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Description of key information

ORAL

The NOAEL of >= 1000 mg/kg bw/day (highest dose) was chosen from the subchronic oral 46-day key study (MHLW SR-9984, 2002).

INHALATION

The NOAEC of >= 60 mg/m3 (highest concentration) with a clearance half-life of 50 days in the lungs was taken from the 5-day inhalation key study (BASF AG, 33I0110/91008, 1994).

DERMAL

Assessment: dermal pathway not relevant due to lack of bioavailability.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
Levels of nickel and antimony in liver and kidneys, respectively, were measured after 1 and 2 months after exposure
Principles of method if other than guideline:
Method: T26-16 (comparable to OECD guideline 408)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
other: SPF-derived Wistar TNO W74
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Winkelmann, Borchen, Germany
- Age at study initiation: 4-5 weeks
- Housing: macrolon cages
- Individual metabolism cages: no
- Diet (e.g. ad libitum): Altromin
- Water (e.g. ad libitum): tap water


ENVIRONMENTAL CONDITIONS
- reported as "standard conditions"
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Mixing appropriate amounts of powdered food with test substance
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Dose / conc.:
0 mg/kg diet
Remarks:
0 mg/kg bw/day
Dose / conc.:
10 mg/kg diet
Remarks:
0.5 mg/kg bw/day
Dose / conc.:
100 mg/kg diet
Remarks:
5 mg/kg bw/day
Dose / conc.:
1 000 mg/kg diet
Remarks:
50 mg/kg bw/day
Dose / conc.:
10 000 mg/kg diet
Remarks:
500 mg/kg bw/day
No. of animals per sex per dose:
15 (control: 30). Additionally, 10 animals were used for analytical investigations (control: 20).
Control animals:
yes, concurrent vehicle
Details on study design:
- Post-exposure period: no
Observations and examinations performed and frequency:
The animals were observed daily, food consumption and body weight were determined once a week. Haematological, clinical and biochemical investigations (RBC, reticulocytes, platelets, haemoglobin, haematocrit, total and differential WBC, MCV, ALP, GOT, GPT, creatinine, urea, glucose, cholesterol, total plasma and urine proteins, urinalysis) were conducted using recommended methods after one month and at the end of the study on 5 male and 5 female rats of each group. In addition, thromboplastin time and glutamate dehydrogenase activities were measured after 3 months.
Sacrifice and pathology:
All animals, killed at the end of treatment by exsanguination under ether anaesthesia, were subjected to detailed macroscopic examination. Thyroid gland, thymus, heart, lung, liver, spleen, kidneys, adrenals, gonads were weighed. Liver, aorta, eyes, intestines, femur, brain, urinary bladder, pituitary, cervical lymph nodes, stomach, oesophagus, epididymides, pancreas, prostate, seminal vesicle, sternum (bone marrow), trachea, uterus, skeletal muscle (M. quadriceps with N. ischiadicus) from 5 males and 5 females of the control and top dose groups were investigated histopathologically. Paraffin slices were stained with haematoxylin and eosin. Additional kidney slices were stained by PAS and cryostat slices of liver with Oil Red O.
Other examinations:
After 1, 2 and 3 months, liver and kidneys from 5 animals per sex and dose group were analysed for their nickel and antimony contents by AAS. The detection limit for antimony was 5 ppb and for nickel 10 ppb.
Statistics:
The results of the body and organ weight determination as well as the haematological and clinical chemical data were compared using the U-test according to WiIcoxon (1947). A difference was considered to be significant at P<=0.05.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified
Details on results:
No substance related effects on mortality, clinical signs, body weight, hematology, clinical chemistry, organ weights, gross pathology and histopathology
Key result
Dose descriptor:
NOAEL
Effect level:
>= 500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: systemic toxicity
Critical effects observed:
not specified

CHEMICAL ANALYSIS Antimony

No antimony detectable in liver and kidneys after 1 and 2 months at any dose.

After three months treatment with 10000 ppm test substance antimony was detectable in liver (6 ppb) and kidney (5 ppb) of males slightly above the detection limit and in females at levels of 6 (liver) and 10 ppb (kidney). 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1991-06-24 to 1991-09-10
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline available
Principles of method if other than guideline:
Study of the bioavailability of metal ions from the substance after inhalation as a dust aerosol in rats
GLP compliance:
yes
Remarks:
Deviations: The analysis of Ni and Sb content in the organs of the test animals was performed in a laboratory without quality assurance unit. Therefore, the report was not audited by QAU; the stability of the test substance has not been proven.
Limit test:
yes
Specific details on test material used for the study:
- Batch No.: Pt 8817
Species:
rat
Strain:
other: Wistar/Chbb:THOM
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach, Germany.
- Age at study initiation: 7 weeks
- Weight at study initiation: 230 - 232 g (the average weight of the additional set of animals 304 g ± 1.7 g).
- Housing: Singly in Makrolon/wire cages (type MD III of Becker, Castrop-Rauxel, Germany).
- Diet: KLIBA rat/mouse/hamster laboratory diet 24-343-4 10 mm pellets; Klingentalmühle AG, Kaiseraugst, Switzerland.
- Water: Not during exposure.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose/head only
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: 0.6 - 1.0 µm/ 2.8 - 4.1 (measurements on d 3 and d 5)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: aerodynamic exposure apparatus (INA 60, volume V 90 l, BASF Aktiengesellschaft)
- Method of fixing animals in test chamber: exposure tubes; animal snouts projecting into the inhalation chamber
- Rate of air: Supply air (L/h): compressed air 1,500, blast air 4,500; Exhause air (L/h): 5,400
- System of generating particulates/aerosols: dust generator
- Temperature, humidity: 23.3-23.6 °C , 50.6-54.0 %
- Method of particle size determination: Gravimetrical determination

TEST ATMOSPHERE
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
5 days
Frequency of treatment:
6 hours/day, daily
Dose / conc.:
60 mg/m³ air
Remarks:
nominal concentration
No. of animals per sex per dose:
50 (divided into 5 groups with differing post-exposure periods)
Control animals:
other: During analyses of livers and kidneys of the first test groups the need occurred to analyse kidneys of untreated animals (blank values). Therefore, another set of animals was delivered age-matched to the test animals of test group 1 at sacrifice.
Details on study design:
Post-exposure period: 0, 3, 10, 31, 60 days
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least 3 times on exposure days and, as a rule, once during the preflow period and the post-exposure observation period.
BODY WEIGHT: Yes
- Time schedule for examinations: at the beginning of preflow, at the beginning of exposure period and then once a week
Sacrifice and pathology:
Control group was sacrificed on day of arrival
Group 1 on test day four (after the last exposure)
Group 2 at day 7 (post-exposure day 3)
Group 3 at day 14 (post-exposure day 10)
Group 4 at day 35 (post-exposure day 31)
Group 5 at day 64 (post-exposure day 60)
Other examinations:
ANALYSIS: Ni and Sb concentrations in lung, liver and kidneys were determined by ICP-MS; Food analysis: contaminations in the used commercial feed were 1.42 mg Ni/kg and 13 µg Sb/kg.
Statistics:
no statistical evaluation because no concurrent control.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Details on results:
No effects on mortality, clinical signs, body weights and body weight gains
Key result
Dose descriptor:
NOAEC
Effect level:
60 mg/m³ air
Based on:
test mat.
Sex:
male
Basis for effect level:
clinical signs
mortality
body weight and weight gain
Key result
Critical effects observed:
no

CONTENT OF Ni AND Sb in:

LIVER: Mean Sb concentration (quantification limit 0.2 ng/g) in unexposed animals was 1.1 ng/g; directly post-exposure and on day 3-post-exposure the concentration was about 4-fold higher in exposed animals. During observations the concentration was similar to unexposed animals (1.3 ng/g on day 10). Mean Ni concentration was in the same range in exposed and unexposed animals (however, below the quantification limit of 10 ng/g; outliers not considered). 

KIDNEYS: Mean Sb concentration in unexposed animals was below the detection limit (1 ng/g), in exposed animals it was above the detection limit but below the quantification limit (3 ng/g), only the day 3 post exposure group reached a value of 5.6 ng/g (2-3-fold increase compared with other observation days). Mean Ni concentration was below the detection limit (1 ng/g) in unexposed animals and above detection limit but below quantification limit (25 ng/g) in exposed animals, except on day 3 post-exposure 94 ng/g were determined (10-fold more than in other exposure groups. Authors comment: presumably due to contamination of the sample).  

LUNGS: Directly post-exposure the mean Ni and Sb concentration was 79 and 202 µg/lung , respectively (corresponding to 2 mg of pigment/lung). The concentration declined during the post-exposure period, following first order kinetics; the clearance half-life was 50 days.

Endpoint conclusion
Endpoint conclusion:
no study available (further information necessary)
Dose descriptor:
NOAEC
60 mg/m³
Study duration:
subacute
Species:
rat

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

ORAL

For the oral exposure pathway two valid subchronic key-studies were performed in rats.

In a GLP-compliant subchronic study performed according to OECD guideline 422, CD rats were administered orally 250, 500 or 1000 mg/kg bw/day for 46 days with the test substance (MHLW SR-9984, 2002). No abnormal findings were observed at a dose of 250 mg/kg bw/d. In the 500 and 1000 mg/kg bw/d groups, all of the males and females showed yellow or yellowish brown feces throughout the administration period. Gross pathological examination of these groups revealed yellowish green discoloring of the contents in the cecum in some of the animals. However, it was considered that the contents in the digestive organs were colored yellow due to oral administration of the yellow-coloured test substance, and that these changes did not indicate biological adversity. There were no treatment related adverse effects on body or organ weights, food consumption, findings of urinalysis, hematological and blood chemical examinations, and histopathological examination in any animal in these groups. The NOAEL is considered to be 1000 mg/kg bw/day or more for males and females.

In a subchronic study performed similar to OECD guideline 408, male and female Wistar rats were treated with 0.5, 5, 50 and 500 mg/kg bw/day for 90 days (Bomhard et al., 1982). No substance related effects on mortality, clinical signs, body weight, hematology, clinical chemistry, organ weights, gross pathology and histopathology were observed. There were no indications for bioavailability.

In three further studies (TSCA OTS001087, 1987), performed on rats, dogs and cats respectively, no abnormal changes or test substance related effects were noted.

 

INHALATION

For the inhalative exposure pathway a valid subacute study was performed in rats.

In a GLP-compliant bioavailability study, male Wistar rats were exposed to 60 mg/m3 of the test substance for 5 days; the observation period was 0, 3, 10, 31 and 60 d (BASF AG, 33I0110/91008, 1994). No effects on mortality, clinical signs, body weights and body weight gains were found. Clearance half time was ca. 50 d in the lung; no systemic bioavailability was not found in other organs. 

 

DERMAL

No leaching of metal ions was detected in a leaching study (CAS Nr. 8007-18-9; see chapter 7.9.3).  Therefore, the dermal exposure pathway is assessed as not relevant.

CONCLUSIONS

The study data on oral and inhalation exposure revealed no treatment related adverse effects in any study.

The investigation of the dermal pathway was not considered relevant due to the lack of bioavailability.

 

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As a result the substance does not need to be classified and labelled for repeated dose toxicity under Regulation (EC) No 1272/2008, as amended for the ninth time in Regulation (EC) No 2016/1179.