  1-2
Hypoactivity and reduced fecal volume 2
  dead 3
 3104 Hypoactivity 0(1 hr)
dead 0(3 hrs)
 3106 active and healthy 0 (1-4.5 hrs)
Piloerection and reduced fecal volume 1
  dead 2

Animal Number Tissue Findings
175 mg/kg Dose level    
3101   All tissues and organ   No gross abnormalities
3103 All tissues and organs No gross abnormalities
3105   All tissues and organ  No gross abnormalities 
550 mg/kg Dose level  
3102   Intestines  Red
3104 Intestines Red
3106  Intestines  Red

DEVIATION FROM PROTOCOL:

The protocol requires that all decedents will be wheight immediately, or as soon as possible after death. Due to a technician error, the terminal bodywheights for animal n° 3106 was not recorded at the time of death. This deviation had no material impact on the results of study.

Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
Under the conditions of this study, the acute oral LD50 of nickel fluoride tetrahydrate is estimated to be 310.2 milligrams per kilogram of body weight in female rats an approximate 95% confidence interval of 175 mg/kg bw (lower) to 550 mg/kg bw (upper). This value is derived from the study of Nickel fluoride tetrahydrate. The correspondent value of Nickel fluoride anhydrous is 178mg/kg bw, justifying the classification in Category 3 of the CLP regulation
Executive summary:

An acute oral toxicity test (up and down Procedure) was conduced with rats to determine the potential for nickel (II) fluoride tetrahydrate to procedure toxicity from a single dose via the oral route. Under the conditions of this study, the acute oral LD50 of the test substance is estimated to be 310.2 mg/kg of body weight in female rats with an approximate 95% confidence interval of 175 mg/kg (lower) to 550 mg/kg (upper).

A main test was conducted using a default starting dose level of 175 mg/kg, which was administered to one healty female rat oral gavage. Following the up and down procedure, five additional animals were dosed at levels of 175 or 550 mg/kg. Females were selected for the test because they are frequently more sensitive to the toxicity of test compounds than males. All animals were observed for mortality, signs of gross toxicity, and behavioral changes at least once daily for 14 days after dosing or until death occured. Body weights were recorded prior to administration and again on days 7 and 14 (termination) following dosing or after death. Necropsies were performed on all animals.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
178 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From May 29, 2009 to July 13, 2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP Guideline Study
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Sprague-Dawley derived, albino
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Ace Animals, Inc., Boyertown, PA
- Age at study initiation: Young adult (8-10 weeks)
- Weight at study initiation: Males 242-372 grams; Females 185-241 grams
- Housing: The animals were singly housed in suspended stainless steel caging with mesh floors which conform to the size recommendations in the most recent Guide for the Care and Use of Laboratory Animals DHEW (NIH). Litter paper was placed beneath the cage and was changed at least three times per week.
- Diet (e.g. ad libitum): Purina Rodent Chow #5012
- Water (e.g. ad libitum): Tap water was supplied ad libitum by an automatic water dispensing system
except during exposure.
- Acclimation period: 8, 14 or 17 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 57-68%
- Air changes (per hr): 284
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle

Route of administration:
other: aerosolized dust
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Mini Nose Only Inhalation Chamber, ADG Developments LTD
- Exposure chamber volume: 6.7 liters
- Method of holding animals in test chamber: Animals individually housed in polycarbonate holding tubes
- Source and rate of air: Air compressor (JUN-AIR, Model #6-15); Compressed air tank (Airgas); Average Total Air=31.7 Lpm
- Method of conditioning air:
- System of generating particulates/aerosols: The test substance was aerosolized using a modified Wright Dust Generator driven by a variable speedmotor (Dayton, Model #4Z538A) D.C. speed control with 0-100 potentiometer. The test substance was packed into the dust container (Wright, Model OF 183 or 183A) and compressed to 250 Ibs/in2 using a lab press (Carver, Model C). The container was then fitted with a stainless steel cutting head(Model OF 1945S or 1935S) and cutting blade (Model OF 191 SS or 1905S). Compressed air was supplied to the dust generator at 30 psi. The aerosol ized dust was then fed directly into the chamber through the dust outlet assembly.
- Method of particle size determination: An eight-stage Andersen cascade impactor was used to assess the particle size distribution of the test atmosphere. Samples were withdrawn from the breathing zone of the animals at two intervals during each exposure. The filter paper collection stages were weighed before and after sampling to determine the mass collected upon each stage. The aerodynamic mass median diameter and geometric standard deviation were determined graphically using two-cycle logarithmic probit axes.
- Temperature, humidity, pressure in air chamber: Temperature Range 20-23oC; Relative Humidity Range 62-72; Average Total Air 31.7 Lpm


TEST ATMOSPHERE
- Brief description of analytical method used: Compressed airflow was measured with a Mass Flowmeter (Omega, Model #FMA-5613). Chamber airflow was monitored throughout the exposure period and recorded periodically.

The temperature and relative humidity within the exposure tube as well as the room were monitored continuously during each exposure. The measurements inside the exposure tube were made with a Humidity-Temperature Indicator (Taylor, Model #5502) and room conditions were measured with a Temperature-Humidity Monitor (Dickson, Model #TH550). Temperature and relative humidity values were recorded every 15 minutes for the first hour of exposure and every 30 minutes thereafter.

Gravimetric samples were withdrawn at six intervals from the breathing zone of the animals during each exposure. Samples were collected using 25 mm glass fiber filters (GFIB Whatman) in a filter holder attached by 1/4 inch tygon tubing to a vacuum pump (Reliance Electric, Model #G557X). Filter papers were weighed before and after collection to determine the mass collected. This value was dividedby the total volume of air sampled to determine the chamber concentration. Sample airflows were measured using a Mass Flowmeter (Omega, Model #FMA-561 0).

- Samples taken from breathing zone: yes


VEHICLE -no vehicle was used


TEST ATMOSPHERE (if not tabulated)
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): The MMAD was estimated based on the particle size distribution as measured with an Andersen Cascade Impactor.

0.063 mg/L; MMAD=2.4 um, GSD=2.02 (sample #1)/2.13 (sample #2)
0.53 mg/L; MMAD=3.0 um, GSD=2.00 (sample #1)/2.03 (sample #2)
2.12 mg/L; MMAD=2.8 um(sample #1)/2.9 um(sample #2), GSD=1.93 (sample #1)/1.97 (sample #2)
5.08 mg/L; MMAD=2.7 um, GSD=1.83 (sample #1)/1.83 (sample #2)


CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration: Prior to initiation of the full inhalation study, pre-test trials were conducted to establish generation procedures to achieve, to the extent possible, the targeted chamber concentration and desired particle size distribution (mass median aerodynamic diameter between 1 and 4 um).
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
>= 4 h
Concentrations:
Target Exposure levels: 0.06, 0.5, 2.0, and 5.0 mg/L
Actual (Gravimetric) Exposure levels: 0.063, 0.53, 2.12, and 5.08 mg/L
No. of animals per sex per dose:
5 males and 5 females per exposure level. The females assigned to test were nulliparous and non-pregnant.
Control animals:
no
Details on study design:
- Duration of observation period following administration: up to 14 days or until death occurred
- Frequency of observations and weighing: Observations occurred once daily; Body weights were recorded prior to exposure and again on Days 7 and 14 or after death.
- Necropsy of survivors performed: Yes - Surviving rats were euthanized via CO2 inhalation on Day 14. Gross necropsies were performed on all
decedents and euthanized animals. Tissues and organs of the thoracic and abdominal cavities were examined.
- Other examinations performed: body weight, gross toxicity, behavioral changes, gross evaluations
Statistics:
Biostat 2007 Professional Build 3.6.0.0, AnalystSoft, BioStat - statistical analysis program, Version
2007 was used for data analysis of LC50 and confidence limit calculations.
Preliminary study:
Not applicable
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
2.48 mg/L air
95% CL:
> 1.3 - < 4.5
Exp. duration:
4 h
Mortality:
Cumulative mortality observed (number of mortalities observed/total number of animals tested) at each exposure level:
0.063 mg/L: 0/5 males; 0/5 females
0.53 mg/L: 0/5 males; 0/5 females 
2.12 mg/L: 1/5 males; 0/5 females (death occurred one day after exposure)
5.08 mg/L: 5/5 males; 5/5 females (1 male and 1 female death occurred in exposure chamber; remaining deaths occurred within 3
days of exposure)
Clinical signs:
other: 0.063 mg/L: Immediately following exposure and throughout the 14-day observation period all animals appeared active and healthy. 0.53 mg/L: Immediately following exposure and throughout the 14-day observation period all animals appeared active and health
Body weight:
Individual body weights of the animals were recorded prior to test substance exposure (initial) and
again on Days 7 and 14 (termination) or after death.

0.063 mg/L: Although five rats failed to gain or lose body weight through Day 7, all animals gained weight over the entire observation period.
0.53 mg/L: Although one rat failed to gain body weight through Day 7, all animals gained weight over the entire observation period.
2.12 mg/L: Although two male survivors lost body weight through Day 7, all survivors gained weight over the entire observation period.
5.08 mg/L: Although there were no survivors to weigh on Day 7, all decedents except for one had a lower weight at death than their initial starting weight.
Gross pathology:
0.063 mg/L: No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.
0.53 mg/L: No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.
2.12 mg/L: Gross necropsy of the decedent revealed discoloration of the lungs and liver, and rigor mortis. No gross abnormalities were noted for any of the euthanized animals necropsied at the conclusion of the 14-day observation period.
5.08 mg/L: Gross necropsy of most decedents revealed discoloration of the lungs, liver and/or intestines, distention of the stomach and/or intestines, and/or rigor mortis. For one male and one female decedent the thymus appeared gray with dark spots.
Other findings:
0.063 mg/L:  There were no signs ofgross toxicity, adverse pharmacologic effects, or abnormal behavior.
0.53 mg/L: There were no signs ofgross toxicity, adverse pharmacologic effects, or abnormal behavior.
2.12 mg/L: There were no additional findings.
5.08 mg/L: There were no additional findings.

NOAEC was 0.53 mg NiSO4.6H2O/L air (or 120 mg Ni/m3)

Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
Data generated with the related substance NiSO4 is used for endpoint coverage. The LC50 for acute inhalation toxicity in rats was determined to be 2.48 mg NiSO4.6H2O/L air for males and females, corresponding to 0.91 mg/L of nickel fluoride (i.e. 910 mg/m³) in a key study conducted according to OECD guideline 403 (K1; EPSL, 2009).
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
910 mg/m³ air
Physical form:
inhalation: aerosol

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because inhalation of the substance is likely
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

 


Acute toxicity: oral 


 


Eurofins (2008) investigated acute oral toxicity (by gavage) of the test substance in female rats. The study was performed according to OECD Guideline 425 (up and down procedure, key study, K1). A main test was conducted using a default starting dose level of 175 mg/kg bw, which was administered to one healty female rat. Following the up and down procedure, five additional animals were dosed at levels of 175 or 550 mg/kg bw. The LD50 was estimated to be 310.2 mg Nickel fluoride tetrahydrate/kg of body weight in female rats with an approximate 95% confidence interval of 175 mg/kg (lower) to 550 mg/kg (upper). For the dose level of 175 mg/kg bw, no mortality was observed. In the 550 mg/kg bw dose group, all three animals died. No clinical signs were observed in the groups dosed 175 mg/kg bw. In the 550 mg/kg bw group, the following clinical signs were observed: ano-genital staining, hypoactivity, piloerection and reduced fecal volume. In all animals that were found dead after exposure, red intestines were found after necropsy. The corresponding LD50 of nickel fluoride anhydrous is 178 mg/kg bw, justifying the classification as category 3. 


Supporting data with the related substance NiSO4 is included in the dossier.


 


Acute toxicity: Inhalation


A background document justifying the use of Ni sulfate as a source substance for read-across to other nickel compounds has been attached to Section 7.2.1 of this  IUCLID dossier. 


No reliable data with the test substance nickel fluoride is not available. Data generated with the related substance NiSO4 is used for endpoint coverage. 


EPSL (2009) identified in an acute inhalation study in male and female rats via aerosolized dust, an LC50 of 2.48 mg NiSO4.6H2O/L air. The study was performed according to OECD Guideline 403 (key study, K1). This result corresponds to an LC50 of 0.91 mg/L of Nickel Fluoride, i.e. 910 mg/m³, using a read across approach. 5 males and 5 females were exposed to he test atmosphere for 4 hours at exposure levels of 0.063, 0.53, 2.12, and 5.08 mg/L. The animals were observed for mortality, signs of gross toxicity, and behavioral changes at least once daily for 14 days following exposure or until death occurred. 1/5 males died at the exposure level of 2.12 mg/L and all 10 animals died at the exposure level of 5.08 mg/L. No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period for 0.063 mg/L and 0.53 mg/L. For 2.12 mg/L, gross necropsy of the decedent revealed discoloration of the lungs and liver, and rigor mortis were observed. For 5.08 mg/L, gross necropsy of most decedents revealed discoloration of the lungs, liver and/or intestines, distention of the stomach and/or intestines, and/or rigor mortis. For one male and one female decedent the thymus appeared gray with dark spots.


FOR AN EXTENSIVE DISCUSSION, REFER TO THE NICKEL SULFATE DOSSIER WHICH IS BASED ON THE CONCLUSIONS EXPLAINED IN THE 2008/2009 EUROPEAN UNION EXISITING SUBSTANCE RISK ASSESSMENT OF NICKEL (EU RAR) (EEC 793/93)


 


Acute toxicity: dermal


 


According to the REACH Regulation, in addition to the oral route, for substances other than gases, the information mentioned under sections 8.5.2 to 8.5.3 shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure. Based on the properties of the substance, the dermal route of exposure is not considered to be relevant (column 2 adaptation, Annex VIII, section 8.5). As oral and inhalation routes of exposure are more relevant and data for these have been provided, testing for acute dermal toxicity is therefore waived based on this information.

Justification for classification or non-classification

Based on the available data and according to the criteria laid down in the CLP Regulation (EC) 1272/2008, the test substance nickel fluoride anhydrous should be classified as acute tox category 3 via the oral (LD50: 178 mg/kg) and inhalation (LC50: 0.91 mg/L) routes.


No reliable acute dermal toxicities studies are available for the test substance. Therefore, no conclusion can be made on the classification for acute dermal toxicity for this substance.


- Acute oral toxicity: the substance is considered to be classified as acute oral toxicant category 3 with LD50 178 mg/kg bw


- Acute inhalation toxicity: As data were not available at the time of classification, the EU Risk Assessment based the classification for acute inhalation toxicity on read-across from the oral data. However, a newly conducted GLP OECD guideline compliant study reported an LC50 =2.48 mg/L for Ni sulfate hexahydrate as aerosolised dust. This value corresponds to LC50=0.91 mg/L for nickel fluoride anhydrous. This value is used to justify the classification as Acute Tox. 3: H331 for acute inhalation toxicity.


- Acute dermal toxicity: There is no data on toxicity following cutaneous administration. Dermal absorption is expected to be very limited. Therefore, this endpoint is not considered in the risk characterisation and no classification for acute toxicity via the dermal route is proposed.