Antimony nickel titanium rutile

Endpoint summary

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

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study 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 or test system 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 or test system 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:

body weight and weight gain

clinical signs

mortality

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.